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The Phenomenon of the Acute Phase Response
... Local and systemic inflammatory responses have the same goal: to destroy or capture infectious agents, remove damaged tissue, and repair the affected tissue [19,20]. Proinflammatory cytokines such as interleukin-1 beta (IL-β), interleukine-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) are secreted locally at the site of injury [19,20]. ...
... Local and systemic inflammatory responses have the same goal: to destroy or capture infectious agents, remove damaged tissue, and repair the affected tissue [19,20]. Proinflammatory cytokines such as interleukin-1 beta (IL-β), interleukine-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) are secreted locally at the site of injury [19,20]. In the liver they induce the production of acute phase proteins (APPs) such as serum amyloid A (SAA) and haptoglobin (Hp) [19,20]. ...
... Proinflammatory cytokines such as interleukin-1 beta (IL-β), interleukine-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) are secreted locally at the site of injury [19,20]. In the liver they induce the production of acute phase proteins (APPs) such as serum amyloid A (SAA) and haptoglobin (Hp) [19,20]. Many different pathological conditions have been shown to elevate bovine serum SAA and Hp, i.e., mastitis [21,22], respiratory infection [23], and hoof disorders [24][25][26][27]. ...
Simple Summary
The environment seems to first damage the skin allowing secondary bacteria to cause a local skin disease in bovines: digital dermatitis. Markers of inflammation, cytokines, are activated, but this does not initiate a systemic reaction and thus the body does not seem to be able to eliminate the disease.
Abstract
Digital dermatitis is a disease of the digital skin and causes lameness and welfare problems in dairy cattle. This study assessed the local and systemic inflammatory responses of cows with different digital dermatitis lesions and compared macroscopical and histological findings. Cow feet (n = 104) were evaluated macroscopically and skin biopsies histologically. Serum samples were analyzed for acute phase proteins (serum amyloid A and haptoglobin) and pro-inflammatory cytokines (interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha). Cows with macroscopically graded active lesions (p = 0.028) and non-active lesions (p = 0.008) had higher interleukin-1 beta levels in their serum compared to healthy cows. Interleukin-1 beta serum concentrations were also higher (p = 0.042) when comparing lesions with necrosis to lesions without necrosis. There was no difference when other cytokine or acute phase protein concentrations in healthy cows were compared to those in cows with different digital dermatitis lesions. A novel histopathological grading was developed based on the chronicity of the lesions and presence of necrosis and ulceration. The presence and number of spirochetes were graded separately. In the most severe chronic lesions, there was marked epidermal hyperplasia and hyperkeratosis with necrosis, deep ulceration, and suppurative inflammation. Spirochetes were found only in samples from necrotic lesions. This study established that digital dermatitis activates proinflammatory cytokines. However, this did not initiate the release of acute phase proteins from the liver. A histopathological grading that takes into account the age and severity of the lesions and presence of spirochetes was developed to better understand the progression of the disease. It is proposed that necrosis of the skin is a result of ischemic necrosis following reduced blood flow in the dermal papillae due to pressure and shear stress caused by thickened epidermis, and that the spirochetes are secondary invaders following tissue necrosis.
... C-reactive protein (CRP) circulates in the blood and is deposited at sites of inflammation (1). CRP is composed of five identical subunits arranged in a cyclic pentameric symmetry and whose production and secretion by hepatocytes are increased in inflammatory states (2)(3)(4). CRP is a dual pattern recognition molecule; however, which pattern is recognized by CRP depends upon its pentameric structural conformation (5). In the plasma and elsewhere where CRP is present in its native conformation, CRP binds to phosphocholine (PCh)-containing substances and subsequently activates the classical pathway of complement (6)(7)(8)(9). ...
... It has also been shown that the serum levels of IL-17, IL-6, TNF-a, IL-10, IL-2 and IL-1b are altered in RA patients (28,34,35). CRP is used as a nonspecific biomarker of inflammation during the development of RA (3,36). Previously published reports suggest that pentameric CRP protects against the development of inflammatory arthritis in mice; however, the mechanism of action of CRP in vivo including the effects of CRP on the production of cytokines in vivo are not fully elucidated yet (37)(38)(39). ...
The biosynthesis of C-reactive protein (CRP) in the liver is increased in inflammatory diseases including rheumatoid arthritis. Previously published data suggest a protective function of CRP in arthritis; however, the mechanism of action of CRP remains undefined. The aim of this study was to evaluate the effects of human CRP on the development of collagen-induced arthritis (CIA) in mice which is an animal model of autoimmune inflammatory arthritis. Two CRP species were employed: wild-type CRP which binds to aggregated IgG at acidic pH and a CRP mutant which binds to aggregated IgG at physiological pH. Ten CRP injections were given on alternate days during the development of CIA. Both wild-type and mutant CRP reduced the incidence of CIA, that is, reduced the number of mice developing CIA; however, CRP did not affect the severity of the disease in arthritic mice. The serum levels of IL-17, IL-6, TNF-α, IL-10, IL-2 and IL-1β were measured: both wild-type and mutant CRP decreased the level of IL-17 and IL-6 but not of TNF-α, IL-10, IL-2 and IL-1β. These data suggest that CRP recognizes and binds to immune complexes, although it was not clear whether CRP functioned in its native pentameric or in its structurally altered pentameric form in the CIA model. Consequently, ligand-complexed CRP, through an as-yet undefined mechanism, directly or indirectly, inhibits the production of IL-17 and eventually protects against the initiation of the development of arthritis. The data also suggest that IL-17, not TNF-α, is critical for the development of autoimmune inflammatory arthritis.
... Acute phase proteins (APPs) are non-specific markers of inflammation, the concentration of which increases in response to various stimuli such as infections, non-infectious inflammatory conditions, trauma or neoplasia [13]. In cats, most studies evaluated the two major APPs, serum amyloid A (SAA) and α 1 -acid glycoprotein (AGP), and moderate APP haptoglobin (HP) [14]. ...
... Cats included in this study were presented to the Clinic for Small Animals of Justus-Liebig-University Giessen, Germany, over a period of two years. Samples were collected as part of diagnostic investigations from cats that presented a variety of clinical signs (dyspnoea, enlarged abdomen, fever, anorexia, lethargy, etc.), in which a pleural, peritoneal Animals 2023, 13,1918 3 of 17 or pericardial effusion, or a combination thereof, was identified. In cats presented with more than one effusion, only one effusion was analysed in the present study. ...
The traditional veterinary classification (TVC) of effusions based on cell count and total protein (TP) does not adequately reflect the aetiology. Light’s criteria (LC) (activity of lactate dehydrogenase [LDH] in the effusion [LDHef], effusion/serum LDH ratio [LDHr], effusion/serum TP ratio [TPr]), serum–effusion albumin gradient (ALBg), acute phase proteins (APPs) [serum amyloid A (SAA), α1-acid glycoprotein (AGP), haptoglobin] might aid classification. The aim was to evaluate the utility of these parameters except LDHr in differentiating exudates from transudates. Sixty-five cats with effusions (33 peritoneal, 31 pleural, 1 pericardial), with 18 transudates and 47 exudates based on aetiological classification (AC), were included. The sensitivity, specificity and accuracy of several parameters to identify exudates (based on AC) was assessed. APPs were compared between exudates and transudates based on AC and TVC, with receiver operating characteristics analysis identifying the best APP to recognise exudates. Simplified LC (LDHef, TPr) had an accuracy of 79% and TVC of 48%. ALBg had the highest sensitivity (98%) and LDHef the highest specificity (83%) in identifying exudates in cats. All APPs but effusion SAA could differentiate exudates from transudates based on AC (effusion AGP had the largest area under the curve 0.79) but not TVC. All parameters were better than TVC in identifying exudates. The conformity of APPs with AC but not TVC favours the use of AC to classify effusions.
... The acute phase response is an important pathophysiological phenomenon that accompanies inflammation. 4,5 Attention to this phenomenon occurred for the first time with the discovery of high concentrations of CRP during the acute phase of pneumococcal pneumonia, so called for reacting with pneumococcal polysaccharide C. 6 Since then, such systemic changes have been reported as an acute phase response 7 although they also follow chronic inflammatory states. CRP can occur in association with a wide variety of diseases, including infections, trauma, infarction, inflammatory arthritis, various neoplasms, and many cardiovascular diseases. ...
... From the first steps of leukocyte recruitment in the nascent atherosclerotic lesion to the development of atheroma plaque, culminating in its rupture and thrombosis in the acute coronary event, we found a constant release of inflammatory mediators, soluble in plasma, from macrophages, T lymphocytes, endothelial cells and smooth muscle vessels of the vessels, hepatocytes, and adipocytes. 4,21,28 The greatest evidence relating inflammation to the future development of cardiovascular events has been verified in large-scale population studies. High concentrations of inflammatory markers such as TNF-α, IL-6, ICAM-1, P-selectin, E-selectin, CRP, fibrinogen, and amyloid Serum A, in apparently healthy individuals, have shown predictive value for future vascular events. ...
The involvement of inflammation is described in all stages of atherosclerosis as well as in dyslipidemias, particularly in lipoproteins (especially oxidized LDL), coronary syndromes, hypertension, diabetes, infections, obesity, and also in the use of sexual replacement hormones. From the first steps of leukocyte recruitment in the nascent atheromatic lesion to the development of atheroma plaque, culminating in its rupture and thrombosis in the acute coronary event, we found a constant release of inflammatory mediators, soluble in plasma, from macrophages, T lymphocytes, endothelial cells and smooth muscle vessels of the vessels, hepatocytes, and adipocytes. The greatest evidence relating inflammation to the future development of cardiovascular events has been verified in large-scale population studies. High concentrations of inflammatory markers such as TNF-α, IL-6, ICAM-1, P-selectin, E-selectin, C Reactive Protein, fibrinogen, and amyloid serum A, in apparently healthy individuals, have shown predictive value for future vascular events. Considering the multifactorial etiology of coronary artery disease and its inflammatory nature, it was possible to find an association between the presence of risk factors and the increase in the concentration of biomarkers of inflammation. TNF-α is a multifunctional cytokine derived from smooth endothelial and muscle cells, as well as macrophages present in the coronary atheroma. It is involved in a number of cardiovascular processes, being increased in congestive heart failure.
... In this study, we found a significant positive correlation between CXCL10 levels and serum ferritin in PMR patients, which belongs to the acute time-phase response proteins and is elevated in acute inflammation, malignancy, autoimmune diseases, and infections [12]. Ferritin-like structures have also been found in various bacterial species. ...
Objective
To investigate the significance of CXC chemokine ligand 10 (CXCL10) in the pathogenesis of isolated polymyalgia rheumatica (PMR).
Methods
The serum of six PMR patients diagnosed and treated at the First Affiliated Hospital of Wannan Medical College from September 2019 to December 2020 before treatment and after remission was collected, and the serum of six active rheumatoid arthritis (RA) patients and six healthy medical checkups were also collected, and protein microarray technology was used to detect 24 cytokines, including IL-6, IL-4, CXCL10, CXCL8, and CXCL2. Subsequently, serum was collected from other 28 patients with active PMR, 26 patients with PMR in remission, 24 patients with active RA, and 24 healthy medical checkups who were diagnosed and treated at the First Affiliated Hospital of Wannan Medical College from January 2021 to July 2023, and the enzyme-linked immunosorbent assay (ELISA) was used to validate and compare the levels of CXCL10 in each group and analyze the correlation between the levels of serum CXCL10 and the parameters of the clinical activities of PMR.
Results
Protein microarray screening revealed significant differences in CXCL10 before and after PMR treatment, and ELISA validation revealed that peripheral serum CXCL10 levels were significantly higher in the PMR-active group than in the remission group ( P < 0.001), and also significantly higher than in the RA-active group ( P = 0.003) and in the healthy control group ( P < 0.001); correlation analysis showed a significant positive correlation between serum CXCL10 levels and serum ferritin in PMR patients ( r = 0.450, P = 0.024). In the ROC curve for distinguishing PMR and RA, the area under the curve is 0.741, sensitivity = 0.643, and specificity = 0.792.
Conclusion
CXCL10 may play a role in the pathogenesis of isolated PMR and its level might contribute to the differential diagnosis of PMR and RA. Key Points • The concentration of CXCL10 was higher in peripheral blood of isolated PMR patients. • CXCL10 is a potential diagnostic biomarker for isolated PMR patients. • The level of CXCL10 might contribute to the differential diagnosis of PMR and RA.
... In addition to RPR, we examine the association between PCR-positives and CRP values. CRP, as an indicator of inflammation [29], a typically remains below 0.3 mg/dL in most healthy individuals, with normal or minor elevations falling within the range of 0.3-1.0 mg/ dL [30]. ...
Background
The challenges in culturing Treponema pallidum have hindered molecular-biological analysis. This study aims to establish a molecular epidemiological analysis of syphilis among Japanese men who have sex with men (MSM) and to investigate the relationship between bacteremia and associated pathophysiology.
Methods
We used whole blood specimens from syphilis-diagnosed individuals in Tokyo, collected between February 2019 and June 2022. All individuals were MSM, and most were people with HIV (97.2%). We used a multi-locus sequence typing (MLST) scheme for epidemiological analysis. Sequences for MLST (TP0136, TP0548, and TP0705) were obtained.
Results
Out of 71 whole blood samples, 26 samples (36.6%) were positive for TP0136, and we sequenced three loci for MLST in 22 samples (31.0%). The most frequently detected sequence type (ST) was ST3 (n = 9), followed by ST6 (n = 6). Phylogenetic analysis revealed that 12 samples belonged to the SS14-like group (60%), and 8 samples belonged to the Nichols-like group (40%). Treponema pallidum subsp. endemicum (TEN), the cause of bejel was detected in three samples (12%). There was a significant association between TP0136 detection rate and C- reactive protein (CRP) (77.0% at a cut-off:0.5 mg/dL).
Conclusion
Both SS14-like and Nichols-like strains were circulating concurrently, and TEN could have been sexually transmitted among MSM with HIV. Elevated CRP may indicate the presence of the pathogen in the blood.
... As the effect of CRP on voriconazole metabolism has been previously quantified [4][5][6], we included the latter correlation to show the effect of inflammation on voriconazole. As more than half of ICU patients have an infection during ICU admission [9,34,50], these opposing effects of induction due to the DDI and inhibition of metabolism by inflammatory cytokines may be relevant for all extensively metabolized drugs in ICU patients. ...
Voriconazole administered concomitantly with flucloxacillin may result in subtherapeutic plasma concentrations as shown in a patient with Staphylococcus aureus sepsis and a probable pulmonary aspergillosis. After switching our patient to posaconazole, therapeutic concentrations were reached. The aim of this study was to first test our hypothesis that flucloxacillin competes with voriconazole not posaconazole for binding to albumin ex vivo, leading to lower total concentrations in plasma.
A physiologically based pharmacokinetic (PBPK) model was then applied to predict the mechanism of action of the drug–drug interaction (DDI). The model included non-linear hepatic metabolism and the effect of a severe infectious disease on cytochrome P450 (CYP) enzymes activity.
The unbound voriconazole concentration remained unchanged in plasma after adding flucloxacillin, thereby rejecting our hypothesis of albumin-binding site competition. The PBPK model was able to adequately predict the plasma concentration of both voriconazole and posaconazole over time in healthy volunteers. Upregulation of CYP3A4, CYP2C9, and CYP2C19 through the pregnane X receptor (PXR) gene by flucloxacillin resulted in decreased voriconazole plasma concentrations, reflecting the DDI observations in our patient. Posaconazole metabolism was not affected, or was only limitedly affected, by the changes through the PXR gene, which agrees with the observed plasma concentrations within the target range in our patient.
Ex vivo experiments reported that the unbound voriconazole plasma concentration remained unchanged after adding flucloxacillin. The PBPK model describes the potential mechanism driving the drug–drug and drug–disease interaction of voriconazole and flucloxacillin, highlighting the large substantial influence of flucloxacillin on the PXR gene and the influence of infection on voriconazole plasma concentrations, and suggests a more limited effect on other triazoles.
... Among these, SAA stands out as a hydrophobic apolipoprotein of high-density lipoprotein with several isoforms [14,15]. It exhibits high sensitivity, increasing rapidly during APR, up to 100-1000 times in both humans and animals [16][17][18][19]. While the precise maintenance period varies among animals, peaks tend to occur within 24-72 h, followed by a rapid decrease [20,21]. ...
Within the field of clinical research, reports on the stability of avian serum amyloid A (SAA) under varying storage conditions are currently scarce. In this study, avian plasma samples were evaluated for SAA, a major acute-phase protein in birds, to assess how varying storage periods and repeated freeze-thaw cycles impact the stability of SAA in the frozen samples. Seven plasma samples from two species and six plasma samples from three species stored at ‒20 °C were used to evaluate the time and temperature effects accordingly. A chicken-specific SAA ELISA kit was used for the measurements. Statistical analysis was performed using SPSS, and the Kruskal-Wallis test and Spearman’s correlation coefficient were applied, with statistical significance set at P < 0.05. The SAA concentrations measured daily for 30 days showed no statistically significant differences over time. Freezing-thawing was repeated five times, and a significant negative relationship was confirmed over the cycles ( r =‒0.8857, P < 0.05). Although no significance was observed between a decreased concentration and the number of cycles, a decrease in the concentration of > 10% was observed after the fourth cycle in four out of six samples. However, one to three freeze-thaw cycles did not result in a significant decline. Taken together, the results indicate that a negative correlation existed between the mean concentration and multiple freeze-thaw cycles, indicating that these should be avoided where possible.
... This response is classified as either positive or negative APP, depending on whether the protein levels increase or decrease. Additionally, positive APP can be further categorized into three groups based on the degree of increase: group I for proteins that increase by one-fold, group II for those that increase between two-to five-fold, and group III for those that increase up to 1000-fold (128). Chicken APPs are primarily synthesized in the liver, but APP mRNA has also been identified in other healthy chicken tissues. ...
This article provides a comprehensive classical overview of the avian immune system, highlighting its unique components and functions. Although fundamentally similar to mammals, the avian immune system possesses distinct features in its tissues, cells, molecules, and genes. The study elaborates on the innate and adaptive immune components and critical functions in birds, detailing and artistically drawing the various organs such as the Bursa of Fabricius, thymus, spleen, and Harderian gland and cells involved in immunity. It discusses the role of innate immune cells and molecules along with the significance of B-and T lymphocytes immunoglobulins, antigen-presenting cells (APCs), especially macrophages and dendritic cells (DCs) and their related cytokines, including interleukins (ILs), emphasizing their crucial role in adaptive immunity especially activating various T lymphocytes. The article also underscores the complexity and efficiency of the avian immune system in combating pathogens and highlights the evolutionary adaptations that distinguish those from mammalian immune systems. This knowledge contributes to a better understanding of avian immunology and should go beyond this classical immune system, which is vital for improving disease management and vaccination strategies in birds.
... CRP is an acute-phase inflammatory protein, which can increase by 1000-fold during an acute response in various settings. 81 CRP is a pentameric protein with five non-covalently linked subunits of 206 amino acids and a molecular weight of 23 kDa. 82 CRP has numerous functions within the human immune system. ...
The incidence and prevalence of inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease, are rapidly increasing. Currently, colonoscopy is the gold standard for diagnosing and monitoring the course of IBD. However, the recently implemented “treat-to-target” strategy, which involves meticulously pursuing multiple therapeutic objectives, has opened avenues for non-invasive diagnostic and monitoring tools. These tools aim to assess disease activity and predict the likelihood of recurrence. Research studies into serum and fecal biomarkers in IBD have been ongoing for several years. Among the most relevant biomarkers, fecal calprotectin and C-reactive protein have shown the best accuracy, with good-to-optimal correlation with endoscopic, histologic, or transmural activity. Numerous studies have explored the potential advantages of using multi-target tools that combine serum and fecal biomarkers with clinical activity indexes to enhance diagnostic and monitoring effectiveness. Encouraging findings have emerged for fecal lactoferrin, autoantibodies, micro-RNA, gene expression, and many other serological and fecal markers. However, limited evidence has hindered their widespread adoption in routine clinical practice. This review aimed to summarize the available data on the utilization of biomarkers in IBD.
... Acute phase proteins (APPs) are defined as plasma proteins for which concentration increases (positive APP) or decreases (negative APP) more than 25% during inflammation. They can be further classified as minor APP, if responding with a fold change less than 50%, moderate if responding 2-4 times, and major if responding 100 times or more [48]. Major APPs are generally characterized by reacting rapidly and being normalized again rapidly [49]. ...
As an alternative to traditional serological markers, that is, antibodies, for serum-based specific diagnosis of infections, circulating non-antibody markers may be used to monitor active disease. Acute phase proteins (APPs) are a prominent class of such markers widely used for diagnosing ongoing inflammation and infection. In this chapter, basic theoretical and practical considerations on developing APP assays and using APPs as markers of ongoing infection are presented with a specific focus on intracellular infections in pigs. Examples on APP-based monitoring of infection in pigs with viruses such as porcine respiratory and reproductive syndrome virus (PRRSV), porcine endemic diarrhea virus (PEDV), and influenza A virus (IAV), as well as intracellular bacteria (Lawsonia intracellularis) and the protozoan intracellular parasites Toxoplasma gondii and Cryptosporidium parvum are presented, with an emphasis on major pig APPs C-reactive protein (CRP), haptoglobin, serum amyloid A (SAA), and pig major acute phase protein (pig-MAP). The performance of these APPs as biomarkers in a range of experimental infection studies in pigs is described as examples on their use for estimating the severity of infection, vaccine efficacy, herd health characterization, and differential diagnosis.
... As albumin is the main plasma transport protein for cefazolin, the effects of hypoalbuminemia, which occurs in approximately 40 % of critically ill patients [26,27] should be considered. Albumin concentrations in the samples ranged from 19 to 51 g/L, with only four samples falling within the reference range (39-50 g/L). ...
Objectives
Therapeutic drug monitoring of β-lactam antibiotics has become an important tool for treatment of severe infections, especially for critically ill patients who often exhibit altered PK/PD. Therapeutic targets are based on MIC, which refers to the active concentration of the drug. Cefazolin, a β-lactam agent used for treating of MSSA bacteraemia, has a protein binding of approximately 80 %. Therefore, a reliable determination of the active, non-protein-bound concentration is required to ensure optimal therapeutic outcome.
Methods
From seven critically ill patients who received an initial dose of 2 g cefazolin, followed by a continuous 24 h infusion, a total of 24 serum samples were obtained. The non-protein-bound concentration was directly measured after ultrafiltration and compared to prediction based total concentrations and protein binding values from the literature. For the analysis, a rapid and reliable LC-MS³ based assay was established, offering maximum sensitivity and specificity.
Results
The measured non-protein-bound concentration varied over a wide range (7.6–118 mg/L), with 22 out of 24 samples exhibiting cefazolin levels above the therapeutic target values (8–16 mg/L). Additionally, the observed protein binding ranged from 29 to 78 % (median 66.8 %), which was significantly lower than that reported in the literature. When comparing the measurements to the predictive performance of total concentrations and protein binding values, poor results were obtained.
Conclusions
The results show a high variability in plasma protein binding of cefazolin in critically ill patients. Therefore, the “one-dose-fits-all” principle can no longer be considered up to date. For personalised cefazolin therapy based on therapeutic drug monitoring (TDM) it is recommended to determine the active, non-protein-bound drug concentration, as calculations from the total fraction yield poor results.
... Given his hyperferritinemia, further investigation into viral, bacterial, autoimmune, and malignant etiologies was performed [6]. It was found through this effort that the patient's EBV markers were elevated indicating acute EBV infection. ...
Epstein-Barr Virus (EBV), also known as human herpesvirus 4, is a rare cause of hepatitis and myocarditis. Severe cases of EBV hepatitis have been documented in immunocompromised cases; however, it is even more uncommonly seen in the immunocompetent population. Our case highlights EBV hepatitis presenting as acute abdominal pain in a young male with no known medical conditions.
... It is a phylogenetically backward-looking plasma protein [23], providing Ca 2+ -dependent binding to ligands and damaged cell membranes [40]. Inflammatory cytokines (for instance, TNF-α) increase CRP generation during an inflammatory response, indicated by the rising levels, a characteristic employed for clinical targets [4,30,32,49,58]. Several publications have reported the CRP level association with bone mineral density (BMD) [10,11,16,29,39,46], nonvertebral fractures [39,46], and radiographic vertebral fractures [46]. ...
Inflammation disrupts bone metabolism and leads to bone damage. C-reactive protein (CRP) is a typical inflammation marker. Although CRP measurement has been conducted for many decades, how osteoblastic differentiation influences molecular mechanisms remains largely unknown. The present study attempted to investigate the effects of CRP on primary cultured osteoblast precursor cells (OPCs) while elucidating the underlying molecular mechanisms. OPCs were isolated from suckling Sprague-Dawleyrats. Fewer OPCs were observed after recombinant C-reactive protein treatment. In a series of experiments, CRP inhibited OPC proliferation, osteoblastic differentiation, and the OPC gene expression of the hedgehog (Hh) signaling pathway. The inhibitory effect of CRP on OPC proliferation occurred via blockade of the G1-S transition of the cell cycle. In addition, the regulation effect of proto cilium on osteoblastic differentiation was analyzed using the bioinformatics p. This revealed the primary cilia activation of recombinant CRP effect on OPCs through in vitro experiments. A specific Sonic Hedgehog signaling agonist (SAG) rescued osteoblastic differentiation inhibited by recombinant CRP. Moreover, chloral hydrate, which removes primary cilia, inhibited the Suppressor of Fused (SUFU) formation and blocked Gli2 degradation. This counteracted osteogenesis inhibition caused by CRP. Therefore, these data depict that CRP can inhibit the proliferation and osteoblastic differentiation of OPCs. The underlying mechanism could be associated with primary cilia activation and Hh pathway repression.
... CRP can rise 1000-fold within a few hours after the onset of stimuli such as infection, tissue necrosis, trauma, cancer, or various inflammatory diseases. The level of CRP rises to a peak 48 h after the initial stimulus and falls to baseline levels within 7-12 days when the inflammatory stimulus has disappeared [22,23]. CRP is also stimulated by interleukin-1 (IL-1), which is correlated with the pathogenesis of CVS [22,24,25]. ...
Background: Subarachnoid hemorrhage is a devastating disease. Even after state-of-the-art treatment patients suffer from complications, including cerebral vasospasm (CVS), delayed cerebral ischemia (DCI), and chronic hydrocephalus (CH) following aneurysmal subarachnoid hemorrhage (aSAH). The aim of our study is to identify the predictive value of the C-reactive protein to lymphocyte ratio (CLR) for neurological functional outcome and complications after aSAH. Methods: We retrospectively analyzed a total of 166 aSAH patients who met the inclusion criteria enrolled in our study. Multivariate logistic regression analyses were performed to evaluate the independent risk factors. The predictive value of different models was compared by calculating the areas under the receiver operating characteristic (ROC) curve. Results: On-admission levels of CLR in patients with poor outcomes (6 months mRS 3–6), CVS, DCI, and CH were significantly higher than those in patients with good outcomes (6 months mRS 0–2), non-CVS, non-DCI, and non-CH. Multivariate logistic regression analysis revealed that admission CLR was independently associated with CVS (OR [95% CI] 2.116 [1.507–2.971]; p < 0.001), and DCI (OR [95% CI] 1.594 [1.220–2.084]; p = 0.001). In ROC analysis, the area under the curve (AUC) of CLR for poor outcomes (6 months mRS 3–6), CVS, DCI, and CH prediction were (AUC [95% CI] 0.639 [0.555–0.724]; p = 0.002), (AUC [95% CI] 0.834 [0.767–0.901]; p < 0.001), (AUC [95% CI] 0.679 [0.581–0.777]; p < 0.001), and (AUC [95% CI] 0.628 [0.543–0.713]; p = 0.005) revealing that admission CLR had a favorable predictive value for CVS after aSAH. The sensitivity and specificity of admission CLR for CVS prediction were 77.1% and 75.4%. On-admission CLR of 0.757 mg × 10−6 was identified as the best cutoff threshold to discriminate between CVS and non-CVS (CVS: CLR < 0.757 mg × 10−6 11/100 [11.0%] vs. CLR ≥ 0.757 mg × 10−6 37/66 [56.1%]; p < 0.001). Conclusions: High levels of on-admission CLR serve as an independent risk factor for CVS and DCI after aSAH. Admission CLR is an easy-to-quantify laboratory parameter that efficiently predicts the CVS after aSAH, which can provide some guidance for clinicians to evaluate for possible progression and treatment strategies in patients with aSAH.
... Acute phase proteins (APPs) are a class of proteins synthesized and released during acute inflammation and injury in the body, with important biological functions. They include C-reactive protein (CRP), pre-albumin (PA), and albumin (Alb) [32]. IL-6 is the main regulatory factor for APP synthesis and release, and studies have shown that IL-6 levels are positively correlated with APP levels. ...
The origins of late-life depression are multifaceted and remain challenging to fully understand. While the traditional monoamine neurotransmitter hypothesis provides some insights, it falls short in explaining the disease's onset and progression, leaving treatments often less than optimal. There is an emergent need to uncover new underlying mechanisms. Among these, the "inflammation hypothesis" has been gaining traction in scientific discussions regarding late-life depression. There is compelling evidence linking inflammation processes to the emergence of this form of depression. This review delves into the nuanced relationship between inflammation and late-life depression, emphasizing the pivotal role and implications of inflammation in its pathogenesis. Changes in Ca2+ homeostasis, cytokine levels, brain-derived neurotrophic factor (BDNF), white cell ratios, and the involvement of the NOD-, LRR-, and Pyrin domain-containing protein 3 (NLRP3) inflammasome have all been suggested as potential biomarkers that tie inflammation to late-life depression. Furthermore, factors such as aging-induced DNA damage, oxidative stress, mitochondrial impairments, disruptions in the hypothalamic-pituitary-adrenal axis, activated microglia and associated neuroinflammation, as well as the gut-brain axis dynamics, could serve as bridges between inflammation and depression. Deepening our understanding of these connections could usher in innovative anti-inflammatory treatments and strategies for late- life depression.
... The liver synthesizes C-reactive protein (CRP) in response to inflammatory processes. CRP acts as an acute phase reactant in acute and chronic human inflammation (Kushner, 1982). The regulation of CRP expression involves trans-acting cytokines like tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1 (IL-1), which are produced by hepatocytes (Li & Fang, 2004;Visser et al., 1999). ...
... By far the highest upregulated gene was the one coding for the acute phase reactant serum amyloid A2 (SAA2) (adjusted p-value Padj = 0.002). A limited extrahepatic production occurs locally in the epidermis after exposure to stress e.g. to trauma, infection and inflammation [42,43]. One of its many functions is to promote the chemotaxis of lymphocytes [44], monocytes [45] and polymorphonuclear leukocytes [45]. ...
Udder cleft dermatitis (UCD) is a skin condition affecting the anterior parts of the udder in dairy cattle. In the present study, we aimed to shed light on the microbiota in severe UCD lesions versus healthy udder skin by putting forward a taxonomic and functional profile based on a virulence factor analysis. Through shotgun metagenomic sequencing, we found a high proportion of bacteria in addition to a low abundance of archaea. A distinct clustering of healthy udder skin versus UCD lesion samples was shown by applying principal component analysis and (sparse) partial least squares analysis on the metagenomic data. Proteobacteria, Bacillota, and Actinomycetota were among the most abundant phyla in healthy udder skin samples. In UCD samples, Bacteroidota was the most abundant phylum. At genus level, Bifidobacterium spp. had the highest relative abundance in healthy skin samples, whereas Porphyromonas spp. and Corynebacterium spp. had the highest relative abundance in UCD samples. In the differential abundance analysis, Porphyromonas spp. and Bacteroides spp. were significantly differentially abundant in UCD samples, whereas Bifidobacterium spp., Staphylococcus sp. AntiMn-1, and Staphylococcus equorum were more commonly found in healthy samples. Moreover, the abundance of several treponeme phylotypes was significantly higher in lesion samples. The streptococcal cysteine protease speB was among the most abundant virulence factors present in severe UCD lesions, while a plethora of virulence factors such as the antitoxin relB were downregulated, possibly contributing to creating the ideal wound climate for the dysbiotic community. Network analysis showed healthy lesion samples had a large network ofpositive, correlations between the abundances of beneficial species such as Aerococcus urinaeequi and Bifidobacterium angulatum, indicating that the healthy skin microbiome forms an active protective bacterial network, which is disrupted in case of UCD. In UCD samples, a smaller microbial network mainly consisting of positive correlations between the abundances of Bacteroides fragilis and anaerobic Bacteroidota was exposed. Moreover, a high correlation between the taxonomic data and virulence factors was revealed, concurrently with 2 separate networks of microbes and virulence factors. One network, matching with the taxonomic findings in the healthy udder skin samples, showcased a community of harmless or beneficial bacteria, such as Bifidobacterium spp. and Butyrivibrio proteoclasticus, associated with hcnB, hcnC, relB, glyoxalase, and cupin 2. The other network, corresponding to UCD samples, consisted of pathogenic or facultative pathogenic and mainly anaerobic bacteria such as Treponema spp., Mycoplasmopsis spp., and bovine gammaherpesvirus 4, that correlated with virulence factors SpvB, fhaB, and haemagglutination activity domain–associated factor. Our results point toward a dysbiotic community with a notable decrease in diversity and evenness, with a loss of normal skin inhabitants and innocuous or useful species making way for predominantly anaerobic, facultative pathogens. The shift in the abundance of virulence factors such as fhaB and SpvB could play a role in the manifestation of a local micro-environment favorable to the microbiome associated with udder skin lesions. Lastly, the presence of specific networks between microbial species, and between microbes and virulence factors was shown.
... Interferons amongst other pro-inflammatory cytokines, such as Interleukin-1 beta (IL-1b) and IL-6, activate the acute phase response in the liver with IL-6 exhibiting the strongest effect. The acute phase response is by definition those serum proteins that increase or decrease their circulatory concentrations by 25% or more, representing positive and negative reactants, respectively, a response that may occur not only acutely but also chronically [76]. This raises the notion for shifts in the baseline immune inflammatory balance affecting acute phase reactants and the metabolic development of HDL particles. ...
Background
Low levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling.
Methods
In the UK Biobank, ~ 270,000 individuals have data on HDL subclasses derived from nuclear magnetic resonance analysis. We estimated the association of particle count of total HDL and HDL subclasses (small, medium, large, and extra-large HDL) with sepsis, sepsis-related death, and critical care admission in a Cox regression model. We subsequently utilised genetic data from UK Biobank and FinnGen to perform Mendelian randomisation (MR) of each HDL subclass and sepsis to test for a causal relationship. Finally, we explored the role of IL-6 signalling as a potential causal driver of changes in HDL subclasses.
Results
In observational analyses, higher particle count of small HDL was associated with protection from sepsis (Hazard ratio, HR 0.80; 95% CI 0.74–0.86, p = 4 × 10 –9 comparing Quartile 4, highest quartile of HDL to Quartile 1, lowest quartile of HDL), sepsis-related death (HR 0.80; 95% CI 0.74–0.86, p = 2 × 10 –4 ), and critical care admission with sepsis (HR 0.72 95% CI 0.60–0.85, p = 2 × 10 –4 ). Parallel associations with other HDL subclasses were likely driven by changes in the small HDL compartment. MR analyses did not strongly support causality of small HDL particle count on sepsis incidence (Odds ratio, OR 0.98; 95% CI 0.89–1.07, p = 0.6) or death (OR 0.94, 95% CI 0.75–1.17, p = 0.56), although the estimate on critical care admission with sepsis supported protection (OR 0.73, 95% CI 0.57–0.95, p = 0.02). Bidirectional MR analyses suggested that increased IL-6 signalling was associated with reductions in both small (beta on small HDL particle count − 0.16, 95% CI − 0.10 to − 0.21 per natural log change in SD-scaled CRP, p = 9 × 10 –8 ).and total HDL particle count (beta − 0.13, 95% CI − 0.09 to − 0.17, p = 7 × 10 –10 ), but that the reverse effect of HDL on IL-6 signalling was largely null.
Conclusions
Low number of small HDL particles are associated with increased hazard of sepsis, sepsis-related death, and sepsis-related critical care admission. However, genetic analyses did not strongly support this as causal. Instead, we demonstrate that increased IL-6 signalling, which is known to alter infection risk, could confound associations with reduced HDL particle count, and suggest this may explain part of the observed association between (small) HDL particle count and sepsis.
... In a study evaluating the potential use of leukocytosis in the differentiation of PNES and epileptic seizures, it was observed that leukocyte elevation started 2 hours after the event, and there was a significant difference in epilepsy to the PNES. 30 The fact that hemogram analyses were performed in the early phase of the seizure (within 2 hours of the seizure onset) in our study may have caused these results. The CRP is one of the major acute phase reactants in humans, 31 and a significant difference was found in the epilepsy group only for the CRP test from the parameters in this study (p = 0.031). ...
Aims: Differential diagnosis of epilepsy and psychogenic non-epileptic seizures (PNES) is a great challenge. Intense neuronal activity during epileptic seizures can cause neuroinflammation. Immature granulocyte (IG) is a new inflammatory marker analyzed in hemogram. This study investigated the role of IG in differentiating epilepsy from PNES. Methods: In this retrospective study, patients who applied to the emergency department for the first time with seizures and were diagnosed with epilepsy/PNES (clinical evaluation and electroencephalography) after included the seizure by the neurology clinical follow-up. Of the 84 patients, 54 had epilepsy, and 30 had PNES. Hemogram analyses were performed within 2 hours of the onset of the seizure. Results: The IG count was 0.03 x109/L (0.02-0.06) and 0.03 x109/L (0.02-0.05) in the epilepsy and PNES groups, respectively. The two groups had no statistically significant difference (p=0.291). Only serum C-reactive protein (CRP) levels significantly differed between the two groups (p=0.031). The ROC curve analysis for the CRP test yielded a serum CRP value of 2.35 mg/L, with a sensitivity of 0.57 and a specificity of 0.73, as the optimal cut-off value for distinguishing epilepsy from PNES. The ROC analysis for the AUC yielded an estimate of 0.64 (95% confidence interval: 0.52-0.77). Conclusion: In conclusion, only CRP was useful in differentiating epilepsy from PNES in the study. However, the IG count did not help to separate the two seizures. Therefore, these findings should be confirmed by further prospective studies with large samples assessing the IG count. This study evaluating the IG count, a new inflammatory marker, will contribute to the literature.
... Changes occur due to suppression in synthesis or increase in consumption in chronic events while increases in acute phase proteins are generally parallel to the severity and prevalence of inflammation in acute events. The acute phase response may not fully reflect the inflammation activity and prevalence in the case of chronic inflammation(Gabay & Kushner, 1999;Kushner, 1982). ...
... Hyperferritinemia is a key acute-phase reactant used by clinicians to predict the level of inflammation in various pathologies including trauma, viral and bacterial infections, autoimmune diseases, and neoplasms [6] and is associated with higher mortality [7]. Significantly elevated ferritin level in EBV infections is exceptionally rare and has been reported with complicated infectious mononucleosis [3], cold-type autoimmune hemolytic anemia [4], and hemophagocytic lymphohistiocytosis [5]. ...
Elevated aminotransaminases and hyperbilirubinemia are common in primary Epstein-Barr Virus (EBV) infection in the adult and pediatric population and the disease course is usually subclinical and self-limited. However, EBV-induced hepatitis is an uncommon diagnosis, accounting for less than 1% of acute hepatitis causes. Acute EBV-hepatitis usually affects immunocompromised and older populations, with nearly half of patients being aged greater than 60 years. Significantly elevated ferritin levels correlate with severe infection and have been associated with EBV complications such as infectious mononucleosis, autoimmune hemolytic anemia, and hemophagocytic lymphohistiocytosis. We present a case of isolated acute cholestatic EBV-hepatitis and hyperferritinemia in an adult immunocompetent patient.
... In humans, the C-reactive protein CRP is a protein with expression that increase more than 1,000-fold in acute-phase responses associated with a severe inflammatory state, trauma and infection (40). CRP is composed of noncovalently bound subunits comprising 206 amino acid residues with a molecular weight of~23 kDa. ...
Innate immunity constitutes the first nonspecific immunological line of defense against infection. In this response, a variety of mechanisms are activated: the complement system, phagocytosis, and the inflammatory response. Then, adaptive immunity is activated. Major opsonization mediators during infections are immunoglobulins (Igs), the function of which is mediated through Fc receptors (FcRs). However, in addition to their role in adaptive immunity, FcRs have been shown to play a role in innate immunity by interacting directly with bacteria in the absence of their natural ligands (Igs). Additionally, it has been hypothesized that during the early phase of bacterial infection, FcRs play a protective role via innate immune functions mediated through direct recognition of bacteria, and as the infection progresses to later phases, FcRs exhibit their established function as receptors in adaptive immunity. This review provides detailed insight into the potential role of FcRs as innate immune mediators of the host defense against bacterial infection independent of opsonins.
... It is a phylogenetically backward-looking plasma protein (23), that provides Ca 2+dependent binding to ligands and the membranes of damaged cells (40). In ammatory cytokines (for example, TNF-α) increase CRP generation during an in ammatory response, the rising levels of which are re ective of a systemic in ammatory state, a characteristic employed for clinical targets (4,30,32,49,58). A number of publications have reported the association of CRP level with a reduction in bone mineral density (BMD) (10,11,16,29,39,46), nonvertebral fractures (39,46), and radiographic vertebral fractures (46). ...
Inflammation disrupts bone metabolism and causes bone damage. C-reactive protein (CRP) is a typical marker of inflammation. Although the measurement of CRP has been conducted for many decades, the precise influence on the molecular mechanisms of osteoblastic differentiation remains largely unknown. The present study aimed to investigate the effects of CRP on primary cultured osteoblast precursor cells (OPCs) and elucidate the underlying molecular mechanisms. OPCs were isolated from suckling Sprague-Dawleyrats. Fewer OPCs were observed after treatment with recombinant C-reactive protein. In a series of experiments, it was found that CRP inhibited the proliferation of OPCs, osteoblastic differentiation, and the gene expression of the hedgehog(Hh) signaling pathway in OPCs cells. The inhibitory effect of CRP on the proliferation of OPCs occurred via blockade of the G1-S transition of the cell cycle. In addition, the regulation effect of regulation of protocilium on osteoblasticdifferentiation was analyzed from the perspective of bioinformatics, from which the effect of primary cilia activation of recombinantCRP on OPCs was revealed in in vitro experiments. A specific Sonic Hedgehog signaling agonist (SAG) rescued osteoblasticdifferentiation that was inhibited by recombinantCRP. Moreover, chloral hydrate, which removes primary cilia, inhibited the formation of Suppressor of Fused (SUFU) and blocked the degradation of Gli2, counteracting the inhibition of osteogenesis caused by CRP. Thus, these data indicate that CRP can inhibit the proliferation and osteoblastic differentiation of OPCs. The underlying mechanism may be related to the activation of primary cilia and repression of the Hh pathway.
... By far the highest upregulated gene was the one coding for the acute phase reactant serum amyloid A2 (SAA2) (adjusted p-value Padj = 0.002). A limited extrahepatic production occurs locally in the epidermis after exposure to stress e.g. to trauma, infection and inflammation [42,43]. One of its many functions is to promote the chemotaxis of lymphocytes [44], monocytes [45] and polymorphonuclear leukocytes [45]. ...
This study is the first to investigate the transcriptomic changes occurring in severe udder cleft dermatitis lesions (UCD) in Holstein-Friesian cows. An examination of the gene expression levels in natural UCD lesions and healthy udder skin through RNA Seq-Technology provided a deeper insight into the inflammatory pathways associated with this disease. A clear distinction between the gene expression patterns of UCD lesions and healthy skin was shown in the principal component analysis. Genes coding for inflammatory molecules were upregulated such as the chemokines C-X-C motif ligand 2 (CXCL2), 5 (CXCL5) and 8 (CXCL8), and C-C motif ligand 11 (CCL11). Moreover, the genes coding for the multifunctional molecules ADAM12 and SLPI were amongst the highest upregulated ones, whereas the most downregulated genes included the ones coding for keratins and keratin-associated molecules. Predominantly inflammatory pathways such as the chemokine signaling, cytokine receptor interaction and IL-17 signaling pathway were significantly upregulated in the pathway analysis. These results point towards a fulminant, dysregulated inflammatory response concomitant with a disruption of the skin barrier integrity and a hampered wound repair mechanism in severe UCD lesions.
... We examined Alb and CRP levels as indicators of surgical invasiveness. These are considered to be acute phase reactants, and inflammation in the body causes a decrease in Alb and an increase in CRP [26,27]. Significant differences in Alb levels were observed before and on days 1, 4, and 7 after surgery. ...
Introduction
This retrospective study aims to clarify if there are benefits of performing unicompartmental knee arthroplasty (UKA) on just one indicated side in patients who undergo simultaneous bilateral knee arthroplasty.
Materials and methods
We compared 33 cases of simultaneous bilateral UKA/total knee arthroplasty (TKA) (S-UT) with 99 cases of simultaneous bilateral TKA (S-TT). Comparison included blood tests [C-reactive protein (CRP), albumin, and D-dimer], the incidence of deep vein thrombosis (DVT), range of motion (ROM), and clinical scores before and 1 year after surgery.
Results
Clinical scores were not significantly different between the groups. The postoperative flexion angle was significantly better in UKA sides. Blood tests showed that the S-UT had a significantly higher albumin value at 4 and 7 days after surgery. The CRP value at 4 and 7 days, and the D-dimer value at 7 and 14 days after surgery were significantly lower in the S-UT. The S-UT had significantly lower incidence of DVT.
Conclusions
In cases of bilateral arthroplasty, if there is an indication on only one side, a better flexion angle can be obtained by UKA on that side, and with less surgical invasion. Moreover, the incidence of DVT is low, which is considered to be a benefit of performing UKA on just one side.
... MARV and EBOV infection induce initial inflammation, evidenced primarily by an acute phase response. Acute phase proteins (APP) are produced by hepatocytes in the liver in response to inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor α (TNFα), and are an important part of the innate immune response [37][38][39]. Upon inflammation, the concentration of positive APPs, including serum amyloid A1 (SAA1) and serum amyloid A2 (SAA2), increase dramatically (> 10-fold) in the serum [40], while the concentration of negative APPs, including transferrin (TF) and albumin (ALB), decreases [41]. ...
The Marburg and Ebola filoviruses cause a severe, often fatal, disease in humans and nonhuman primates but have only subclinical effects in bats, including Egyptian rousettes, which are a natural reservoir of Marburg virus. A fundamental question is why these viruses are highly pathogenic in humans but fail to cause disease in bats. To address this question, we infected one cohort of Egyptian rousette bats with Marburg virus and another cohort with Ebola virus and harvested multiple tissues for mRNA expression analysis. While virus transcripts were found primarily in the liver, principal component analysis (PCA) revealed coordinated changes across multiple tissues. Gene signatures in kidney and liver pointed at induction of vasodilation, reduction in coagulation, and changes in the regulation of iron metabolism. Signatures of immune response detected in spleen and liver indicated a robust anti-inflammatory state signified by macrophages in the M2 state and an active T cell response. The evolutionary divergence between bats and humans of many responsive genes might provide a framework for understanding the differing outcomes upon infection by filoviruses. In this study, we outline multiple interconnected pathways that respond to infection by MARV and EBOV, providing insights into the complexity of the mechanisms that enable bats to resist the disease caused by filoviral infections. The results have the potential to aid in the development of new strategies to effectively mitigate and treat the disease caused by these viruses in humans.
... Among the concomitant changes observed during systemic tissue injury is a dramatic, coordinate increase in the synthesis of plasma proteins by the liver, collectively known as APP (5). APP have specific roles in tissue repair and neutralization of tissue damage, and in the rat include Fb, HP, Hpx, a2-macroglobulin, TST, AT, ACT, C3, and AGP. ...
The rat hepatoma cell line, H-35, responds to IL-1- and IL-6-type cytokines by an increased transcription of specific acute phase plasma protein (APP) genes. Transforming growth factor-beta (TGF-beta), although ineffective on its own in regulating APP genes, modulates the action of the IL-type cytokines. In growing cultures, the IL-6 and IL-11 stimulation of thiostatin and hemopexin is enhanced by TGF-beta, whereas the stimulation of other APP is reduced. The effects of leukemia inhibitory factor, ciliary neurotrophic factor, IL-1, and TNF-alpha are generally attenuated by TGF-beta. Enhancement by TGF-beta of the IL-6-induced response can be explained in part by the fact that TGF-beta, in combination with dexamethasone, stimulates severalfold the expression of the 80-kDa ligand-binding subunit of IL-6R. Serum deprivation of H-35 cells for 3 days leads to an enhanced basal and cytokine-stimulated level of APP gene expression concomitant with a loss of the divergent regulatory effect of TGF-beta. In growth-arrested H-35 cells, TGF-beta still enhances the IL-6R expression but it attenuates all IL-6 effects on APP genes. These data suggest that TGF-beta influences the signal transduction of the IL-type cytokines by separate mechanisms and that the manifestation of the TGF-beta action is modulated by the growth state of the cell culture.
... It is detected in 50%-60% of patients with RA in the early stage (within 3-6 months after the onset of symptoms) [29]. ACPA is known to have superior sensitivity and specificity and shows a positive sign Acute phase reactants are substances whose concentrations increase or decrease in response to acute tissue inflammation or trauma [30]. Representative items related to these are erythrocyte sedimentation rate (ESR) and ESR, a diagnostic test that has been used for a long time, is measured by the distance at which erythrocytes are separated from plasma and sink in a pipette for 1 hour. ...
... From this brief description of the immune system, it should be clear that mounting a rapid and effective inflammatory response to physical injury or the first signs of a pathogen is critical for resolving infection, repairing tissue damage, and promoting survival (Kushner, 1982;Medzhitov, 2008). Unfortunately, though, what can save us in the short run can also kill us in the long run. ...
Psychoneuroimmunology (PNI) is the study of how psychological, neural, and immunologic processes interact and affect human health and behavior. Although once a relatively small field, some of the most exciting discoveries in psychopathology and mental health research have recently involved ideas and methods from PNI. In reviewing this work, I first summarize the structure and function of the human immune system, focusing primarily on inflammation. Second, I describe neural and physiologic pathways that link the brain and immune system, which give neurocognitive processes the ability to regulate the immune system and immunologic processes the ability to affect neural, cognitive-emotional, and behavioral outcomes. Third, I review studies examining associations between life stress and inflammation, and inflammation and mental health. Finally, I highlight several promising avenues for future research. Overall, despite the notable impact that PNI has already had on our understanding of mental and physical health, many important questions remain unanswered.
Disease may be both a cause and consequence of stress, and physiological responses to infectious disease may involve stress coping mechanisms that have important fitness consequences. For example, glucocorticoid and glycemic responses may affect host fitness by altering resource allocation and use in hosts, and these responses may be affected by competing stressors. To better understand the factors that affect host responses to infection, we challenged the immune system of field acclimatized pygmy rattlesnakes, Sistrurus miliarius, with a sterile antigen, lipopolysaccharide (LPS), and measured the glucocorticoid and glycemic response in healthy non-reproductive snakes, snakes afflicted with an emerging mycosis (ophidiomycosis), and pregnant snakes. We hypothesized that LPS challenge would result in a glucocorticoid and glycemic response typical of the vertebrate acute phase response (APR), and therefore predicted that LPS challenge would result in an acute increase in plasma corticosterone (CORT) and a decline in plasma glucose in all individuals. Additionally, we hypothesized that the APR would be attenuated in individuals simultaneously coping with additional challenges to homeostasis (i.e., disease or reproduction). As predicted, immune challenge elicited an acute increase in plasma CORT and a decrease in plasma glucose. Snakes coping with ophidiomycosis and pregnant snakes were able to mount a robust glucocorticoid and hypoglycemic response to LPS challenge, which was contrary to our hypothesis. Our findings clarify directions of causality linking infection, glucocorticoids, and glucose, and emphasize the importance of future research examining the fitness consequences of interactions between stress and disease in wildlife threatened by emerging pathogens.
The acute phase reaction is a molecular response to noxious stimuli. Over 50 glycoproteins have been identified as reactants. While this is likely a protective response, some of the changes could be detrimental to body homeostasis. The objective of this study was to examine whether an acute phase reaction occurs in diabetic patients with foot ulcers. In age- and sex-matched populations, measurements of C-reactive protein, fibrinogen, albumin, hematocrit, whole blood viscosity and protein C were performed on: (i) 24 diabetic patients with a foot ulcer (group A); (ii) eight diabetic patients without foot ulcer (group B); and (iii) seven patients without diabetes (group C). Analysis of variance was used to compare means of each respective group (mean (s.d.)). Group A demonstrated an increase in C-reactive protein (5.6 (5.4) mg/dl) compared with group B (0.78(0.46) mg/dl; P = 0.013) and group C (0.71 (0.26) mg/dl; P = 0.026). Fibrinogen was also increased in group A (619 (205) mg/dl) compared with group B (310 (58) mg/dl; P = 0.005) and group C (370 (88) mg/dl; P = 0.04). Hematocrit (37(6)%) and albumin (3.5 (0.5) g/dl) were decreased in group A compared with group B (hematocrit 46 (4)%; P < 0.0001: albumin 4.3 (0.3) g/dl; P = 0.0005) and group C (hematocrit 45 (3)%; P = 0.005; albumin 4.6 (0.3) g/dl; P < 0.0001). No difference was found in whole blood viscosity and levels of protein C. There also was no significant difference demonstrated between any of the parameters studied when comparing groups B and C. In conclusion, these results indicate that diabetic patients with a foot ulcer undergo an acute phase reaction as evidenced by a rise in C-reactive protein and fibrinogen compared with diabetic patients without a foot ulcer and normal control patients. As more is learned about the acute phase reaction, this information may prove valuable in the management of the diabetic patient.
The use of inflammatory markers (IMs) in the pediatric emergency department (PED) is broad and non-specific. This retrospective, cross-sectional study of children aged 3 months to 18 years evaluated the use of IMs in the PED. The reasons for IM use were provider practice (38%), ruling out a differential diagnosis (36%), and presence of comorbidities (18%). IMs are commonly used for gastroenterology, infectious diseases, and orthopedic diseases. A third had IMs without an indication. Forty-six percent of IM testing was indicated based on medical documentation, of which only 21% had abnormal IMs. Compared to the abnormal IM values by the on-site laboratory, the IM assessment using a receiver operating characteristic (ROC) curve threshold criterion had improved specificity and negative predictive value (NPV) based on the reason for IM use. This study suggests that the rate of abnormal IMs is low and does not affect patient outcomes in the PED.
The brain-gut axis represents a bidirectional communication network that integrates neural, hormonal, and immunological signaling between the central nervous system and the gastrointestinal tract. Adverse childhood experiences (ACEs) have increasingly been recognized for their profound impact on this axis, with implications for both mental and physical health outcomes. This mini-review explores the emerging field of epigenomics—specifically, how epigenetic modifications incurred by ACEs can influence the brain-gut axis and contribute to the pathophysiology of various disorders. We examine the evidence linking epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs to the modulation of gene expression involved in stress responses, neurodevelopment, and immune function—all of which intersect at the brain-gut axis. Additionally, we discuss the emerging potential of the gut microbiome as both a target and mediator of epigenetic changes, further influencing brain-gut communication in the context of ACEs. The methodological and therapeutic challenges posed by these insights are significant. The reversibility of epigenetic marks and the long-term consequences of early life stress require innovative and comprehensive approaches to intervention. This underscores the need for comprehensive strategies encompassing psychosocial, pharmacological, neuromodulation, and lifestyle interventions tailored to address ACEs’ individualized and persistent effects. Future directions call for a multi-disciplinary approach and longitudinal studies to uncover the full extent of ACEs’ impact on epigenetic regulation and the brain-gut axis, with the goal of developing targeted therapies to mitigate the long-lasting effects on health.
Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer’s disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard −/− mice which lack ASC. Treatment with anti-ASC PYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC 50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.
Background Fatty liver disease is a condition that can be detected incidentally during routine checkups or imaging tests. The rise in obesity and metabolic syndrome has also contributed to an increase in fatty liver diagnoses. This condition can be caused by alcohol consumption (alcoholic fatty liver disease) or by other factors (nonalcoholic fatty liver disease). Aims & Objectives This study aims to investigate the clinical characteristics and inflammatory markers in individuals with asymptomatic fatty liver disease identified through routine imaging tests like ultrasounds (USG) and CT scans of the abdomen. Specifically, the researchers will measure serum levels of high-sensitivity C-reactive protein (hs-CRP) to assess potential inflammation and its association with coronary artery disease (CAD) risk in this patient population. Methods The study appears to be investigating asymptomatic fatty liver disease detected through ultrasounds in adults (age > 14 years) who underwent health checkups at a medical college between October 2022 and September 2023.
The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as 2019-nCoV. Numerous cellular and biochemical issues arise after COVID-19 infection. The severe inflammation that is caused by a number of cytokines appears to be one of the key hallmarks of COVID-19. Additionally, people with severe COVID-19 have coagulopathy and fulminant thrombotic events. We briefly reviewed the COVID-19 disease at the beginning of this paper. The inflammation and coagulation markers and their alterations in COVID-19 illness are briefly discussed in the parts that follow. Next, we talked about NETosis, which is a crucial relationship between coagulation and inflammation. In the end, we mentioned the two-way relationship between inflammation and coagulation, as well as the factors involved in it. We suggest that inflammation and coagulation are integrated systems in COVID-19 that act on each other in such a way that not only inflammation can activate coagulation but also coagulation can activate inflammation.
Peri-implant disease pathogenesis results in production of pro-inflammatory mediators, among which C-reactive protein (CRP) is one of the acute phase reactants. The aim of the study was to comparative CRP levels among peri-implant health and disease conditions. The present study was carried out in the Department of Implantology, Saveetha Dental College and Hospitals, Chennai, India. A total of 40 patients with peri-implant health ( n = 10), peri-mucositis ( n = 10), early peri-implantitis ( n = 10) and advanced peri-implantitis ( n = 10) were enrolled. Unstimulated salivary samples were collected and subjected to latex agglutination assay for CRP analysis. CRP levels were then correlated with peri-implant health and diseases. CRP level in peri-implant health, peri-implant mucositis, early peri-implantitis and advanced peri-implantitis were 0.18 ± 0.04 mg/dL, 2.05 ± 0.61 mg/dL, 4.14 ± 1.82 mg/dL and 6.21 ± 1.35 mg/dL respectively. There was a statistically significant difference in CRP levels between all the tested groups (ANOVA, P = 0.03). Pearson correlation coefficient analysis revealed a strong positive correlation between CRP and peri-implant health status. CRP level was high among patients with peri-implantitis followed by peri-implant mucositis and peri-implant health. Also, CRP level increases with severity of peri-implant diseases and there exists a positive correlation between CRP level and peri-implant health status.
Peri-implant disease pathogenesis is similar to periodontal disease pathogenesis resulting in production of pro-inflammatory mediators. These mediators alter the redox balance leading to decrease in antioxidants, among which catalase is one of the enzymatic antioxidants. The aim of the study was to compare the levels of catalase in peri-implant health and disease. The present observational study was carried out from June 2022 to December 2022 in the Department of Implantology, Saveetha Dental College and Hospitals, Chennai, India. A total of 60 patients with peri-implant health (Group 1; n = 20), peri-implant mucositis (Group 2; n = 20) and peri-implantitis (Group 3; n = 20) were enrolled. Unstimulated salivary samples were collected and subjected to ELISA for catalase analysis. Catalase levels were then compared between the groups using ANOVA. The mean catalase level in peri-implant health, peri-implant mucositis, peri-implanti-tis were 25.07 ± 0.44 U/mL, 18.5 6 ± 0.65 U/mL, and 11.25 ± 0.76 U/mL respectively. The difference between the three groups were statistically significant ( P < 0.05). Catalase level decreases with severity of peri-implant diseases. Therefore, catalase can be used as a diagnostic marker for peri-implant diseases.
Peri-implant disease pathogenesis is similar to periodontal disease pathogenesis resulting in production of pro-inflammatory mediators. These mediators are released during the inflammation phase, among which C-reactive protein (CRP) is one of the acute phase reactants. The aim of the study was to correlate the levels of CRP with the severity of peri-implant diseases. The present observational study was carried out from June 2022 to December 2022 in the Department of Implantology, Saveetha Dental College and Hospitals, Chennai, India. A total of 60 patients with peri-implant health ( n = 20), peri-mucositis ( n = 20) and peri-implantitis ( n = 20) were enrolled. Unstimulated salivary samples were collected and subjected to latex agglutination assay for CRP analysis. CRP levels were then correlated with severity of peri-implant diseases. The mean CRP level in peri-implant health, peri-implant mucositis, peri-implantitis were 0.25 ± 0.36 mg/dl, 3.56 ± 0.85 mg/dl and 5.07 ± 0.74 mg/dl, respectively. Pearson correlation coefficient analysis revealed a strong positive correlation between CRP and peri-implant parameters suggesting that the CRP level increased as the severity of peri-implant disease increased. CRP level increases with severity of peri-implant diseases and there exists a positive correlation between CRP level and peri-implant parameters. Therefore, CRP can be used as a diagnostic marker for peri-implant diseases.
Dietary levels of undegraded neutral detergent fiber (uNDF240) and rumen fermentable starch (RFS) can impact the rumen microbiome and milk composition. The objective of the study is to investigate the use of milk proteins as biomarkers of rumen microbial activity through a comparative evaluation of the rumen microbial and milk protein profiles produced by Holstein cows fed diets with varying contents of physically effective uNDF240 (peuNDF240) and RFS. Eight ruminally cannulated lactating Holstein cows were included in a larger study as part of a 4 × 4 Latin square design with 4 28-d periods to assess 4 diets varying in peuNDF240 and RFS content. For this experiment, cows received one of 2 dietary treatments: 1) low peuNDF240, high RFS (LNHR) diet or 2) high peuNDF240, low RFS (HNLR) diet. Within each period, rumen fluid samples were collected from each cow on d 26 (1400 h) and d 27 (0600 h and 1000 h), and milk samples were collected from each cow on d 25 (2030 h), d 26 (0430 h, 1230 h, and 2030 h), and d 27 (0430 h and 1230 h). Microbial proteins were isolated from each rumen fluid sample. For milk samples, milk proteins were fractionated, and the whey fraction was subsequently isolated. Isolated proteins within each rumen fluid or milk sample were isobarically labeled and analyzed by LC-MS/MS. Product ion spectra acquired from rumen fluid samples were searched using SEQUEST against 71 composite databases. In contrast, product ion spectra acquired from milk samples were searched against the Bos taurus database. Data were analyzed using the PROC MIXED procedure in SAS 9.4 to assess the impact of diet and time of sampling. To increase stringency, the false discovery rate-adjusted P-value (PFDR) was also calculated to account for multiple comparisons. Using the mixed procedure, a total of 129 rumen microbial proteins were quantified across 24 searched microbial species. Of these, the abundance of 14 proteins across 9 microbial species was impacted due to diet and diet × time interaction, including 7 proteins associated with energetics pathways. Among the 159 quantified milk proteins, the abundance of 21 proteins was impacted due to the diet and diet × time interaction. The abundance of 19 of these milk proteins was impacted due to diet × time interactions. Of these, 16 proteins had the disparity across diets at the 0430 h sampling time, including proteins involved in host defense, nutrient synthesis, and transportation, suggesting that biological shifts resulting from diet-induced rumen changes are not diurnally uniform across milkings. The concentration of lipoprotein lipase (LPL) was statistically higher in the milk from the cows fed with the LNHR diet, which was numerically confirmed with an ELISA. Further, as determined by ELISA, the LPL concentration was significantly higher in the milk from the cows fed with the LNHR diet at 0430 h sampling point, suggesting that LPL concentration may indicate dietary carbohydrate-induced ruminal changes. The results of this study suggest that diet-induced rumen changes can be reflected in milk in a diurnal pattern, further highlighting the need to consider sampling time points for using milk proteins as a representative biomarker of rumen microbial activity.
C-reactive protein (CRP) was discovered in 1930 in the sera of patients during the acute phase of pneumococcal pneumonia and was so named because it bound to the C-polysaccharide of the pneumococcal cell wall. During the next half century many questions raised by this discovery were answered. Phosphorylcholine was found to be the moiety of the C-polysaccharide to which CRP bound. The molecular structure of CRP was elucidated: five identical subunits arranged in cyclic symmetry, giving rise to the term pentraxin. Initially felt to be not normally present in the blood, CRP was found to be a component of normal serum in trace amounts. Its site of origin was determined to be the hepatocyte. It became clear that the presumed humoral mediator responsible for CRP induction was of leukocytic origin. Binding of CRP to its ligand activated the complement system, one of the important effector mechanisms of innate immunity. CRP was found to stimulate phagocytosis of some bacterial species via binding to Fc receptors and was found to be protective in vivo against the pneumococcus in mice. It appeared likely that a related function of CRP was clearance of necrotic tissue. CRP was recognized as being a highly evolutionary conserved molecule. Its discovery during the acute phase of pneumococcal pneumonia led to its being dubbed an acute phase protein. What we today call “the acute phase response”, refers to the large number of behavioral, physiologic, biochemical, and nutritional changes that occur during inflammatory states.
Chronic postpartum uterine infection detrimentally affects subsequent fertility. Nonsteroidal anti-inflammatory drugs (NSAID) are used to alleviate pain and treat inflammatory conditions in transition dairy cows with varying success. To screen the efficacy of NSAID in the absence of animal experiments, we have established an in vitro model to study uterine inflammation. Inflammation was induced in cultured bovine endometrial epithelial cells by challenging cells with an inflammation cocktail: lipopolysaccharide and proinflammatory cytokines, interleukin-1β (IL1β) and tumor necrosis factor α (TNFα). Release of the inflammation markers, serum amyloid A (SAA) and α-1-acid glycoprotein (αAGP), was measured by ELISA. Concentration of these markers was used to indicate the effectiveness in dampening inflammation of 5 NSAID: meloxicam, flunixin meglumine, aspirin, ketoprofen, and tolfenamic acid. Three NSAID, meloxicam, flunixin meglumine, and tolfenamic acid, were successful at dampening the release of SAA and αAGP into cell-culture supernatant, and the corresponding treated cells were selected for down-stream mRNA expression analysis. Expression of 192 genes involved in regulation of inflammatory pathways were investigated using Nanostring. Of the genes investigated, 81 were above the mRNA expression-analysis threshold criteria and were included in expression analysis. All SAA genes investigated (SAA2, SAA3, M-SAA3.2) were upregulated in response to the inflammation cocktail, relative to mRNA expression in control cells; however, AGP mRNA expression was below the expression analysis threshold and was, therefore, excluded from analysis. Treatment with NSAID downregulated genes involved in regulating chemokine signaling (e.g., CXCL2, CXCR4, CXCL5, and CXCL16) and genes that regulate the eicosanoid pathway (e.g., LTA4H, PTGS2, PLA2G4A, and PTGDS). Of the 5 NSAID investigated, meloxicam, flunixin meglumine, and tolfenamic acid are recommended for further investigation into treatment of postpartum uterine inflammation. The results from this study confirm the immunomodulatory properties of the endometrial epithelium in response to inflammatory stimuli and suggest that NSAID may be beneficial in alleviating uterine inflammation.
Background: Postoperative delirium is a common complication in elderly patients who have undergone hip fracture surgery. Since postoperative delirium is associated with poor outcomes and the treatment is very complicated, identifying the patients at high risk for delirium and providing more attentive care to prevent postoperative delirium is essential. In this study, we aimed to assess the association of an elevated C-reactive protein (CRP)/albumin ratio with the increased incidence of postoperative delirium in elderly people who had undergone hip fracture surgery. Methods: A total of 629 patients who underwent hip fracture surgery between January 2014 and December 2018 were retrospectively analyzed. Patients were classified into two groups according to preoperative CRP/albumin cut-off levels (
The de novo biosynthesis of the heterotetrameric (alpha 2 beta 2) serum glycoprotein, haptoglobin, was studied using a rabbit reticulocyte cell-free translation system and mRNA preparations from the livers of turpentine-treated rats. Analysis of the translation mixtures with either antisera specific for the alpha-subunit (anti-alpha-IgG) or the beta-subunit (anti-beta-IgG) or the native haptoglobin tetramer (anti-alpha 2 beta 2-IgG) resulted in each instance in the recovery of a single protein exhibiting a Mr = approximately 38,000. Cleavage of the translation product with cyanogen bromide or trypsin resulted in the generation of small peptide fragments that were specifically immunoadsorbed with either anti-alpha-IgG or anti-beta-IgG. These results indicated that the primary translation product of haptoglobin mRNA is a single polypeptide that contains the elements of both the alpha-subunit and the beta-subunit of the protein. Presumably haptoglobin is synthesized in vitro as a single precursor protein that is proteolytically processed post-translationally to form the dissimilar alpha- and beta-subunits of the native protein.
A nonspecific opsonin function has been ascribed to human alpha 2 HS glycoprotein. Its serum level has been shown to be decreased in trauma patients. Recent studies from this laboratory revealed a heterogeneity among the products obtained in the course of the preparation of the protein. To date, no definitive agreement existed with regard to a molecular homogeneous entity of alpha 2 HS glycoprotein (Ba-alpha 2 glycoproteins). The purpose of the current work was to study the variations in serum level of alpha 2 HS in patients suffering from an acute inflammatory process of bacterial etiology and to determine whether a decrease in alpha 2 HS was accompanied by the appearance of fragments of this protein in the serum. A method of preparing alpha 2 HS was thus developed, using an immune absorbent as a final purification step. In an intermediary step of the preparation, alpha 2 HS was found to bind zinc when metal chelate affinity chromatography was employed. Immunologically and physico-chemically pure alpha 2 HS was obtained. The protein consists of a unique polypeptide chain of about 50,000 daltons and has a unique amino-terminal residue, alanine. However, the protein maintained its molecular integrity with difficulty, and spontaneous fragments ranging from 30,000 to less than 10,000 daltons were produced in some of the preparations. No major modification in the molecular structure of the protein was noted in the sera of subjects suffering from an acute inflammatory process. Serum level of alpha 2 HS and alpha 1 antitrypsin (AT)was determined in 23 patients. When the acute-phase (AP-)reactant alpha 1 AT was increased (difference with normal mean greater than +2 or +3 SD), the sera showed a large decrease in alpha 2 HS (difference with normal mean less than -2 or -3 SD). The serum level of alpha 2 HS, albumin, alpha 2 macroglobulin, and of positive AP-reactants, orosomucoidinal study of seven patients. The results were submitted to a principal components analysis. Alpha 2 HS showed a negative correlation with the AP-reactants alpha 1 AT, orosomucoid, and haptoglobin (P less than 0.05) and a positive correlation with albumin (P less than 0.05); these findings indicate that alpha 2 HS is a negative AP-reactant. In addition, analysis of the principal components confirms thestrong analogy between alpha 2 HS and albumin and indicates that serum level behavior of the AP-reactants during the course of the disease closely depends on the protein studied.
Current concepts of protein turnover, synthesis, and breakdown in man are reviewed. Emphasis is placed on the distinction between protein breakdown, by which constituent amino acids are released, and amino acid catabolism, which leads to the formation of excretory products, mainly urea and carbon dioxide. Methods of measuring overall rates of turnover, synthesis, and breakdown of body protein in many by the continuous or intermittent administration of radioactive or stable isotopes of amino acids are reviewed. Data from the published literature and from ongoing studies reveal that the overall rate of protein synthesis declines with age. There is close agreement between results obtained with different isotopes in normal adults. Malnourished infants have significantly lower rates of protein turnover, synthesis, and breakdown before than after recovery. These findings may represent another example of metabolic adaptation in the malnourished child. After surgical trauma in adults, the rate of protein synthesis is significantly reduced and neither protein turnover nor breakdown shows a significant change from preoperative values. It is concluded from these studies that the negative nitrogen balance found after injury is accounted for by a reduction in protein synthesis and that protein breakdown remains unchanged after orthopedic operations. The relevance of these findings to the changes in nitrogen metabolism seen in infection is discussed.
THE acute-phase reaction in mammals is characterised by an increase in the concentration of certain plasma proteins which starts within hours or days of most forms of acute tissue damage or inflammation, and persists with chronic inflammation and malignant neoplasia1-4. Among acute-phase reactants are protease inhibitors, coagulation factors, complement components and transport proteins as well as proteins without known in vivo roles, such as the classical reactant, C-reactive protein (CRP)1-4. The pathophysiological significance of the acute-phase reaction is not known, but it is a usual accompaniment of tissue damage, and it is of clinical value in the assessment of disease activity4. We now report that in the mouse, serum amyloid P-component (protein SAP)5, which is a stable plasma protein in man6, is a major acute-phase reactant. In addition, our observations facilitate investigation of the function of protein SAP and of the pathogenesis of amyloidosis, which is a serious disease in man.
To determine the cell of origin of C-reactive protein (CRP) and to cast light on the mechanisms leading to the acute phase response, we used an immunoenzymatic technique to visualize this protein in livers from rabbits at intervals after intramuscular injection of turpentine. CRP was detected only in hepatocytes. 8 h after turpentine injection, CRP was demonstrated in occasional periportal hepatocytes. With time, larger numbers of positive cells were detected successively in perilobular, midlobular, and centrilobular areas. On electron microscopy, CRP was detected in rough endoplasmic reticulum (RER), smooth endoplasmic reticulum (SER), and Golgi apparatus (GA). When colchicine was administered to inhibit cellular secretion of CRP, intensity of reaction and number of CRP-containing hepatocytes were substantially greater than without colchicine, but the sequence of intralobular distribution was similar. At peak serum response 38 h after turpentine injection, CRP could be demonstrated in most hepatocytes. Electron microscopic studies showed accumulation of CRP on membranes and lumina of RER, SER, GA, and in cytoplasmic vacuoles. These findings indicate that CRP is produced by progressively increasing numbers of hepatocytes after inflammatory stimulus and suggest that a mediator, acting initially in portal zones, is responsible for recruitment of cells to CRP production.
Previous reports have shown that endotoxin decreases serum iron in experimental animals. In this study fever was produced in nine female and nine male normal subjects in order to define the temporal and quantitative changes in serum iron and ferritin concentrations. Six volunteers were randomly given bacterial endotoxin (5 ng/kg) or saline intravenously and received the alternative compound a week later. Serial blood samples were drawn at 4-hr intervals for a 24-hr period, beginning when the compound was administered, for the determination of serum iron and ferritin concentrations. The same study was performed with intramuscular etiocholanolone (0.3 mg/kg) or the vehicle, propylene glycol, as a control, but the first blood sample was obtained 9 hr after the compound was given. In addition, blood samples were obtained at 12-hr intervals in six volunteers for 11 days after an intramuscular injection of etiocholanolone. The results showed a significant increase (p less than 0.005 for etiocholanolone, P less than 0.01 for endotoxin) in serum ferritin and a significant decrease (p less than 0.005 for etiocholanolone, p less than 0.001 for endotoxin) in serum iron for both pyrogenic compounds compared with the control compounds. However, the amount of fever and the changes in the iron parameters were greater with etiocholanolone. One episode of induced fever with etiocholanolone effected changes in serum ferritin and iron concentrations that lasted 10 days. Thus this study demonstrated that a single episode of fever in man produced rapid and prolonged changes in serum iron and ferritin concentrations.
It was almost a century ago that the ability of fresh serum to destroy certain bacteria was noted. This bactericidal capacity was soon resolved into a heat-stable substance, bactericidin, bacteriolysin, or, in modern terms, specific antibody, and a heat-labile substance called alexin by Büchner and complement by Bordet. At the turn of this century, Ehrlich and Morgenroth found similar requirements for the immune lysis of sheep red cells. Since the release of hemoglobin could be quantitated, the sheep cell (E), amboceptor or antibody (A), and complement (C) model system provided a powerful tool for the further study of complement and its actions. It was rapidly established that antibody could combine with the sheep cell in the absence of complement but complement could not exert its lytic action in the absence of antibody.
During the last four years increasing attention has been given to those plasma proteins which increase or decrease in concentration after trauma or during acute infections. As a result of such studies it has become apparent that additions must be made to the category of those which increase in concentration, usually referred to as ‘acute phase proteins’, or ‘acute phase reactants’ (APRs). Recent data on APRs have been summarised by Koj1. Thus information is now available that certain proteins present in plasma after injury which on injection into rats have anti-inflammatory effects should be classified as APRs (table 30.1). Similarly, kininogen, kininogenase, angiotensinogen2 and those constituents of complement which are responsible for reactive lysis must also be considered to be APRs. Greatly increased concentrations of kininogen and kininogenase have recently been detected in the blood of rats after injury3. As shown in figure 30.1, the kininogen and kininogenase concentrations were found to be at a maximum after 2 days, as is typical of many other APRs.
The increase in the erythrocyte sedimentation rate (ESR) has long been used as a measure of the intensity of the systemic effect of inflammation. As fibrinogen, the immunoglobulins and β-lipoprotein influence the height of the ESR, the clinician requires more specific information. Since the introduction of methods for determination of specific plasma proteins, attention has been focussed on the concentration of only one, or at most a few, of these proteins in various acute diseases. In Professor Laurell’s laboratory in Malmö we have tested a battery of specific proteins in a series of diseases to study its potential clinical diagnostic value. A question that has interested us is whether the inflammatory response varies in intensity with the tissue affected. Because of the limited time available, I will confine myself to the proteins, which are the topic of today’s session, i.e. the acute phase proteins. Here I include only those which increase rapidly in acute conditions, i.e. C-reactive protein (CRP), antichymotrypsin, αl-antitrypsin (αl-AT), orosomucoid, haptoglobin and fibrinogen.
The term “acute-phase reactants” (AP-reactants) is generally considered to refer to protein components of plasma whose concentration is significantly increased in the acute phase of inflammatory processes. This category includes several proteins with various physicochemical properties (Table 4.1) and biological functions, but at least two common features may be ascribed to them: almost all contain significant amounts of carbohydrates and all are synthesized in liver parenchymal cells. Hence AP-reactants may be defined as trauma-inducible liver-produced plasma glycoproteins.
Serum amyloid A proteins (SAA), presumed precursors of the tissue amyloid A proteins (AA) characteristic of secondary amyloidosis, have been isolated from the plasma high-density lipoproteins (HDL) of normals after etiocholanolone-induced inflammation and from patients with Wegener's granulomatosis, systemic lupus erythematosis, juvenile rheumatoid arthritis, Waldenstrom's macroglobulinemia, and Goodpasture's syndrome. At least six polymorphic forms of SAA wer identified among the low molecular weight proteins of HDL, and these comprosed up to 27% of the total HDL protein. Gel and ion-exchange chromatography permitted isolation of the SAA polymorphs in homogeneous form. Their amino acid compositions were very similar, they were indistinguishable in cationic and sodium dodecyl sulfate-polyacrylamide gel electrophoresis systems, and each had the terminal sequency COOH-Tyr-Lys-Phe-. Charge heterogeneity in anionic-urea polyacrylamide gel electropherograms was unaffected by neuaminidase treatment, and none of the SAA protein bands stained with the periodate-Schiff reagent. The two major SAA polymorphs, designated SAA4 and SAA5 according to their order of elution from DEAE-cellulose, had different NH2-terminal sequences. Manual Edman degradation demonstrated NH2-arg-ser-phe-phe- for SAA4 and NH2-ser-phe-phe- for SAA5. This NH2-terminal heterogeneity corresponds to that most frequently reported for AA and suggests that microheterogeneity in SAA may underlie that already documented in AA. Sufficient quantitites of the other SAA polymorphs were not available for similar analyses, but the amino acid compositions do not indicate that NH2-terminal heterogeneity accounts for all of the observed polymorphism. Artifactual polymorphism also appears unlikely, and the heterogeneiy of SAA may reflect origin from more than one cell type with or without posttranslational modificaton. We calculate from quantitative COOH-terminal analyses that SAA is of 11,000-11,900 mol wt. Primary structure studies have shown AA t be a single chain protein of 76 residues, and SAA, therefore, appears to contain a peptide of 33 amino acids that is missing from AA.
Female protein (FP), a serum protein present in normal female hamsters was found to be similar to acute-phase reactant, C-reactive protein (CRP) and serum amyloid P component (SAP) in the following ways: (a) hamster FP complexed with phosphorylcholine (PC) in a Ca++-dependent fashion as shown by its isolation from serum by affinity chromatography with PC-Sepharose and selective elution with free PC or EDTA; (b) electron microscopy of FP indicated a pentameric structure similar in size and appearance to other pentraxins; (c) the parent molecule of FP (150,000 mol wt) was composed of five noncovalantly assembled subunits of 30,000 mol wt; and (d) the amino acid analysis and terminal NH2 sequence of FP clearly showed homology with SAP-CRP. Although FP evolved from an ancestral gene common to SAP and CRP, and shares functional, morphological and structural properties with these acute-phase proteins, the biological homology of FP appears quite diverse as this protein is a prominent serum constituent (1-2 mg/ml) of normal female hamsters and under hormonal control (testosterone suppression) in males.
Using tissue-culture techniques, peripheral blood lymphocytes obtained from all patients undergoing various types of major operations have been found to develop depressed immunological competence as reflected by their diminished ability, under maximal stimulation with phytoæmagglutinin, to incorporate 14C-thymidine and synthesise D.N.A. More important, however, was the observation that this biosynthetic defect was most severe in lymphocytes harvested from individuals with heart-disease and cancer. The clinical significance of this abnormality measured in vitro may be reflected by postoperative infectious-mononucleosis-like syndromes, especially in patients with cardiovascular disorders, and the acceleration of metastasis which often takes place postoperatively in patients with carcinoma.
Rho, a newly characterized acute-phase protein, was present in high titer in a group of 109 patients with various rheumatic diseases. Statistically significant titer elevations were demonstrated in patients with rheumatoid arthritis (RA), ankylosing spondylitis, and gout. In individual RA patients, serial titers failed to correlate with disease activity or with rheumatic seropositivity. The natural behavior ofrho antigen is contrasted with that of C-reactive protein. Comments are made regarding the possible association of rubella infection with rheumatoid arthritis.
To assess the importance of disease-induced increases in plasma concentrations of alpha1 acid glycoprotein (an acute-phase plasma protein that binds cationic drugs), we determined binding of propranolol in plasma from 53 patients and 25 healthy volunteers. Binding was increased in 10 patients with Crohn's disease (P less than 0.002), nine with inflammatory arthritis (P less than 0.002) and eight with chronic renal failure with superimposed inflammatory disease (P less than 0.01) as compared with healthy controls. The plasma binding of control subjects did not differ from that of 12 patients with chronic hepatic disease (P greater than 0.45) or 14 with uncomplicated renal failure (P greater than 0.80). Chlorpromazine binding, determined in 60 subjects, yielded similar results. Percentage of free drug and alpha1 acid glycoprotein concentration were inversely correlated (r = -0.77 with propranolol, P less than 0.001, and r = -0.69 with chlorpromazine, P less than 0.001). Increases in plasma protein binding in patients with inflammatory disease appear mediated by increases in alpha1 acid glycoprotein concentration, which may influence drug kinetics.
An increase in the concentration of the acute-phase reactant, serum amyloid A (SAA), following endotoxin treatment, is a consequence of the action of lipopolysaccharide (LPS) on macrophages to produce a monokine, the SAA inducer, which in turn, triggers SAA synthesis by hepatocytes. We have found that murine SAA inducer is closely related, if not identical, to murine lymphocyte activating factor (LAF), otherwise known as Interleukin 1 (IL 1). Furthermore, both rabbit endogenous pryrogen (EP), which is believed to be identical to LAF (IL 1), and human LAF (IL 1), induced elevated SAA concentrations in C3H/HeJ mice. Antiserum previously shown to block both pyrogenic and thymocyte proliferating activities of the species of rabbit EP exhibiting an isoelectric point of pH 7.3 (EP 7), also blocked the SAA inducing activity of EP7. Phenylglyoxal treatment of highly purified murine LAF (IL 1) abrogated both thymocyte proliferating activity and the SAA inducing activity. These studies support and extend previous reports suggesting that within 2 hr of an inflammatory stimulus, macrophages produce a monokine that acts systemically to alter body temperature, activate T cells, and induce hepatic protein synthesis of acute-phase reactants.
1.1. The “acute phase” responses, following surgical trauma, of C-reactive protein, orosomucoid, haptoglobin, the α1-acid glycoprotein of Schultze, fibrinogen, ceruloplasmin and the α2-macroglobulin were investigated in parallel. Of these 7 proteins only the α2-macroglobulin consistently fails to rise following surgery.2.2. The speed and duration of responses of the different proteins was independent, and the relative amplitude of the responses of the different proteins varied from patient to patient.3.3. Changes in individual proteins, estimated immunochemically, were greater than changes in electrophoretic analyses.4.4. C-reactive protein, unique in being undetectable in normal sera, is most consistent in response and is therefore probably the most satisfactory single screening test of an “acute phase” reaction.
Modification in the enzymatic complement and lipogenic functions of rat liver endoplasmic reticulum (ER) were shown to occur during pneumococcal sepsis. Glucose-6-phosphatase, 5'nucleotidase, esterase, and NADPH cytochrome C reductase decreased in activity by as much as 50% with respect to controls. Hydroxymethylglutaryl-CoA and NADH cytochrome C reductases were increased 6-and 2-fold, respectively. Alkaline phosphatase and inosine-5'-diphosphatase did not differ with respect to fasted controls. The lipogenic capacity of the ER was shown to be enhanced. In vitro [14C]acetate incorporation into cholesterol and other lipids by hepatocytes isolated from infected rats was increased 2-to 10-fold. It is concluded that the flow of acetyl-CoA in liver cell of Streptococcus pneumoniae-infected rats is toward lipogenesis rather than ketogenesis.
The effects of intravenously administered rat alpha1 macroglobulin (alpha1M), alone and in combination with pancreatic trypsin, on the synthesis of alpha1 acute-phase globulin (alpha1AP globulin) have been measured in the isolated perfused rat liver 24 h after injection. Maximum promotion (approximately five-fold) of alph1AP globulin synthesis was observed after administration of alpha1M complexed with trypsin or alpha1M alone, which after purification had lost most of its trypsin-protein-esterase (T.P.E.) activity. Slightly lesser but still significant degrees of enhancement (approximately four-fold) of alpha1AP globulin synthesis resulted from the injection of alpha1M alone or complexed with trypsin, which after purification had retained sitnificant T.P.E. activity. All these responses were greater than those generated by injection of trypsin or plasma alone, or rabbit plasma complexed with trypsin. However, the synthetic response did not reach the maximum rate observed 24 h after an intramuscular injection or sterile turpentine. An hypothesis is proposed for the role of alpha1 macroglobulin (and its homologue in man, alpha2 macroglobulin) in the mediation of the acute-phase synthetic response by the liver. This predominantly intravascular glycoprotein serves as the principal circulatory porteinase binder. Proteinases released in response to tissue injury, necrosis or inflammation would be bound and inactivated by alpha1M, and in turn the alpha1M-proteinase complex would stimulate the liver to synthesize a number of acute-phase proteins. Certain of these, e.g. alpha2 acute-phase globulin also possess proteinase binding activity and, being of low molecular weight, would be more effective than alpha1M in the inactivation of released tissue enzymes at extravascualr sites. The data presented in this paper are compatible with this biphasic role for plasma proteinase inhibitors in the biological response to injury.
The effect of acute disease and ACTH infusion on serum zinc proteins was studied in serums from 156 healthy and diseased subjects. The mean (+/-2 S.D.) zinc content of 20 normal serums was 96 +/- 20 microng per 100 ml. In 87 serums from acutely ill patients the zinc ranged from 92 to 40 microng per 100 ml. The mean values for nearly all categories of disease studied were lower than normal (P is less than 0.001). Chromatography of normal serum on Sephadex G-100 separates two protein fractions, I and II, containing 37.8+/-8.8 and 76+/-10 microng of zinc per 100 ml, respectively. In serum from diseased patients the zinc in fraction I is unaltered whereas that in fraction II decreases to 29.8+/-7.5 microng per 100 ml (P is less than 0.001). ACTH administration reduces secrum zinc from 10 to 60 microng per 100 ml, the decrements being due to changes in the zinc content of fraction II. Thus, ACTH may have an important role in the reduction of zinc content associated with pathologic states.
Refractoriness to Gal N toxicity occurs especially in fetal rats, newborn rats, and in rats after partial hepatectomy. An injury however (laparotomy, incision on the back or ip BaSO4 suspension), prior to Gal N administration, also inhibits Gal N toxicity. In all these circumstances high levels of rat α2-macrofetoprotein (αMFP) occur. This protein is an acute phase reactant and is identical to rat α2-macroglobulin. αMFP isolated from the serum of injured rats and then administered to normal rats strongly inhibits Gal N toxicity. When time interval between the preceding injury, provoking αMFP production and Gal N administration shortens, the inhibiting effects are less and αMFP production remains low.During resistance to Gal N, the primary and secondary biochemical lesions of Gal N persist and the protecting effect of αMFP must be due to another mechanism, operating in later phases of cell injury. Very probably this is attributable to the stabilizing effect on membranes of hepatocytic organelles and the plasma membranes. As αMFP is an acute phase reactant the importance of these proteins to the course of hepatitis must be considered.
Studies were performed to determine the effects of septicemia on complement levels and activities and opsonic function in septic and nonseptic burned patients. None of the nonseptic burned patients had consumption of classical pathway activity during their clinical course. Patients who did not survive septicemia had consumption of all of the classical complement components (C1-C5) prior to and during their septic episodes. Patients who survived septicemia had multiple patterns of classical complement pathway consumption. In these patients, classical pathway activity was restored to normal following the last positive blood culture. Alternative complement pathway consumption was demonstrated in only one of the septic burned patients, as evidenced by decreased factor B and C3b INA levels and decreased C3 and C5 conversion in sera treated with 10 mM ethylene glycol tetraacetic acid and 10 mM MgCl(2) (MgEGTA) and in untreated sera. In all of the other septic patients and in the nonseptic patients, reduction in C3 and C5 conversion in MgEGTA sera and untreated sera was not associated with decrease in factor B or C3b INA. Reduction in complement levels and activities did not reduce the ability of the patients' sera to promote phagocytosis and intracellular killing of their infecting micro-organisms by normal human peripheral polymorphonuclear leukocytes. The results indicate that measurement of classical pathway activity in burned patients can be used as a diagnostic tool for predicting the severity of septic episodes and for monitoring recovery. In addition, the observation that complement consumption did not reduce the opsonic capacity of the patients' sera for their infecting micro-organisms suggests that current concepts regarding the role of immunoglobulins and complement in opsonization of opportunist micro-organisms require re-evaluation.
Cholestatic jaundice is one complication of nonhepatic gram-negative bacterial infection. The endotoxin of Escherichia coli has been reported to cause cholestasis by inhibiting the bile salt-independent fraction (BSIF) of bile in the perfused rat
liver. Accordingly, the effects of lipopolysaccharides (LPS) of E. coli and Salmonella enteritidis on the Na+, K+-adenosinetriphosphatase (ATPase) in canalicular-enriched plasma membranes of rat liver were examined. At 20 μg/ml, both endotoxins
inhibited this enzyme by ∼40%. Maximal inhibition (70%–80%) occurred at concentrations of ⩾120 μg/ml. The LPS of neither organism
exerted any effect on the activity of Mg++-ATPase or 5′-nucleotidase in the same preparations. Inhibition by the E. coli LPS appeared to be noncompetitive in nature, and the calculated Ki was 45 μg/ml. Since the Na+, K+-ATPase may be responsible
for the elaboration of BSIF, inhibition of this enzyme could be the underlying mechanism for the endotoxin- induced cholestasis.
The high incidence of fatal septicemia associated with severe thermal injury is believed to result from a loss of immunocompetence. To detect burn-mediated immune defects, lymphocyte function in peripheral blood leukocytes from 18 individuals sustaining 20-80% full thickness thermal burns was investigated. We examined the kinetics of the mitogen responses, the development of suppressive activity, and the correlation of mononuclear cell functional abnormalities with the incidence of sepsis. Patients were divided into three groups corresponding to their clinical course. The phytohemagglutinin responses of Ficoll-Hypaque purified leukocytes from eight of these patients (group III) were normal at day 1-2 after injury, but were significantly depressed (mean 16% of normal) at days 5-10 after injury. All of these group III patients experienced multiple, severe, septic episodes, and septic mortality was 75%. The other 10 burned individuals showed either augmented (group II) or unaltered (group I) mitogen responsiveness. Concomitant with evaluation of their mitogen responses, the cells of burn patients were assessed for development of suppressive activity by addition to on-going normal mixed leukocyte reactions (MLR). Only the addition of mononuclear cells with depressed phytohemagglutinin responsiveness (group III) significantly decreased MLR proliferation (mean 80% reduction) by the previously highly responsive, normal MLR combinations. Addition of cells from group III burn patients collected immediately after injury had no suppressive effect. Addition of cells from patients in group I or II or of normal individual's cells had no suppressive effect. These experimental results strongly suggest that a suppressive mononuclear cell is at least partially responsible for the decreased immunocompetence of burn patients.
Biochemical and morphometric analysis reveal that the peroxisomal content of rat liver cells is markedly reduced during pneumococcal sepsis. It is suggested that during some bacterial infections, hepatic synthesis of acute phase serum proteins occurs at the expense of peroxisomal protein synthesis and results in reduction of the peroxisomal protein pool and number of peroxisomes. This finding is of interest since others have reported increases in hepatic cholesterol and triglycerides in D. pneumoniae infected animals. This inverse relationship between hepatic peroxisomal content and lipid metabolism in infection is analogous to the known relation between liver peroxisome proliferation and drugs which lower serum cholesterol and triglycerides.
Fever appears to have evolved in vertebrate hosts as an adaptive mechanism for controlling infection. This phenomenon is produced by certain exogenous (largely microbial) stimuli that activated bone-marrow-derived phagocytes to release a fever-inducing hormone (endogenous pyrogen). Endogenous pyrogen, in turn, circulates to the thermoregulatory center of the brain (preoptic area of the anterior hypothalamus) where it causes an elevation in the "set-point" for normal body temperature. Warm blooded animals produced fever by increasing heat production (through shivering) or reducing heat loss (by peripheral vasoconstriction), whereas cold blooded animals do so only by behavioral mechanisms (seeking a warmer environment). This paper discusses current concepts that involve the mechanism of endogenous pyrogen production, the role of central transmittors, and the probable function of fever in combating disease.
LP, a saline extract of exudate-derived rabbit granulocytes, shown to be free of endotoxin contamination by sensitive LAL assay, can elicit brisk acute-phase responses in the rabbit. Following a single large intravenous dose of LP (875 mce) there is a brisk fall in serum iron at 8 hr and marked elevations in concentrations of CxRP, haptoglobin, fibrinogen, and ceruloplasmin and a lesser rise in sialic acid in the blood at 24 hr, which return toward baseline to varying degrees by 48 hr. When the crude LP solution is fractionated by column chromatography on Sephadex G75, all detectable acute-phase mediating activity elutes in a fraction (pool C) which contains all the pyrogenic activity and about 15% of the total eluted protein. Within the limitations of the methods employed, the acute phase stimulating activity and the pyrogenic activity of LP preparations appear to be closely linked.
The serum from 109 traumatized patients was examined for immunosuppressive activity which might explain diminished host immune responsiveness following operative or accidental injury. Twenty-eight fo 31 (90%) severely tralmatized patients, 25 of 60 (42%) moderately traumatized patients, and 0 of 18 minimally traumatized patients developed serum which suppressed the response of normal human lymphocytes to phytohemagglutinin. The degree and duration of serum immunosuppressive activity paralleled the severity of the clinical course but did not correlate with serum cortisol or barbiturate levels. Suppressive sera were not cytotoxic. The immunosuppressive factor(s) was contained in a low molecular weight (less than 10,000 daltons) peptide fraction and was present in 5--10 times the amount recoverable from normal serum. By size and activity the trauma serum factor resembled immunoregulatory alpha globulin, a naturally-occurring serum inhibitor of T-lymphocyte reactions. Thus, depressed immunoreactivity following trauma may be due in part to high concentrations of an endogenous immunosuppressive polypeptide.
Mice infected with a standard challenge of Salmonella typhimurium manifest a number of changes associated with endotoxemia. These changes result in profound alterations in the nutritional and metabolic status of the host. Food and water intake approaches levels of total inanition, blood glucose declines more rapidly than in fasted controls, hepatic phosphoenolpyruvate carboxykinase (the enzyme that is rate limiting in gluconeogenesis) shows diminished activity and loss of cortisol inducibility, and hypothermia, rather than hyperthermia, becomes acute. These changes occur at a time when bacteremia is first demonstrable. This occurs on the 3rd day after infection under the conditions employed. Death occurs in most mice within the next 24 to 48 hr. Mice vaccinated with a highly immunogenic ribosomal preparation and subsequently infected with the standard number of organisms did not manifest the above changes. Other work from this laboratory has established that effects of the type described are elicited by bacterial endotoxin as a result of mediating substances released into the blood by cells of the reticuloendothelial system. Presumably these substances appear in blood of infected mice as well.
The pathogenesis of fever in man begins with the production of endogenous pyrogen by phagocytic leukocytes in response to exogenous pyrogens (toxic, immunologic or infectious agents). Endogenous pyrogen, a protein, is released from a variety of phagocytic leukocytes and enters the circulation after new messenger RNA and protein are synthesized. Fever is caused by an interaction of endogenous pyrogen with specialized receptors on or near thermosensitive neurons in the thermoregulatory center of the anterior hypothalamus. This interaction may cause local hypothalamic production of prostaglandins, monoamines and, possibly, cyclic AMP. From the anterior hypothalamus, information is transmitted through the posterior hypothalamus to the vasomotor center, which directs sympathetic-nerve fibers to constrict peripheral vessels and decrease heat dissipation. Antipyretics, such as aspirin, do not affect production of endogenous pyrogen from leukocytes but, rather, interfere with prostaglandin synthesis in the hypothalamus - probably an early step in initiation of fever.
A short summary of some aspects of the history of clinical fever is presented with special reference to its association with inflammation. The role of bacterial endotoxins and endogenous pyrogen (released from inflammatory cells) in the genesis of human fevers is reviewed. Clinical diseases are tabulated within various broad categories and discussed in relation to the frequency with which they are associated with fever and the probable pathogenetic mechanisms involved. Certain unresolved discrepancies are emphasized in the light of our present knowledge.
During the past half century, research and clinical observations have revealed a vigorous competition for growth-essential iron between bacterial, fungal, and protozoan pathogens and their vertebrate hosts. The latter possess an array of mechanisms (collectively termed nutritional immunity) to withhold iron; the ability of microorganisms to overcome these mechanisms is an important component of virulence. Various aspects of nonspecific and immune defenses are impaired in severely iron-deficient hosts, whereas nutritional immunity is stressed in a diversity of conditions of iron overload. A number of possible methods and agents for suppressing or enhancing various facets of the influence of iron on infection are now apparent. Research is needed to determine which of these might be safe, efficacious, and practical.
During infections in man the pattern of change in individual plasma free amino acids is markedly different from that observed in simple starvation. Plasma phenylalanine and tryptophan are both increased in bacterial or viral infections. This increase is correlated with an accelerated rate of release of these amino acids from skeletal muscle. Alanine is also released in increased amounts by skeletal muscle but is utilized rapidly by liver for gluconeogenesis to meet the accelerated rates of glucose turnover and oxidation in the infected host. The rate of release of the branched chain amino acids from the muscles of infected rats is decreased, which results in depression of their plasma concentrations. These data have been interpreted to suggest that during infection, protein catabolism in skeletal muscle is increased and amino acids such as those of the branched chain group are utilized as energy sources or for the synthesis of alanine or glutamine. Those amino acids, such as phenylalanine and tryptophan, which cannot be metabo- lized in skeletal muscle are released in elevated amounts, as are alanine and glutamine, which have been synthesized from other amino acids. The alanine is rapidly taken up by the liver and utilized as a substrate for gluconeogenesis. Because the infected host has an impaired ability to develop starvation ketosis, it continues to break down muscle protein as a source of energy and substrates for glucose synthesis. Am. J. Clin. Nutr. 30: 1269-1280, 1977.
This review describes the scope, complexity, and magnitude of host nutritional responses throughout the course of an infectious process. These responses include prominent changes in nitrogen and protein metabolism, altered rates of carbohydrate and lipid production and utilization, and changes in mineral, electrolyte, trace element, and vitamin metabolism. It is postulated that these responses develop in a relatively predictable sequence which is influenced by the adequacy of host antimicrobial defense mechanisms, the severity and duration of illness, and specific localization of an infectious process within the body. In addition to hormonal regulatory effects, the metabolic and nutritional responses of the host are also influenced by biologically active substances released when host cells participate in phagocytic activity and local inflammatory responses.
Trauma and shock result in activation of a wide variety of endocrine and metabolic systems. Based upon experimental work demonstrating metabolic deficits, a variety of metabolic therapies have been developed to assist in the treatment of patients with shock or trauma. Evidence to date is inconclusive as to whether this therapy will be of significant benefit to critically ill patients. Some of the senior author's previous research has been analyzed as it relates to important health policy issues. We suggest that a peer review mechanism be set up within organized professional groups to assess major research trends and develop informed opinions on key research subjects within their domain. These peer review assessments must be effectively communicated to Congress and the executive branch of the government, as well as to the general public, if support commensurate with the importance of the research is to be achieved.
The effect of intravenous injection of particulate inulin on CRP synthesis and serum C3 levels was studied in 13 rabbits. The rabbits showed a significant increase in serum CRP levels 24 hr after inulin injection, when compared to pretreatment levels and controls. There was a significant reduction in serum C3 levels in the treated animals at 4 hr.
Recent evidence indicates that hypersensitivity reactions, produced in rats by the administration of a protein antigen, alters plasma zinc and iron homeostasis by depressing concentrations of these trace minerals. Studies were performed to determine if altered zinc homeostasis involves, in part, enhanced hepatic metallothionein (MT) synthesis. MT, a high cysteine-containing cytoplasmic protein, possesses a high affinity for zinc and other heavy metals and has been implicated in zinc homeostasis.
Fibrinogen synthesis in rabbits was evaluated following intravenous infusions of stage 3 degradation products of homologous fibrinogen or fibrin, prepared in vitro. Fibrinogen production was measured by determining the rate of appearance of 75SeM into circulating fibrinogen. Fibrinogen synthesis increased threefold after the administration of stage 3 FDP (D and E), dialyzed to remove LMW digestion fragments, In contrast, the fdp obtained by plasminolysis of crosslinked thrombin clots or of noncrosslinked ancrod or thrombin clots failed to enhance basal fibrinogen production. Accelerated fibrinogen production was not accompanied by alterations in haptoglobin concentration or by increased incorporation of 75SeM into haptoglobin. Fibrinogen synthesis was not increased after infusions of FPA and FPB.
Sera from 38 of 72 burn patients have been found to be significantly suppressive to the PHA-induced blastogenesis of normal human lymphocytes in culture. In many of these patients, we have observed that suppression levels decline with recovery. In a study of eight of these patients, we have found that the addition of post recovery serum to cultures of normal lymphoyctes blocked the suppressive effect of autologous serum obtained earlier. Blocking appears to be achieved through the formation of antibodies since: a) IgG levels are greatly elevated in serum samples having blocking activity, b) the time of appearance of blocking substances in the serum is compatible with the generation of antibody, and c) blocking activity is contained in the protein-A isolated IgG fraction of such post recovery serum.
1. The effects of bacterial infection and temperature on serum iron levels were investigated in the lizard Dipsosaurus dorsalis. 2. Changes in body temperature from normal (38 degrees C) to febrile (41 degrees C) did not alter serum iron levels. Injection with Aeromonas hydrophila led to a significant reduction in serum iron levels, comparable to that found in mammals. This reduction in serum iron level was independent of the lizard's body temperature. 3. When grown in vitro, A. hydrophila grew equally well at afebrile (38 degrees C) and febrile (41 degrees C) temperatures. When the iron levels of the growth medium were reduced, the bacterial growth was diminished at the febrile temperature but was not significantly affected at the afebrile temperature. 4. The addition of iron supplements to bacterially infected lizards led to an increase in the percent mortality. 5. These results indicate that one of the mechanisms behind the beneficial, or adaptive value of fever in D. dorsalis is the decrease in iron available to the pathogenic micro-organisms.