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Atherosclerosis – An Inflammatory Disease
Abstract
The advanced lesions of atherosclerosis represent the culmination of a specialized form of chronic inflammation followed by a fibroproliferative process that takes place within the intima of the affected artery. Proliferation of smooth muscle cells and generation of connective tissue occur. Proliferation results from interactions between arterial smooth muscle, monocyte-derived macrophages, T lymphocytes, and endothelium. The initial lesion of atherosclerosis, the fatty streak, begins as an accumulation of monocytederived macrophages and T lymphocytes, which adhere and migrate into the intima of the affected artery. Smooth muscle cells, which are present in the intima or which migrate into the intima from the media, then replicate. Monocyte-derived macrophages and T cells also replicate during lesion formation and progression due to the production of cytokines and growth-regulatory molecules. These molecules determine whether there is proliferation and lesion progression or inhibition of proliferation and lesion regression. Several growthregulatory molecules may play critical roles in this process, including platelet-derived growth factor (PGDF), transforming growth factor beta, fibroblast growth factor, heparinbinding epidermal growth factor-like growth factor, and others. PDGF may be one of the principal components in this process because protein containing the PDGF B-chain has been demonstrated within activated lesion macrophages during every phase of atherogenesis. The presence of this growth factor and its receptors on lesion smooth muscle cells creates opportunities for smooth muscle chemotaxis and replication. Smooth muscle proliferation depends upon a series of complex signals based upon cellular interactions in the local microenvironment of the artery. The intracellular signalling pathways for mitogenesis versus chemotaxis are being investigated for smooth muscle. The roles of the cytokines and growth-regulatory peptides involved in these cellular interactions represent critical points of departure for intervention and the development of new diagnostic methods. In addition, magnetic resonance imaging has been developed to demonstrate the fine structure of lesions of atherosclerosis in peripheral arteries not subject to cardiac motion. This noninvasive methodology holds great promise for the future of these approaches.
... The scientific hypothesis of atherosclerosis has evolved from simple hyperlipidemia (lipid hypothesis) to a complex pathological process that includes not only lipid abnormalities but also endothelial cell (EC) activation and injury, as well as inflammatory processes that regulate the occurrence and progression of lesions [3,4]. The initiation of atherosclerosis is commonly attributed to endothelial damage, inflammation, and dysfunction [5][6][7]. Therefore, gaining insight into the molecular mechanisms that govern endothelial injury and dysfunction is crucial for comprehending and advancing novel therapeutic strategies aimed at preventing or treating atherosclerotic cardiovascular and cerebrovascular diseases. ...
... As a vital structure of the vascular system, ECs play a crucial role in regulating vascular permeability and maintaining vascular homeostasis [8]. Hyperglycemia, hyperlipidemia, reactive oxygen species (ROS), blood flow shear stress, cytokines (e.g., TGFβ), and endotoxin biochemical stimulus are the main factors leading to endothelial inflammation and dysfunction [6,7]. Endothelial-to-mesenchymal-transition (EndMT) is the type of endothelial inflammation and dysfunction in which endothelial cells lose their markers and functions and acquire mesenchymal cell markers and functions [9]. ...
... EndMT has been involved in human and experimental atherosclerosis [16]. EndMT-derived fibroblasts infiltrate atherosclerotic lesions and secrete matrix metalloproteinase [6,19], leading to the progression and destabilization of atherosclerotic plaques. TGFβ1 was considered the main EndMT inducer [16,19,20]. ...
A R T I C L E I N F O Keywords: Adenosine receptor 2 A Endothelial to mesenchymal transition Atherosclerosis ALK5 CREB A B S T R A C T Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and morbidity and mortality rates continue to rise. Atherosclerosis constitutes the principal etiology of CVDs. Endothelial injury, inflammation, and dysfunction are the initiating factors of atherosclerosis. Recently, we reported that endothelial adenosine receptor 2 A (ADORA2A), a G protein-coupled receptor (GPCR), plays critical roles in neovascularization disease and cerebrovascular disease. However, the precise role of endothelial ADORA2A in atherosclerosis is still not fully understood. Here, we showed that ADORA2A expression was markedly increased in the aortic endothelium of humans with atherosclerosis or Apoe-/-mice fed a high-cholesterol diet. In vivo studies unraveled that endothelial-specific Adora2a deficiency alleviated endothelial-to-mesenchymal transition (EndMT) and prevented the formation and instability of atherosclerotic plaque in Apoe-/-mice. Moreover, pharmacologic inhibition of ADORA2A with KW6002 recapitulated the anti-atherogenic phenotypes observed in genetically Adora2a-deficient mice. In cultured human aortic endothelial cells (HAECs), siRNA knockdown of ADORA2A or KW6002 inhibition of ADORA2A decreased EndMT, whereas adenoviral overexpression of ADORA2A induced EndMT. Mechanistically, ADORA2A upregulated ALK5 expression via a cAMP/PKA/CREB axis, leading to TGFβ-Smad2/3 signaling activation, thereby promoting EndMT. In conclusion, these findings, for the first time, demonstrate that blockade of ADORA2A attenuated atherosclerosis via inhibition of EndMT induced by the CREB1-ALK5 axis. This study discloses a new link between endothelial ADORA2A and EndMT and indicates that inhibiting endothelial ADORA2A could be an effective novel strategy for the prevention and treatment of atherosclerotic CVDs.
... 47,48 Very LDL is an apolipoprotein B (apoB)-containing lipoprotein, which, along with LDL and intermediate-density lipoprotein, plays a significant role in the development of atherogenic plaques. 18,49 The diameter of these apoB-containing lipoproteins is small enough for them to pass freely into the endothelial intima of blood vessels where, in the presence of endothelial damage or dysfunction, they may be taken up by macrophages. 49 This leads to further inflammation and endothelial smooth muscle cell proliferation and the development of atherosclerotic plaques typical of CHD. ...
... 18,49 The diameter of these apoB-containing lipoproteins is small enough for them to pass freely into the endothelial intima of blood vessels where, in the presence of endothelial damage or dysfunction, they may be taken up by macrophages. 49 This leads to further inflammation and endothelial smooth muscle cell proliferation and the development of atherosclerotic plaques typical of CHD. 49 In contrast to this direct effect, a larger VLDL diameter is associated with greater CVD risk, 19,20 potentially via modification to other lipoproteins. ...
... 49 This leads to further inflammation and endothelial smooth muscle cell proliferation and the development of atherosclerotic plaques typical of CHD. 49 In contrast to this direct effect, a larger VLDL diameter is associated with greater CVD risk, 19,20 potentially via modification to other lipoproteins. Large VLDL particles, rich in triglycerides, may potentially play a role in the development of CHD through mechanisms such as increased formation of highly atherogenic sdLDL 50 and increased catabolism of HDL. ...
Background and aims
Reduced muscle mass and strength is frequently associated with both alterations in blood lipids and poorer cardiometabolic outcomes in epidemiological studies; however, a causal association cannot be determined from such observations. Two-sample Mendelian randomization (MR) was applied to assess the association of genetically determined appendicular lean mass (ALM) and handgrip strength (HGS) with serum lipid particle diameter.
Methods
MR was implemented using summary-level data from the largest genome-wide association studies (GWAS) on ALM (n = 450,243), HGS (n = 223,315) and lipoprotein (LDL, VLDL and HDL) particle diameters (n = 115,078). Inverse variance weighted method (IVW) was used to calc ulate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out method were applied as sensitivity analysis.
Results
Greater ALM had a statistically significant positive effect on HDL particle diameter (MR-Egger: β=0.055, SE = 0.031, p = 0.081; IVW: β=0.068, SE = 0.014, p < 0.001), and a statistically significant negative effect on VLDL particle diameter (MR-Egger: β= −0.114, SE = 0.039, p = 0.003; IVW: β= −0.081, SE = 0.017, p < 0.001). Similarly, greater HGS had a statistically significant positive effect on HDL particle diameter (MR-Egger: β=0.433, SE = 0.184, p = 0.019; IVW: β=0.121, SE = 0.052, p = 0.021), and a statistically significant negative effect on VLDL particle diameter (MR-Egger: β=−0.416, SE = 0.163, p = 0.011; IVW: β=−0.122, SE = 0.046, p = 0.009). There was no statistically significant effect of either ALM or HGS on LDL particle diameter.
Conclusions
There were potentially causal associations between both increasing ALM and HGS, and increasing HDL particle size and decreasing VLDL particle size. These causal associations may offer possibilities for interventions aimed at improving CVD risk profile.
... CRP (CRP), a sensitive inflammatory marker, is thought to represent a chronic low-grade inflammatory state of the arterial vessel wall at the atherosclerotic sites. [21,22] CRP is found in the vessel wall, where it induces endothelial cell expression of the adhesion molecules vascular adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1) and acts as a chemoattractant for monocytes. [23] CRP binds to damaged cell plasma membranes and activates complement via the classical pathway, and an intact complement system appears to be critical for the maturation of atherosclerotic lesions. ...
... [26] All of these symptoms point to progressive endothelial inflammation and atherosclerosis. [21] CRP may play a direct role in the vascular disease process in addition to being a biomarker of inflammation and vascular health. The pathophysiologic explanations for an increase in CRP in hypertensive people can differ. ...
A BSTRACT
Background
Hypertension is known to be one of the major causes of the global burden of many diseases. It is proving to be a critical medical and public health issue. Previous studies have drawn inconsistent conclusions about the risk of hypertension and its association with gamma-glutamyl transferase and C-reactive protein (CRP). CRP is a marker of systemic inflammation and has been postulated to increase the risk of hypertension. Gamma-glutamyl transferase catalyzes the transfer of gamma-glutamyl functional groups from molecules such as glutathione to an acceptor that may be an amino acid, a peptide, or water. This study was undertaken to evaluate gamma-glutamyl transferase and CRP in essential hypertension and determine the association of these parameters with hypertension, if any.
Materials and Methods
A total of 104 subjects (52 hypertensive cases and 52 healthy controls) between the ages of 30 and 50 were recruited after imposing certain inclusion and exclusion criteria. Gamma-glutamyl transferase and CRP were estimated using commercially available kits. All the data were tested at a 5% level of significance.
Results
Mean levels of gamma-glutamyl transferase and CRP were found to be significantly increased in patients with essential hypertension compared to controls. Elevated levels of gamma-glutamyl transferase and CRP are associated with oxidative stress and inflammation, which are in turn considered to be major factors involved in the pathogenesis of hypertension.
Conclusion
In conclusion, our study suggests that gamma-glutamyl transferase and C-reactive protein are independently associated with hypertension.
... Atherosclerosis, the hardening of the arteries, is a life-threatening contributor to coronary artery diseases (CAD) that affects more than 3 million people in the U.S per year. During atherosclerosis, fatty deposits of cholesterol, fibrin, fats, and waste products build up inside the arterial wallet at the site of damaged inner lining of the artery [1]. Specifically, the cholesterol builds up in the damaged endothelium, called fatty streak, where the cholesterol can become oxidized. ...
... Increased inflammation in the plaque resulting in activation of various inflammatory mediators including toll-like receptors, triggering receptor expressed on myeloid cells, and receptor for advanced glycation end-products and secretion of high mobility group box protein (HMGB)-1 and S100 proteins contribute to plaque vulnerability. These vulnerable plaques can rupture, forming a blood clot in the artery to reduce the blood and oxygen supply to the vital organs [1][2][3][4][5][6][7][8]. During plaque development, the vascular smooth muscle cells (VSMC) within the arterial wall migrate towards the intimal layer to the surface of the plaque and contribute to the formation of a fibrous cap covering the plaque. ...
Atherosclerosis, a critical contributor to coronary artery diseases, involves the accumulation of cholesterol, fibrin, and lipids within arterial walls, inciting inflammatory reactions culminating in plaque formation. This multifaceted interplay encompasses excessive fibrosis, fatty plaque development, vascular smooth muscle cell (VSMC) proliferation, and leukocyte migration in response to inflammatory pathways. While stable plaques demonstrate resilience against complications, vulnerable ones, with lipid-rich cores, necrosis, and thin fibrous caps, lead to thrombosis, myocardial infarction, stroke, and acute cerebrovascular accidents. The nuanced phenotypes of VSMCs, modulated by gene regulation and environmental cues, remain pivotal. Essential markers like alpha-SMA, myosin heavy chain, and calponin regulate VSMC migration and contraction, exhibiting diminished expression during VSMC de-differentiation and proliferation. p27kip, a CDK inhibitor, shows promise in regulating VSMC proliferation and appears associated with TNF-α-induced pathways impacting unstable plaques. Oncostatin M (OSM), an IL-6 family cytokine, correlates with MMP upregulation and foam cell formation, influencing plaque development. Efforts targeting mammalian target of rapamycin (mTOR) inhibition, notably using rapamycin and its analogs, demonstrate potential but pose challenges due to associated adverse effects. Exploration of the impact of p27kip impact on plaque macrophages presents promising avenues, yet its complete therapeutic potential remains untapped. Similarly, while OSM has exhibited potential in inducing cell cycle arrest via p27kip, direct links necessitate further investigation. This critical review discusses the role of mTOR, p27kip, and OSM in VSMC proliferation and differentiation followed by the therapeutic potential of targeting these mediators in atherosclerosis to attenuate plaque vulnerability.
... The oxidation of LDL in the subendothelial space is thought to play a causative role in the development of atherosclerotic plaques (1,23). Hence, antioxidants such as vitamin E gained a lot of attention as potential therapeutic compounds to treat atherosclerosis. ...
... Previous reports have demonstrated that α-tocopherol inhibits the expression of adhesion molecules such as ICAM-1 and VCAM-1 (28,29,37). Upregulation of adhesion molecules by endothelial cells is an important event in early lesions, as they stimulate monocyte infiltration in the lesion (1,23). ...
The impact of α-tocopherol on atherosclerosis is unclear and controversial. While some studies suggest potential benefits, such as antioxidant properties that may reduce oxidative stress, other research indicates no significant preventive effects. The intricate interplay of various factors, including dosage, individual differences, and study methodologies, contributes to the ongoing uncertainty surrounding α-tocopherol’s role in atherosclerosis. Further research is needed to clarify its impact and establish clearer guidelines. Therefore, we aimed to evaluate the impact of α-tocopherol on atherogenesis in ApoE-/- fibrillin (Fbn)1C1039G/+ mice, which is a unique mouse model of advanced atherosclerosis with typical features such as large necrotic cores, high levels of inflammation and intraplaque neovascularization that resemble the unstable phenotype of human plaques. ApoE-/- Fbn1C1039G+/- mice were fed a western-type diet (WD) supplemented with a high dose of α-tocopherol (500 mg/kg diet), while control mice were fed a WD containing a low dose of α-tocopherol (50 mg/kg diet). The high dose of α-tocopherol reduced plaque thickness and necrotic core area in the right common carotid artery (RCCA) after 24 weeks WD. Moreover, α-tocopherol decreased plaque formation and intraplaque neovascularization in the RCCA. In addition to its antiatherogenic effect, chronic supplementation of α-tocopherol improved cardiac function in ApoE-/- Fbn1C1039G/+ mice. However, chronic supplementation of α-tocopherol did not decrease lipid peroxidation. On the contrary, α-tocopherol acted as a prooxidant by increasing plasma levels of oxidized LDL and plaque malondialdehyde, an end product of lipid peroxidation. Our data indicate that α-tocopherol inhibits atherogenesis and improves cardiac function independent of its antioxidant properties.
... 4,5 In aortic intimal spaces, binding and internalization of oxidized low-density lipoprotein (oxLDL) by macrophages aided by scavenger receptors like SRA and CD36 generates a feed-forward athero-inflammatory loop resulting in development of lipid-laden foam cells, a critical early event in atherosclerosis. [4][5][6][7][8][9][10][11][12] Cascades of athero-inflammatory events provoked by macrophage foam cells lead to the development of an early fatty streak and eventually the appearance of advanced atherosclerotic plaque. [4][5][6][7][8][9][10][11][12] Subsequently, the development of unstable plaque can trigger thrombosis and heart attack. ...
... [4][5][6][7][8][9][10][11][12] Cascades of athero-inflammatory events provoked by macrophage foam cells lead to the development of an early fatty streak and eventually the appearance of advanced atherosclerotic plaque. [4][5][6][7][8][9][10][11][12] Subsequently, the development of unstable plaque can trigger thrombosis and heart attack. Although currently approved pharmacotherapies for CVD are effective in reducing mortality, a large percentage of patients receiving current therapies still harbour a discernible residual risk of a CVD-linked complication, and show unwanted side effects such as muscle pain and hepatic toxicity. ...
Atherosclerosis, a chronic inflammatory disease of aorta, remains the major cause of morbidity and mortality among cardiovascular disease patients. Macrophage foam cell formation and inflammation are critically involved in early stages of atherosclerosis, hence chemopreventive targeting of foam cell formation by nutraceuticals may be a promising approach to curbing the progression of atherosclerosis. However, many nutraceuticals including berberine and ginkgetin have low stability, tissue/cell penetration and bioavailability resulting in inadequate chemotherapeutic effects of these nutraceuticals. We have used avocado‐derived extracellular vesicles (EV) isolated from avocado (EV Avo ) as a novel carrier of nutraceuticals, in a strategy to alleviate the build‐up of macrophage foam cells and expression of inflammatory genes. Our key findings are: (i) Avocado is a natural source of plant‐derived EVs as shown by the results from transmission electron microscopy, dynamic light scattering and NanoBrook Omni analysis and atomic force microscopy; (ii) EV Avo are taken up by macrophages, a critical cell type in atherosclerosis; (iii) EV Avo can be loaded with high amounts of ginkgetin and berberine; (iv) ginkgetin plus berberine‐loaded EV Avo (EV Avo(B+G) ) suppress activation of NFκB and NLRP3, and inhibit expression of pro‐inflammatory and atherogenic genes, specifically Cd36 , Tnfα , Il1β and Il6 ; (v) EV Avo(B+G) attenuate oxidized low‐density lipoprotein (oxLDL)‐induced macrophage foam cell formation and (vi) EV Avo(B+G) inhibit oxLDL uptake but not its cell surface binding during foam cell formation. Overall, our results suggest that using EV Avo as a natural carrier of nutraceuticals may improve strategies to curb the progression of atherosclerosis by limiting inflammation and pro‐atherogenic responses.
... The progression of the dyslipidemia potentially affects every system of the body and has mechanistic interplay with end organ's diseases, such as neurologic, immunologic, hepatic, cardiovascular and vascular (Go et al. 2013;Goff et al. 2014b;Greenland et al. 2010). For the past 30 years, Mitochondrial damage mediated by endothelium microvascular system has emerged Extended author information available on the last page of the article as a key regulator of vascular homeostasis (Ross 1999a;Vita and Keaney 2002). ...
... From our previous review we acknowledge that the progression of mitochondrial dysfunction starts with the hallmarks of vasculature damage (Stancel et al. 2016). The pathophysiology of mitochondrial dysfunction and damage mediated by LDL, Ox-LDL, and inflammasomes, deposition of lipids and cholesterol constituent on the arterial walls, as shown in Fig. 1 (Ross 1999a;Stancel et al. 2016). Previously, many scientists have suggested that LDL variants such as Ox-LDL, Lp(a) (lipoprotein (a)) and small dense LDL are important constituents for the pathogenesis of atherosclerosis and CVDs (Carmena et al. 2004;Koba et al. 2006;Libby 2002;Witztum and Steinberg 2001). ...
Acceleration of atherogenesis is an aftermath of cardiovascular diseases (CVDs), which arise with mitochondrial dysfunction (MD). Endothelium restraint inflammation, repair and fluidic exchange with nearby tissues. Endothelium-mediated mitochondrial damage can trigger the molecular mechanisms of vasodilation, pro-inflammation and process of pro-thrombotic accumulation in microvascular endothelial layer. The oxidation of lipid particles generates modified lipoproteins. Modification of mitochondrial function recently emerged a great concern towards the atherosclerosis initiation and progression, because the powerhouse of energy production mitochondria mutation can release mtDNA into cytoplasm and it can be act as sensor for viral DNA or foreign DNA. Another cause is mitochondrial imbalance can lead to product excess amount of reactive oxygen species (ROS) which can cause cellular metabolism and respiration system.
In previous some studies showed that mitochondrial dysfunction plays a vital role in term of cardiac diseases. However, very few studies provide evidence of endothelium-mediated mitochondrial imbalance. This study investigated the potential involvement of mitochondrial impairment in cardiotoxicity using a series of mechanistic endpoints, including mitochondrial respiration and endothelial suppression of inflammation, mitochondrial DNA. Our study provides some molecular mechanisms regarding mitochondrial role in endothelium function. In each section, we are trying to introduce key concepts and then analysis previous studies revealed the importance of that molecular mechanism regarding mitochondrial dysfunction.
The ultimate goal of our review is to find out the novel drug discovery or new approaches of therapy. Our review will target different aspects of mitochondrial protein function and their effect of endothelial and cause of atherosclerosis diseases. To evaluate the healthy lifestyle and better condition of mitochondrial balance nowadays it is urgent to utilize the proper function for therapeutical effect for future direction.
... T he vascular endothelium has important roles in the regulation of vascular tone, platelet activity, thrombosis formation, and leukocyte adhesion. [1][2][3][4] Endothelial dysfunction, a state of impairment of these regulatory functions, is regarded as the first step of atherosclerosis; it is observed in patients with coronary risk factors (e.g., hyperlipidemia, hypertension, diabetes mellitus, and cigarette smoking), even in the absence of obvious atherosclerotic lesions. [5][6][7][8] Furthermore, endothelial dysfunction is presumably caused by systemic inflammation and is associated with increased cardiovascular events; it can eventually lead to acute coronary syndrome (ACS). ...
Periodontitis is a common chronic infection and is associated with cardiovascular disease. This study evaluated whether basic oral care for periodontal disease could improve endothelial function in patients with acute coronary syndrome (ACS).
This study enrolled 54 patients with acute coronary syndrome admitted to Kagoshima City Hospital and who had undergone percutaneous coronary intervention. Flow-mediated endothelium-dependent dilatation (FMD) was measured before discharge (initial FMD) and at 8 months after percutaneous coronary intervention (follow-up FMD). The following periodontal characteristics were measured: periodontal pocket depth (PPD, mm), plaque control record (%), and bleeding on probing (%). All patients received basic oral care instructions from dentists. The oral health condition was generally poor in the participants and there were 24 patients (44.4%) who had severe PPD. Despite the intervention of basic oral care, the periodontal characteristics did not improve during the study period; initial FMD and follow-up FMD did not significantly differ (4.38 ± 2.74% versus 4.56 ± 2.51%, P = 0.562). However, the follow-up FMD was significantly lower in patients with severe PPD (≥ 6.0 mm, n = 24) than in patients without severe PPD (≤ 5.0 mm, n = 30) (FMD: 3.58 ± 1.91% versus 5.37 ± 2.67%, P = 0.007). FMD tended to be worse in patients with severe PPD than in patients without severe PPD (ΔFMD: -0.55 ± 2.12 versus 0.81 ± 2.77 %, P = 0.055). In conclusion, during the use of basic oral care, endothelial function improved in patients without severe PPD, while it worsened in patients with severe PPD.
... The occurrence mechanism of LVT after AMI is similar to most thrombus formations and is associated with Virchow's triad, which includes continuous activation of coagulation mechanisms [21], persistent inflammatory state [22], impaired ventricular wall motion [23], and endocardial injury [24]. In our study, we found varied results between ALVT and CLVT. ...
Background
Left ventricular thrombus (LVT) is a serious complication after myocardial infarction. However, due to its asymptomatic nature, early detection is challenging. We aimed to explore the differences in clinical correlates of LVT found in acute to subacute and chronic phases of myocardial infarction.
Methods
We collected data from 153 patients who were diagnosed with LVT after myocardial infarction at the Affiliated Hospital of Qingdao University from January 2013 to December 2022. Baseline information, inflammatory markers, transthoracic echocardiograph (TTE) data and other clinical correlates were collected. Patients were categorized into acute to subacute phase group (< 30 days) and chronic phase group (30 days and after) according to the time at which echocardiograph was performed. The resolution of thrombus within 90 days is regarded as the primary endpoint event. We fitted logistic regression models to relating clinical correlates with phase-specific thrombus resolution.
Results
For acute to subacute phase thrombus patients: C-reactive protein levels (OR: 0.95, 95% CI: 0.918–0.983, p = 0.003) were significantly associated with thrombus resolution. For chronic phase thrombus patients: anticoagulant treatment was associated with 5.717-fold odds of thrombus resolution (OR: 5.717, 95% CI: 1.543–21.18, p = 0.009).
Conclusions
Higher levels of CRP were associated with lower likelihood of LVT resolution in acute phase myocardial infarction; Anticoagulant therapy is still needed for thrombus in the chronic stage of myocardial infarction.
... First, at the onset of AIS, monocytes bind to adhesion molecules on the injured vascular endothelium, migrate to the subendothelial space, mature into macrophages [26], and are converted to foam cells after internalising accumulated lipids. Foam cells release a variety of proinflammatory and prooxidant cytokines that attract T lymphocytes and more monocytes to accumulate [27]. Foam cells are further transformed into key components of the atherosclerotic core through necrosis. ...
Introduction
The purpose of this study was to examine the relationship between monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) and poor short-term 3-month and long-term 6-month prognosis after intravenous thrombolysis in patients with acute ischaemic stroke.
Material and methods
By retrospective analysis, 763 eligible patients with acute ischaemic stroke with intravenous thrombolysis were included in the study, and the general data and clinical laboratory examination results of the patients were collected. The relationship between MHR and poor prognosis at 3 and 6 months in patients with intravenous thrombolysis was derived by stepwise regression using the R language, followed by 1:1 propensity score matching to determine the MHR threshold and to investigate the relationship between high and low MHR values and poor prognosis.
Results
MHR level was found to predict the prognosis of intravenous thrombolysis patients with acute ischaemic stroke, and it was an effective predictor of poor prognosis at 3 and 6 months after intravenous thrombolysis. MHR has a threshold of 0.584. High MHR levels were strongly associated with a poor 3-month prognosis of intravenous thrombolysis in patients with acute ischaemic stroke (OR = 5.657; 95% CI: 4.124–7.762; p < 0.001). High MHR level was closely associated with poor prognosis of acute ischaemic stroke patients with intravenous thrombolysis at 6 months (OR = 4.923; 95% CI: 3.603–6.726; p < 0.001).
Conclusions
MHR level is a valid predictor for poor prognosis at 3-6 months after intravenous thrombolysis in patients in acute ischaemic stroke.
... The diuretic effect and oxidative stress induced by the alcohol leads to increase of the urine levels of the oxidized metabolites, which causes a higher risk of development of various pathological diseases (Evans et al., 2004) [105] demonstrated that hypertension patients could be at a higher risk of developing oxidative stress, since they had to deal with higher oxidative stress markers -8-OHdG. Unlike what already has been reported in the scientific publications that there is a substantive connection between DNA damage and atherosclerosis formation (Maria Grazia Andreassi et al., 2003; [85,106] , the direct cause of the damage in the development and formation of the illness remains a puzzle. Consequently, it's still necessary for more innovative and extensive research programs to discover. ...
... Estas patologias estão associadas a diversos fatores de risco, os principais, considerados maiores e independentes por serem reconhecidos em aumentar a probabilidade do indivíduo desenvolver doença arterial coronariana (DAC), são: diabetes melito (DM), níveis sanguíneos elevados de colesterol LDL, hipertensão arterial sistêmica (HAS), radicais livres produzidos pelo tabaco e predisposição genética. Outras características como sexo, idade, sedentarismo, estresse e obesidade também contribuem, em menor grau, e associados aos demais fatores, para o aparecimento da coronariopatia aterosclerótica (ROSS, 1999 utilizando-se das palavras chaves "Reabilitação" AND "cardiovascular" AND "educação" no idioma português, publicados nos últimos 10 anos (2012 a 2022). ...
Diante do cenário atual de alta morbidade e mortalidade das doenças cardiovasculares (DCV), assim como da necessidade urgente de medidas de prevenção e tratamento destas patologias, associada à escassez de serviços e equipes capacitados em Reabilitação Cardiovascular (RCV), o presente estudo justifica-se ao propor uma revisão sistemática da literatura em busca de trabalhos que tratem da difusão do conhecimento em RCV, proporcionando a interação multidisciplinar na prevenção e tratamento das DCV. Trata-se de um estudo explicativo no qual foi realizada uma ampla revisão bibliográfica sobre RCV, em que foram verificadas várias lacunas nos PRCV, dentre as quais a qualificação ideal dos profissionais da área de saúde em RCV. A partir dessa revisão verificou-se uma lacuna na produção científica que relacione a educação em saúde e a RCV.
... Acute coronary syndrome (ACS) is becoming the leading cause of morbidity and mortality in developing countries like India. The spectrum of presentation is wide from unstable angina to acute myocardial infarction 1 . Platelets play a crucial role in the pathogenesis of atherosclerosis and thrombus formation after coronary plaque rupture. ...
... [2] This is likely to occur at the sites of endothelial damage which are caused by Ox -LDL itself as well as physical or chemical forces and infection. [3] Endothelial cells, smooth muscle cells (SMCs), and macrophages are the sources of oxidants for the oxidative modification of phospholipids. Ox -LDL can damage endothelial cells and induce the expression of adhesion molecules such as P -selectin [4] and chemotactic factors such as monocyte chemoattractant protein -1 (MCP -1) and macrophage colony stimulating factor (mCSF). ...
... The second one is related to increase in free radicals and reactive oxygen species causing cell damage 7 and increase vascular tonicity causing pre eclampsia 8 .It implies that abnormal lipid profile has direct effect on endothelial dysfunction leading to decrease in PGI-TxA2 Ratio and subsequent fribrinoid necrosis at uteroplacental implantation site. 9 Natural rising of plasma lipids is being seen in normal pregnancy, but this event is not atherogenic and it is believed that this process is under hormonal control i.e. elevated levels Of estrogen and progesterone .But in complicated pregnancy, ( previous history of pre-eclampsia , primiparity, multifetal pregnancy, H.mole , triploidy), there is a possible defect in mechanism of adjusting physiologic hyperlipidemia 24 .There are evidences that abnormal lipid profile in pregnancy could be one of the factors for subsequent development of pre eclampsia, hence serum lipid parameters can be used as a useful predictive tool for it and would be helpful in lowering the mortalities and morbidities associated, by early detection of pre eclampsia, prompt measures can be taken for better management and ultimately lowering down the burden of associated morbidities and mortalities, perinatal outcomes around the world. Therefore, our study was conducted to study the relation between abnormal lipid profile and pre-eclampsia in order to aid in early prediction of the spectrum and timely management. ...
... Vulnerability of atherosclerotic plaques is associated with an increased risk for myocardial infarction and ischemic stroke [1][2][3][4][5][6][7]. Instability of a vulnerable plaque is characterized by enhanced lipid accumulation (lipid core), inflammation and thrombus formation [5][6][7]. ...
In vulnerable atherosclerotic plaques intraplaque hemorrhages (IPH) result in hemolysis of red blood cells and release of hemoglobin and free hemin. Hemin activates platelets and leads to thrombosis. Agonism of the inhibitory platelet receptor ACKR3 inhibits hemin-dependent platelet activation and thrombus formation.
To characterize the effect of hemin and ACKR3 agonism on isolated human platelets, multi-color flow cytometry and classical experimental setup such as light transmission aggregometry and a flow chamber assay have been used.
Hemin induces platelet aggregation and ex vivo platelet-dependent thrombus formation on immobilized collagen under low shear rate 500 s-1 indicating that free hemin is a strong activator for platelet-dependent thrombosis. Recently, we described that ACKR3 is a prominent inhibitory receptor of platelet activation. Specific ACKR3 agonists but not conventional antiplatelet compounds such as COX-1 inhibitor (indomethacin), ADP-receptor blocker (cangrelor), or PAR1 inhibitor (ML161) inhibit both hemin-dependent aggregation and thrombus formation. To further characterize the effect of hemin on platelet subpopulations we established a multi-color flow cytometry assay. We found that hemin induces procoagulant (CD42bpos/ PAC-1neg/AnnexinVpos), aggregatory (CD42bpos/PAC-1pos/AnnexinVneg) and inflammatory (CD42bpos/CXCR4pos/ACKR3pos/AnnexinVpos) platelet subpopulations. Treatment with ACKR3 agonists significantly decrease the formation of procoagulant and ACKR3pos platelets in response to hemin. We conclude that hemin is a strong activator for the formation of procoagulant platelets and thrombus formation which is dependent on the function of ACKR3. Activation of ACKR3 through specific agonists may offer a therapeutic strategy to control vulnerability of atherosclerotic plaques in areas of IPH.
... It is worth noting that LXRs in macrophages are primarily associated with chronic inflammation and dyslipidemia [48]. These receptors play a critical role in reducing cellular cholesterol levels by promoting cholesterol efflux through activation of ABC transporters (ABCA1 and ABCG1) and facilitating the production of apolipoproteins involved in cholesterol transport and lipoprotein remodelling [38]. ...
... The endothelium and the underlying collagen layers overlying the enlarged intima-the so-called fibrous cap-for a long time during atherosclerosis progression prevent the contact of the highly thrombogenic lipid core of the plaque with the circulating blood. The sudden rupture of the eventually thin fibrous cap, from the outside or from the inside (in the latter case due to the rupture of vasa vasorum penetrating the intima), transforms this slow process into an acute event, with the sudden development of thrombosis (Ross, 1999). When this occurs in a coronary artery, the consequent myocardial ischemia, in appropriate conditions, may precipitate an acute coronary syndrome, that is, acute myocardial infarction or unstable angina. ...
... In general, for patients with ESRD, antioxidant status often deteriorates [25]. Altered dietary restrictions and preferences may exaggerate the depletion of antioxidant defense mechanisms, such as low levels of vitamins C and E, reduced selenium levels, decreased function of the glutathione scavenging system, and loss of vitamins during HD [26,27]. However,the present study revealed a prominent increase in TAS in the COVID-ESRD group (Table 2, Fig. 1). ...
Background
Oxidative stress, an imbalance between reactive oxygen species production and antioxidant capacity, increases in patients with coronavirus disease (COVID-19) or renal impairment. We investigated whether combined COVID-19 and end-stage renal disease (ESRD) would increase oxidative stress levels compared to each disease alone.
Methods
Oxidative stress was compared among three groups. Two groups comprised patients with COVID-19 referred to the hospital with or without renal impairment (COVID-ESRD group [n = 18]; COVID group [n = 17]). The third group (ESRD group [n = 18]) comprised patients without COVID-19 on maintenance hemodialysis at a hospital.
Results
The total oxidative stress in the COVID-ESRD group was lower than in the COVID group (p = 0.047). The total antioxidant status was higher in the COVID-ESRD group than in the ESRD (p < 0.001) and COVID (p < 0.001) groups after controlling for covariates. The oxidative stress index was lower in the COVID-ESRD group than in the ESRD (p = 0.001) and COVID (p < 0.001) groups. However, the three oxidative parameters did not differ significantly between the COVID and COVID-ESRD groups.
Conclusions
The role of reactive oxygen species in the pathophysiology of COVID-19 among patients withESRD appears to be non-critical. Therefore, the provision of supplemental antioxidants may not confer a therapeutic advantage, particularly in cases of mild COVID-19 in ESRD patients receiving hemodialysis. Nonetheless, this area merits further research.
... It is characterized by progressive stenosis of coronary arteries caused by atheromatous plaque resulting from endothelial damage, chronic inflammation, and lipid infiltration [2]. Most patients with CHD are recognized to have additional comorbidities known as risk factors, such as hypertension, diabetes, and dyslipidemia [3,4]. Recent clinical trials have shown that comorbidities pose a significant challenge to the treatment of coronary artery disease. ...
Disorders of lipid metabolism are a common cause of coronary heart disease (CHD) and its comorbidities. In this study, ultra‐performance liquid chromatography–high‐resolution mass spectrometry in data‐independent acquisition (DIA) mode was applied to collect abundant tandem mass spectrometry data, which provided valuable information for lipid annotation. For the lipid isomers that could not be completely separated by chromatography, parallel reaction monitoring (PRM) mode was used for quantification. A total of 223 plasma lipid metabolites were annotated, and 116 of them were identified for their fatty acyl chain composition and location. In addition, 152 plasma lipids in patients with CHD and its comorbidities were quantitatively analyzed. Multivariate statistical analysis and metabolic pathway analysis demonstrated that glycerophospholipid and sphingolipid metabolism deserved more attention for CHD. This study proposed a method combining DIA and PRM for high‐throughput characterization of plasma lipids. The results also improved our understanding of metabolic disorders of CHD and its comorbidities, which can provide valuable suggestions for medical intervention.
... The rapid advances in the science of inflammation and WBC biology led to decades of focus on the secondary processes that occur in lipid-rich arterial lesions. Widely quoted reviews by Ross promoted atherosclerosis as an inflammation disease 2) . This led to a focus on WBC biology, especially macrophages, and studies in this area have dominated atherosclerosis research for several decades, see reviews 3,4) . ...
Atherosclerosis begins with the infiltration of cholesterol-containing lipoproteins into the arterial wall. White blood cell (WBC)-associated inflammation follows. Despite decades of research using genetic and pharmacologic methods to alter WBC function, in humans, the most effective method to prevent the initiation and progression of disease remains low-density lipoprotein (LDL) reduction. However, additional approaches to reducing cardiovascular disease would be useful as residual risk of events continues even with currently effective LDL-reducing treatments. Some of this residual risk may be due to vascular toxicity of triglyceride-rich lipoproteins (TRLs). Another option is that LDL transcytosis continues, albeit at reduced rates due to lower circulating levels of this lipoprotein. This review will address these two topics. The evidence that TRLs promote atherosclerosis and the processes that allow LDL and TRLs to be taken up by endothelial cells leading to their accumulation with the subendothelial space.
... In accordance with the notion that ongoing infiltration of leukocytes into the diseased vessel wall -i.e. circulating monocytes that are locally converted into macrophagesis the driving force in the development of atherosclerotic lesions (Ross, 1999;Ye et al. 2011), the lower total plaque area was paralleled by a similar decrease in the aortic root MOMA-2 + macrophage content (Fig. 4C). Since the studies by Seime et al. (2021) have shown that rhPRG4 is able to inhibit fibrosis development, we also investigated a potential effect on lesional collagen content. ...
Recombinant human proteoglycan 4 (rhPRG4) is a macromolecular mucin‐like glycoprotein that is classically studied as a lubricant within eyes and joints. Given that endogenously produced PRG4 is present within atherosclerotic lesions and genetic PRG4 deficiency increases atherosclerosis susceptibility in mice, in the current study we investigated the anti‐atherogenic potential of chronic rhPRG4 treatment. Female low‐density lipoprotein receptor knockout mice were fed an atherogenic Western‐type diet for 6 weeks and injected three times per week intraperitoneally with 0.5 mg rhPRG4 or PBS as control. Treatment with rhPRG4 was associated with a small decrease in plasma‐free cholesterol levels, without a change in cholesteryl ester levels. A marked increase in the number of peritoneal foam cells was detected in response to the peritoneal rhPRG4 administration, which could be attributed to elevated peritoneal leukocyte MSR1 expression levels. However, rhPRG4‐treated mice exhibited significantly smaller aortic root lesions of 278 ± 21 × 10³ μm² compared with 339 ± 15 × 10³ μm² in the aortic root of control mice. The overall decreased atherosclerosis susceptibility coincided with a shift in the monocyte and macrophage polarization states towards the patrolling and anti‐inflammatory M2‐like phenotypes, respectively. Furthermore, rhPRG4 treatment significantly reduced macrophage gene expression levels as well as plasma protein levels of the pro‐inflammatory/pro‐atherogenic cytokine TNF‐alpha. In conclusion, we have shown that peritoneal administration and subsequent systemic exposure to rhPRG4 beneficially impacts the inflammatory state and reduces atherosclerosis susceptibility in mice. Our findings highlight that PRG4 is not only a lubricant but also acts as an anti‐inflammatory agent. image
Key points
Endogenously produced proteoglycan 4 is found in atherosclerotic lesions and its genetic deficiency in mice is associated with enhanced atherosclerosis susceptibility.
In this study we investigated the anti‐atherogenic potential of chronic treatment with recombinant human PRG4 in hypercholesterolaemic female low‐density lipoprotein receptor knockout mice.
We show that recombinant human PRG4 stimulates macrophage foam cell formation, but also dampens the pro‐inflammatory state of monocyte/macrophages, eventually leading to a significant reduction in plasma TNF‐alpha levels and a lowered atherosclerosis susceptibility.
Our findings highlight that peritoneal recombinant human PRG4 treatment can execute effects both locally and systemically and suggest that it will be of interest to study whether rhPRG4 treatment is also able to inhibit the progression and/or induce regression of previously established atherosclerotic lesions.
... Endothelial disorders in non-insulin-dependent DM (type 2 diabetes), which accounts for 90%-95% of diabetic patients, are caused by chronic microinflammation [22] and are closely associated with organ failure and other diseases such as cardiovascular disease, nephropathy, retinopathy, and neuropathy [23]. Diabetes also increases the risk of skin flap necrosis during surgery that uses free skin flaps [1]. ...
The success rate of flap tissue reconstruction has increased in recent years
owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.
... The data suggested a close interaction between the endothelial lipoprotein lipase and triglyceride-rich (TG-rich) lipoproteins [3]. While subsequent research implicated the role of oxidative stress in the development and progression of atherosclerotic disease [1,[4][5][6], the role of TG-rich lipoproteins in this process is not understood. ...
Many commonly known antioxidants, from probucol to vitamin E, are fat-soluble and have been shown to be most effective when administered with meals. Following meal consumption, these compounds are incorporated into intestinal lipoproteins, known as chylomicrons, and secreted into the circulation. These lipid-carrying particles are responsible for the transport of newly absorbed dietary fat for delivery to peripheral tissues. In the bloodstream, chylomicrons interact with heparin-releasable lipases common known as lipoprotein lipase and hepatic triglyceride lipase. Bothe lipases are anchored along the endothelial wall via heparan sulfate proteoglycans and have triglycerides as their preferred substrate. During this process, as dietary triglycerides are hydrolyzed and transported across the endothelium, we hypothesize that antioxidants carried in chylomicrons would be delivered directly to the arterial wall where they would be most effective in quenching reactive oxygen species generated by activated macrophages. Thus, the metabolism of postprandial lipoproteins is a key process in the defense against oxidative stress and may provide the path for effective antioxidant management. In this chapter, we will review the evidence in support of the hypothesis that postprandial lipoproteins may contribute to the delivery of fat-soluble antioxidants that are administered orally.
... In recent years, it has become increasingly clear that other systemic diseases should also be counted as inflammatory diseases. These include atherosclerosis and thus cardiovascular inflammation [5] and metabolic inflammation [6,7]. Moreover, they are all associated with periodontitis, as well as other conditions [8][9][10][11][12][13][14]. ...
... Lakin Ürəyin işemik xəstəliyinin destabilləşməsiaterosklerotik piləyin tamlığının pozulması və sonradan trombun əmələ gəlməsidir. Bu prosesdə makrofaqların fəallaşmasına və ateroma kapsulunun dağılmasına yardım edən immun iltihab reaksiyaları mühüm rol oynayır [1,2]. Hesab edilir ki, iltihab aşağı sıxlıqlı oksidləşmiş lipoproteidlərin (ASOL) damar divarında yığılmasına yardım edir və aterosklerotik piləyin destabilizasiyası və aterotrombotik ağırlaşmaların inkişafında mühüm rol oynayır [3]. ...
Tədqiqat işinin məqsədi miokard infarktından sonrakı stenokardiyaların inkişafında immun iltihab reaksiyalarının rolunun müəyyən edilməsi olmuşdur. Bu məqsədlə tədqiqata ürəyin işemik xəstəliyindən (ÜİX) əziyyət çəkən 110 xəstə daxil edilmişdir . Ürəyin işemik xəstəliyi diaqnozu klinik-instrumental müayinələr əsasında verifikasiya olunmuşdur. İmmun iltihab reaksiyalarının immunoferment metodla təyin edilməsi üçün C-reaktiv zülal (C-RZ), proiltihab interleykinlər [İL] - İL-6 və şişlərin nekrozu amilinin (ŞNA-α) səviyyəsi müəyyən edilmişdir. Nəticə. Postinfarkt stenokardiyalar zamanı İL-6 səviyyəsinin artmasi , ŞNA-α hiperekspressiyası və S-RZ-in yüksək sintezi aşkar olunmuşdur. Sabit stenokardiya zamanı minimal immunoloji dəyişikliklər qeydə alınmışdır. ÜİX-nin destabilizasiyası və eləcə də ifadə olunma dərəcəsi miokard infaktinin agırlaşması ilə bağlı olan immun iltihab reaksiyalarının aktivləşməsi ilə xarakterizə olunur. İmmun iltihab reaksiyalarının qabarıq ifadə olunması miokard infarktının gedişatının proqressivləşməsi ilə assosiasiya olunur.
... trained immunity, for example, confers a proatherogenic phenotype to monocytes and macrophages [56][57][58]. In conclusion, there has been a paradigm shift in atherogenesis: the historical view of a single culprit agent inducing atherosclerosis (either lipoproteins [59] or inflammation [60]) has been upgraded to a complex metabolic-immune process in which a metabolic switch of ECs starts the inflammatory process that involves many immune and vascular cells. Moreover, the complexity of the challenges to the ECs has also expanded in these last decades and noxious substances or abnormal hemodynamic stresses are assembled in the exposome concept [25]. ...
Atherosclerosis, a complex metabolic-immune disease characterized by a chronic inflammation driven by the buildup of lipid-rich plaques within arterial walls, has emerged as a pivotal factor in the intricate interplay between cancer and cardiovascular disease. This bidirectional relationship, marked by shared risk factors and pathophysiological mechanisms, underscores the need for a comprehensive understanding of how these two formidable health challenges intersect and influence each other. Cancer and its treatments can contribute to the progression of atherosclerosis while atherosclerosis with its inflammatory microenvironment can exert profound effects on cancer development and outcomes. Both cancer and cardiovascular disease involve intricate interactions between general and personal exposomes. In this review we want to summarize the state-of-the-art of translational data and try to show how oncologic studies on cardiotoxicity can broaden our knowledge of crucial pathways in cardiovascular biology with a positive impact on precision cardiology and cardioncology.
... It is characterized by the formation of intimal plaques and accumulation of cholesterol in arterial walls [4]. Atherosclerosis involves fat deposition accompanied by macrophages and a fibrotic layer comprising smooth muscle cells, connective tissue, and leukocytes [5]. ...
... Atherosclerosis (AS) is a chronic disease that leads to clinical complications known as major adverse cardiovascular events (MACEs) and is the leading cause of death worldwide. [1][2][3][4] It is characterized by excessive lipid deposition in the intimal space of larger arteries where low-density lipoprotein cholesterol (LDL-C) retention elicits arterial inflammation. To date, the most common clinical treatment is to use lipid-lowering agents (e.g., statins) to effectively reduce blood lipid levels. ...
Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1 ⁺ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.
... In addition, neutrophils contribute to the progression of CKD through migration, production of ROS, secretion of neutrophil serine proteases (NSPs), and release of neutrophil extracellular traps (NETs) [26,27]. Patients with CKD also experience premature aging of their T lymphocytes, which express high levels of pro-inflammatory cytokines that interact with the chronic inflammatory milieu of the patients with CKD, exacerbating the progression of the CKD and increasing the patient's susceptibility to atherosclerosis and ischemic organ damage [28][29][30]. In addition, the decrease in lymphocyte count also reflects patients' impaired immune resistance, making them more prone to infections and deterioration of renal function [25]. ...
Background
Chronic kidney disease (CKD) is linked to immunity and inflammation. Systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) are novel measures for gauging an individual’s systemic inflammatory activity. We aim to investigate the potential associations between them.
Methods
This study encompassed a cohort of 40,937 adults from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. SII and SIRI were log2-transformed before conducting regression analysis, considering that these inflammatory markers were right skewed distributed. Weighted logistic regression models assessed the association of log2-SII and log2-SIRI levels with CKD prevalence. Weighted Cox regression models were utilized to estimate the risk of death. Subgroup analyses were performed to further clarify the effects of other covariates on the associations. Sensitivity analyses were performed to assess the robustness of our results.
Results
6986 participants with CKD were recorded, and 2818 patients died during a mean follow-up time of 100 months. After adjusting for all covariates, the highest level of log2-SII increased the CKD incidence (odds ratio [OR]: 1.47, 95% confidence intervals [CI]: 1.32–1.65, P < 0.001), as well as log2-SIRI (OR: 1.79, 95% CI 1.60–2.01, P < 0.001) when compared with the lowest level reference group. The highest level of log2-SII significantly increased all-cause mortality (hazard risk [HR]: 1.29; 95% CI 1.13–1.48, P < 0.001), cardiovascular mortality (HR: 1.61, 95% CI 1.25–2.09, P < 0.001), and hypertension mortality (HR: 1.73, 95% CI 1.23–2.42, P = 0.001) in CKD patients. Additionally, the positive associations were also found between log2-SIRI and all cause (HR: 1.54, 95% CI 1.35–1.76, P < 0.001), cardiovascular (HR: 1.90, 95% CI 1.38–2.60, P < 0.001), and hypertension mortality (HR: 2.15, 95% CI 1.56–2.94, P < 0.001). Subgroup analyses unveiled variations in these effects among different populations.
Conclusion
There existed a substantial association of SII and SIRI levels with CKD prevalence, as well as mortality in patients with CKD in the U.S. population.
... In early medical research, atherosclerosis was regarded as deposition of lipids within the vessel wall of medium-sized and large arteries. In recent years, many researchers have shown that atherosclerosis is actually a chronic inflammatory disease with accumulation of LDL (low-density lipoprotein), monocytes, macrophages and foam cells at the site of inflammation (see [7,22]). This accumulation process is often referred to as plaque formation. ...
We consider a mathematical model of the initiation and development of atherosclerosis in the early stage, defined in different domains. The existence of nonnegative weak solutions is proved via studying an auxiliary system with absolute value terms and applying a novel semi-discrete, operator splitting numerical scheme. Numerical simulations were performed in an idealized two-dimensional geometry in order to verify our assumptions in model building and theoretical analysis. The framework we developed can also be used for nonlinear reaction–diffusion systems defined in other different domains with more complex coupling conditions.
... While inflammation is a well-established pathway that drives cancer and atherogenesis 32,33 , EAT has been tied to local perivascular inflammation. EAT, a metabolically active visceral fat depot, encases the coronary arteries directly without a basal membrane functioning as a barrier. ...
Background
Heavy smokers are at increased risk for cardiovascular disease and may benefit from individualized risk quantification using routine lung cancer screening chest computed tomography. We investigated the prognostic value of deep learning-based automated epicardial adipose tissue quantification and compared it to established cardiovascular risk factors and coronary artery calcium.
Methods
We investigated the prognostic value of automated epicardial adipose tissue quantification in heavy smokers enrolled in the National Lung Screening Trial and followed for 12.3 (11.9–12.8) years. The epicardial adipose tissue was segmented and quantified on non-ECG-synchronized, non-contrast low-dose chest computed tomography scans using a validated deep-learning algorithm. Multivariable survival regression analyses were then utilized to determine the associations of epicardial adipose tissue volume and density with all-cause and cardiovascular mortality (myocardial infarction and stroke).
Results
Here we show in 24,090 adult heavy smokers (59% men; 61 ± 5 years) that epicardial adipose tissue volume and density are independently associated with all-cause (adjusted hazard ratios: 1.10 and 1.38; P < 0.001) and cardiovascular mortality (adjusted hazard ratios: 1.14 and 1.78; P < 0.001) beyond demographics, clinical risk factors, body habitus, level of education, and coronary artery calcium score.
Conclusions
Our findings suggest that automated assessment of epicardial adipose tissue from low-dose lung cancer screening images offers prognostic value in heavy smokers, with potential implications for cardiovascular risk stratification in this high-risk population.
... Endothelial to mesenchymal transition (EndMT) has been identified to participate in the pathological development of atherosclerosis (Wesseling et al. 2018). EndMT facilitates atherosclerosis progression through promoting the secretion of pro-inflammatory molecules extracellular matrix protein synthesis that contributes to plaque buildup (Ross 1999). Previous studies have reported that pro-inflammatory molecule IL-1β and ox-LDL can induce EndMT, thereby promoting the progression of atherosclerosis (Maleszewska et al. 2013;Yoshimatsu et al. 2020). ...
Background
Endothelial-to-Mesenchymal Transformation (EndMT) plays key roles in endothelial dysfunction during the pathological progression of atherosclerosis; however, its detailed mechanism remains unclear. Herein, we explored the biological function and mechanisms of upstream stimulating factor 1 (USF1) in EndMT during atherosclerosis.
Methods
The in vivo and in vitro atherosclerotic models were established in high fat diet-fed ApoE −/− mice and ox-LDL-exposed human umbilical vein endothelial cells (HUVECs). The plaque formation, collagen and lipid deposition, and morphological changes in the aortic tissues were evaluated by hematoxylin and eosin (HE), Masson, Oil red O and Verhoeff-Van Gieson (EVG) staining, respectively. EndMT was determined by expression levels of EndMT-related proteins. Target molecule expression was detected by RT-qPCR and Western blotting. The release of pro-inflammatory cytokines was measured by ELISA. Migration of HUVECs was detected by transwell and scratch assays. Molecular mechanism was investigated by dual-luciferase reporter assay, ChIP, and Co-IP assays.
Results
USF1 was up-regulated in atherosclerosis patients. USF1 knockdown inhibited EndMT by up-regulating CD31 and VE-Cadherin, while down-regulating α-SMA and vimentin, thereby repressing inflammation, and migration in ox-LDL-exposed HUVECs. In addition, USF1 transcriptionally activated ubiquitin-specific protease 14 (USP14), which promoted de-ubiquitination and up-regulation of NLR Family CARD Domain Containing 5 (NLRC5) and subsequent Smad2/3 pathway activation. The inhibitory effect of sh-USF1 or sh-USP14 on EndMT was partly reversed by USP14 or NLRC5 overexpression. Finally, USF1 knockdown delayed atherosclerosis progression via inhibiting EndMT in mice.
Conclusion
Our findings indicate the contribution of the USF1/USP14/NLRC5 axis to atherosclerosis development via promoting EndMT, which provide effective therapeutic targets.
... Cigarette smoking contains a large number of free radicals and may downregulate key exogenous and endogenous antioxidants such as vitamin D, carotenes, GPx, and SOD, leading to the dysfunction of monocytes and vascular smooth muscle cells. Proatherogenic agents such as oxidized lipids, high glucose, and cigarette constituents increase free radical production [33,34]. ...
... Studies have shown that reactive oxygen species (ROS) such as hydrogen peroxide ROS (such as hydrogen) play an important role in TNF-α-induced inflammation [67][68][69][70]. These reactive oxygen species have been shown to regulate TNF-α by activating various pro-inflammatory cytokines [71]. ...
Carbon nanodots (CNDs) are a new type of nanomaterial with a size of less than 10 nanometers and excellent biocompatibility, widely used in fields such as biological imaging, transmission, diagnosis, and drug delivery. However, its potential and mechanism to mediate endothelial inflammation have yet to be explored. Here, we report that the uptake of CNDs by EA.hy926 endothelial cells is both time and dose dependent. The concentration of CNDs used in this experiment was found to not affect cell viability. TNF-α is a known biomarker of vascular inflammation. Cells treated with CNDs for 24 h significantly inhibited TNF-α (0.5 ng/mL)-induced expression of intracellular adhesion molecule 1 (ICAM-1) and interleukin 8 (IL-8). ICAM-1 and IL-8 are two key molecules responsible for the activation and the firm adhesion of monocytes to activated endothelial cells for the initiation of atherosclerosis. ROS, such as hydrogen peroxide, play an important role in TNF-α-induced inflammation. Interestingly, we found that CNDs effectively scavenged H2O2 in a dose-dependent manner. CNDs treatment also increased the activity of the antioxidant enzyme NQO1 in EA.hy926 endothelial cells indicating the antioxidant properties of CNDs. These results suggest that the anti-inflammatory effects of CNDs may be due to the direct H2O2 scavenging properties of CNDs and the indirect upregulation of antioxidant enzyme NQO1 activity in endothelial cells. In conclusion, CND can inhibit TNF-α-induced endothelial inflammation, possibly due to its direct scavenging of H2O2 and the indirect upregulation of antioxidant enzyme NQO1 activity in endothelial cells.
... (i) Alzheimer's Disease: Vascular dysfunction is closely linked to the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline and memory loss. Deposition of aggregated amyloid β (Aβ) peptide is considered the main cause of AD [37]. In normal brains, Aβ is cleared mainly through perivascular pathways [38]. ...
Degenerative diseases, encompassing a wide range of conditions affecting various organ systems, pose significant challenges to global healthcare systems. This comprehensive review explores the intricate interplay between the vascular system and degenerative diseases, shedding light on the underlying mechanisms and profound implications for disease progression and management. The pivotal role of the vascular system in maintaining tissue homeostasis is highlighted, as it serves as the conduit for oxygen, nutrients, and immune cells to vital organs and tissues. Due to the vital role of the vascular system in maintaining homeostasis, its dysfunction, characterized by impaired blood flow, endothelial dysfunction, and vascular inflammation, emerges as a common denominator of degenerative diseases across multiple systems. In the nervous system, we explored the influence of vascular factors on neurodegenerative diseases such as Alzheimer’s and Parkinson’s, emphasizing the critical role of cerebral blood flow regulation and the blood–brain barrier. Within the kidney system, the intricate relationship between vascular health and chronic kidney disease is scrutinized, unraveling the mechanisms by which hypertension and other vascular factors contribute to renal dysfunction. Throughout this review, we emphasize the clinical significance of understanding vascular involvement in degenerative diseases and potential therapeutic interventions targeting vascular health, highlighting emerging treatments and prevention strategies. In conclusion, a profound appreciation of the role of the vascular system in degenerative diseases is essential for advancing our understanding of degenerative disease pathogenesis and developing innovative approaches for prevention and treatment. This review provides a comprehensive foundation for researchers, clinicians, and policymakers seeking to address the intricate relationship between vascular health and degenerative diseases in pursuit of improved patient outcomes and enhanced public health.
Aging is a physiological and immunological process involving the deterioration of human health, characterised by the progressive alteration of organs and their functions. The speed and extent of such decline are dependent on lifestyle, environment, and genetic factors. Moreover, with advancing age, humans become progressively more fragile and prone to acute and chronic diseases. Although the intestinal microbiota is predisposed to perturbations that accompany aging and frailty, it is generally accepted that the gut microbiota engages in multiple interactions that affect host health throughout the host life span. In the current study, an exhaustive in silico investigation of gut-associated bifidobacteria in healthy individuals from birth to old age revealed that Bifidobacterium longum subsp. longum is the most prevalent member, especially during infancy and in centenarians. Moreover, B. longum subsp. longum genome reconstruction and strain tracing among human gut microbiomes allowed the identification of prototypes of this taxon in the human gut microbiota of healthy elderly individuals. Such analyses guided culturomics attempts to isolate B. longum subsp. longum strains that matched the genomic content of B. longum subsp. longum prototypes from healthy elderly individuals. The molecular effects of selected B. longum subsp. longum strains on the human host were further investigated using in vitro microbe-host interactions, revealing differences in the host immune system transcriptome, with a reduction in gene expression of inflammation-related cytokines. These intriguing findings support the potential anti-aging effects of elderly associated prototypes of B. longum subsp. longum .
An excellent paper that provides a comprehensive analysis of biomarkers, which can disclose a variety of information about health or illness, such as the kind or extent of environmental exposure, genetic Vulnarability, genetic responses to exposures, indicators of preclinical or clinical illness, or indications of the treatment response. Indicators of disease trait , disease stage (preclinical or clinical), or illness rate are thus a basic approach to conceptualize biomarkers. A trait that can be objectively measured and evaluated is called a biomarker. as a gauge for biological activities that are pathogenic, healthy, or pharmaceutical responses to a treatment As a result, this paper examines the wealth of research on the function of bioactive compounds in a range of pathological processes associated with different
As apresentações clínicas da angina instável (AI) e do infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) podem ser idênticas e foram recentemente agrupadas pelo termo síndrome coronariana aguda sem supradesnivelamento do segmento ST (SCASEST). Os pacientes que apresentam SCASEST no eletrocardiograma (ECG) são classificados como tendo AI ou IAMSSST dependendo da ausência ou presença de marcadores bioquímicos de necrose miocárdica, respectivamente. A SCASEST é causada por uma artéria coronária parcialmente ocluída, em oposição à oclusão completa encontrada no IAMCSST, geralmente como resultado da formação de um trombo não oclusivo, que muitas vezes se desenvolve dentro de uma placa aterosclerótica rompida. Suas apresentações clínicas variam amplamente, sendo que alguns pacientes são assintomáticos na apresentação, enquanto outros podem apresentar isquemia contínua, instabilidade hemodinâmica ou parada cardíaca.
Nutritional and genetic deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis, which is a major cause of cardiovascular disease (CVD). Impaired autophagy causes the accumulation of damaged proteins and organelles and is associated with CVD. Biochemically, HHcy is characterized by elevated levels of Hcy and its metabolites, Hcy-thiolactone and N-Hcy-protein. However, whether these metabolites can dysregulate mTOR signaling and autophagy in endothelial cells is not known. Here, we examined the influence of Hcy-thiolactone, N-Hcy-protein, and Hcy on autophagy human umbilical vein endothelial cells. We found that treatments with Hcy-thiolactone, N-Hcy-protein, or Hcy significantly downregulated beclin 1 (BECN1), autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and microtubule-associated protein 1 light chain 3 (LC3) mRNA and protein levels. We also found that these changes were mediated by upregulation by Hcy-thiolactone, N-Hcy-protein, and Hcy of autophagy-targeting microRNA (miR): miR-21, miR-155, miR-216, and miR-320c. The effects of these metabolites on levels of miR targeting autophagy as well as on the levels of BECN1, ATG5, ATG7, and LC3 mRNA and protein were abrogated by treatments with inhibitors of miR-21, miR-155, miR-216, and mir320c. Taken together, our findings show that Hcy metabolites can upregulate miR-21, miR-155, miR-216, and mir320c, which then downregulate autophagy in human endothelial cells, important for vascular homeostasis.
Over the past two decades, research efforts into cardiovascular disease (CVD) have uncovered findings that fundamentally challenge our understanding of CVD, particularly atherosclerosis. Atherosclerosis was primarily attributed to the well-described abnormal lipid accumulation theory, involving plaque growth with subsequent plaque hemorrhage resulting in acute vessel thrombosis that may or may not rupture. This perspective has now evolved to encompass more complex pathways, wherein the accumulation of abnormal products of oxidation and inflammation is the most likely factor mediating atherosclerotic plaque growth. Furthermore, atherosclerosis was traditionally thought of as a disease in patients aged 40 and older. However, mounting evidence has demonstrated that significant atherosclerosis and CVD events are more prevalent in younger patients than previously realized and accelerating in incidence. With this alarming trend among younger individuals, our review sought to explore why this trend may be happening and what can be done about this developing problem.
Background and aims
This study aimed to validate the role of high low-density lipoprotein cholesterol [LDL-C] and triglyceride [TG] treatment target levels on the microcirculation in a very high and high cardiovascular risk group.
Methods
119 patients with high or very high cardiovascular [CV] risk were included. We have registered the main co-morbidities, smoking habits, body mass index [BMI] and the lipid lowering medication. Hematocrit, whole blood viscosity [WBV] and plasma viscosity [PV], red blood cell [RBC] aggregation and deformability and fibrinogen, total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], LDL-C and TG levels were determined.
Results
The investigation found significantly higher PV values in patients with non-target LDL-C, associated with higher fibrinogen level. Non-target TG was related to deteriorated microcirculatory parameters, as significantly higher RBC aggregation, lower RBC deformability, and higher WBV and PV. The main microcirculatory benefit in diabetes could be gained from target level of TG, in chronic coronary syndrome [CCS] patients it is more advantageous to reach both LDL-C and TG target.
Conclusion
The results could highlight, that TG should play a role in failing microcirculation and cause potentially life-threatening complications, which would worsen the survival and quality of life of high or very high risk CV patients.
Objectives: In the present study, we investigated the relationship between mentioned markers and chronic total occlusion collateral development. Patients and methods: A total of 243 patients (210 males, 33 females; mean age: 63.3±11.5; range, 51 to 76 years) who underwent coronary angiography due to typical chest pain or myocardial ischemia detected in noninvasive stress tests and diagnosed with ≥1 major coronary artery occlusion between January and September 2020 were included in the cross-sectional observational study. The angiographic collateral index was determined according to the Cohen-Rentrop classification. The patients were divided into two groups according to the sufficiency of collateral development: the well-developed collaterals group (n=155) and the poor-developed collaterals group (n=88). Results: Statistically significant parameters in univariate logistic regression analysis were evaluated with multivariate (stepwise) logistic regression analysis; as a result, presence of chronic total occlusion in left anterior descending artery (odds ratio [OR]=2.447; 95% confidence interval [CI], 1.160-5.162; p=0.019), total number of occlusions (OR=3.503; 95% CI, 1.445-8.494; p=0.006), left ventricular ejection fraction (OR=1.056; 95% CI, 1.022-1.091; p=0.001), and the atherogenic index of plasma (OR=0.017; 95% CI, 1.022-1.091; p<0.001) were independently associated with well-developed collaterals. Although the triglyceride-glucose index had statistical significance in the univariate analysis, it was not detected as an independent variable in the multivariate analysis. The monocyte-lymphocyte ratio was not significant in the univariate analysis. Conclusion: Of the new atherosclerosis markers, only the atherogenic index of plasma had an independent association with poor collateral development.
Since the discovery that Helicobacter pylori (H. pylori) is a central player in the pathogenesis of gastric and duodenal ulcers, there have been many studies that demonstrate the role of H. pylori infection in extragastric diseases. New research is showing that it may also be linked to hyperlipidemia and heart diseases. However, there is still plenty of skepticism concerning cardiovascular diseases in which this widespread microbe may be implicated. Therefore, more studies, especially prospective randomized multicenter studies, are needed to illuminate the role of H. pylori infection in heart diseases.
Background: Chronic coronary syndrome (CCS) patients have a high mortality rate globally. Atherosclerosis, a cause of CCS, is influenced by inflammation. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) have a key role in the process of atherosclerosis. Moreover, gut microbiota dysbiosis can lead to leaky gut syndrome, subsequently triggering abnormal immune responses and contributing to diseases, including atherosclerosis and coronary artery disease (CAD). Objective: To study the relationship between pro-inflammatory cytokines and gut microbiome in CCS patients undergoing coronary angiography. Material and Methods: Participants were divided into two groups by using statistical matching techniques with age and gender, as CCS patients and healthy participants. Each patient’s blood was collected on the day of the appointment. All patients’ feces were collected one day before an appointment. The present research was a cross-sectional study. Results: Fifty-three patients, including 28 CCS patients and 25 healthy participants were enrolled. CCS patients had a higher level of TNF-α compared to healthy participants with statistical significance at 79.31 pg/mL. Phascolarctobacterium, Sutterella, and Prevotella could distinguish CCS patients from healthy participants based on receiver operating characteristic (ROC) analysis. Proteus and Phascolarctobacterium were positively correlated with TNF-α. Conclusion: There is a potential relationship between gut microbiome composition and inflammatory biomarkers in CCS patients. Pro-inflammatory cytokines and specific bacterial genera may be related to indicate significant CAD in CCS patients undergoing coronary angiography. Keywords: Cardiovascular disease; Interleukin-1; Interleukin-6; Tumor necrosis factor-alpha; Pro-inflammatory cytokines; Gut microbiome; Chronic coronary syndrome
This thesis explores the association between oral status and coronary artery disease, with specific focus on endodontic inflammatory disease and acute myocardial infarction.
The role of protein tyrosine kinases in the expression of interleukin-1β (IL-1β) gene in response to phorbol esters (PMA) in THP-1 cell line was investigated. Genistein, a specific tyrosine kinase inhibitor, inhibited PMA induced IL-1β protein and mRNA levels in THP-1 cells. Genistein did not have a significant effect on PMA induced activity in transient transfection assays using reporter gene constructs containing the PMA responsive sequence of the IL- 1β gene linked to IL- 1β promoter, or five repeats of PMA responsive sites (AP-1 sites) in front of a thymidine kinase promoter. This indicates that the tyrosine kinase activity required for the PMA induced IL-1β expression is coupled downstream from or functions independent of the PMA induced AP-1 activity.
The past decade of research has brought us closer to an understanding of the mechanisms whereby alcohol promotes fibrosis in liver. The perivenular and perisinusoidal fibrosis that characterizes alcoholic cirrhosis suggests that it is a unique entity, distinct from other types of fibrotic liver disease. On a cellular level, though, the target population and the regulatory events that control fibrogenesis may be typical of all types of fibrotic liver disease. The putative pathways to alcoholic fibrosis are exemplified in Figure 1. Fibrosis can be either the direct result of a stimulus from ethanol or one of its metabolites to a target cell population, presumably the lipocytes, or it can begin indirectly in response to hepatic inflammation. The indirect pathway to hepatic fibrosis is likely to be initiated by cytokines, elaborated by inflammatory cells. In addition, invasion of the liver by inflammatory cells may disrupt the normal hepatic extracellular matrix, which may in itself act as a stimulus for fibrogenesis by altering critical cell-matrix interactions. If alteration of the normal hepatic matrix is sufficient to promote fibrogenesis, it may act as a fixed stimulus that perpetuates fibrogenesis in the absence of ongoing inflammation. This may explain the progression of alcoholic fibrosis in some patients in the apparent absence of alcoholic hepatitis. It has been gratifying to observe a consensus emerge among experimental observations regarding the process of alcoholic fibrosis. In particular, the discovery of transitional cells in fibrotic liver tissue, and their relationship to lipocytes, correlates well with studies documenting activation of lipocytes in culture to a fibrogenic phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
It was reported earlier that in the lungs of individuals with idiopathic pulmonary fibrosis, many cells lining small air spaces have intimate associations with underlying interstitial cells. The present study confirms and extends these previous observations by describing changes seen in a different patient group. Light microscopy of lung biopsy tissue showed thickened alveolar walls with infiltrates of mixed inflammatory cells. There were undefined associations between interstitial cells and cuboidal and attenuated epithelial cells lining smaller air spaces. Electron microscopy demonstrated that cytoplasmic processes from the lining cells protruded through discontinuities in underlying basement membranes, and that intimate connections between lining cells and interstitial cells frequently were present. In addition, some of the cells lining air spaces had few microvilli, rare pinocytotic vesicles, and did not lie on basement membranes. These cells were mesenchymal-like in appearance and were clearly associated with interstitial cells and connective tissue. Similar pulmonary lesions were observed in mice that received a single intraperitoneal injection of butylated hydroxytoluene and were exposed subsequently to 70% oxygen for 6 days. Our findings suggest that communication between a regenerating epithelium and the underlying mesenchyme is an integral step for ongoing alveolar repair.