[Show abstract][Hide abstract] ABSTRACT: Introduction:
Sepsis is an exaggerated and dysfunctional immune response to infection. Activation of innate immunity recognition systems including complement and the Toll-like receptor family initiate this disproportionate inflammatory response. The aim of this study was to explore the effect of combined inhibition of the complement component C5 and the Toll-like receptor co-factor CD14 on survival, hemodynamic parameters and systemic inflammation including complement activation in a clinically relevant porcine model of polymicrobial sepsis.
Norwegian landrace piglets (4 ± 0.5 kg) were blindly randomized to a treatment group (n = 12) receiving the C5 inhibitor coversin (OmCI) and anti-CD14 or to a positive control group (n = 12) receiving saline. Under anesthesia, sepsis was induced by a 2 cm cecal incision and the piglets were monitored in standard intensive care for 8 hours. Three sham piglets had a laparotomy without cecal incision or treatment. Complement activation was measured as sC5b-9 using enzyme immunoassay. Cytokines were measured with multiplex technology.
Combined C5 and CD14 inhibition significantly improved survival (p = 0.03). Nine piglets survived in the treatment group and four in the control group. The treatment group had significantly lower pulmonary artery pressure (p = 0.04) and ratio of pulmonary artery pressure to systemic artery pressure (p < 0.001). Plasma sC5b-9 levels were significantly lower in the treatment group (p < 0.001) and correlated significantly with mortality (p = 0.006). IL-8 and IL-10 were significantly (p < 0.05) lower in the treatment group.
Combined inhibition of C5 and CD14 significantly improved survival, hemodynamic parameters and inflammation in a blinded, randomized trial of porcine polymicrobial sepsis.
Critical Care 12/2015; 19(1). DOI:10.1186/s13054-015-1129-9 · 4.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
This review aims to summarize current knowledge regarding the underlying patho-mechanisms of delayed fracture healing in polytraumatized patients.
Data sourcesand study selection:
The following search terms were used: 'fracture', 'hemorrhage', 'chest trauma', 'inflammation', 'inflammatory response', 'fracture healing', 'delayed healing', 'non-union', 'fracture stabilisation', 'intramedullary nailing', 'external fixation', 'Early Total Care' and 'Damage Control'. Medline, Embase and Cochrane Library were searched for studies published between 1.1.1990through 3.30.2014. Of 1,322 publications, 68 were included in the current summary.
Concomitant injuries and the strategy for fracture stabilization seem to affect bone metabolism and fracture healing. Among the relevant patho-mechanisms, interactions between the local and systemic inflammatory response appear to play a role. However, the consequences of fracture fixation strategies in case of severe concomitant injuries on local inflammation and bone healing remain unknown.
Level of evidence:
Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Journal of orthopaedic trauma 11/2015; DOI:10.1097/BOT.0000000000000489 · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe tissue trauma-induced systemic inflammation is often accompanied by evident or occult blood-organ barrier dysfunctions, frequently leading to multiple organ dysfunction. However, it is unknown whether specific barrier molecules are shed into the circulation early after trauma as potential indicators of an initial barrier dysfunction. The release of the barrier molecule junctional adhesion molecule-1 (JAM-1) was investigated in plasma of C57BL/6 mice 2 h after experimental mono- and polytrauma as well as in polytrauma patients (ISS ≥ 18) during a 10-day period. Correlation analyses were performed to indicate a linkage between JAM-1 plasma concentrations and organ failure. JAM-1 was systemically detected after experimental trauma in mice with blunt chest trauma as a driving force. Accordingly, JAM-1 was reduced in lung tissue after pulmonary contusion and JAM-1 plasma levels significantly correlated with increased protein levels in the bronchoalveolar lavage as a sign for alveolocapillary barrier dysfunction. Furthermore, JAM-1 was markedly released into the plasma of polytrauma patients as early as 4 h after the trauma insult and significantly correlated with severity of disease and organ dysfunction (APACHE II and SOFA score). The data support an early injury- and time-dependent appearance of the barrier molecule JAM-1 in the circulation indicative of a commencing trauma-induced barrier dysfunction.
Mediators of Inflammation 11/2015; 2015(4):463950. DOI:10.1155/2015/463950 · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The activated forms of the complement lectin pathway (LP) proteases MASP-1 and -2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and TAFI in vitro. In vivo studies also show that MASP-1 is involved in thrombogenesis, OBJECTIVES: To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions.
Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2 RESULTS: Activated platelets were shown by flow cytometry to bind Ficolin-1, -2, and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were as previously reported inactivated by C1-INH. In SLE patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1INH were associated with markers of thrombotic disease and contact/coagulation system activation.
MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions in vitro and in vivo, and may represent a novel activation/amplification mechanism in thromboinflammation. This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 11/2015; DOI:10.1111/jth.13208 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Severe tissue trauma leads to an early excessive activation of the complement and the coagulation system which is associated with a poor outcome. Besides extensive interactions between the two cascades on a fluid-phase level, studies suggest that key molecules in coagulation are expressed on leukocytes. Therefore, we examined the potential crosstalk between complement and coagulation on the leukocyte surface, and aimed to identify the involved molecular mechanisms especially after polytrauma.
A prospective clinical study was conducted in patients after severe trauma (ISS≥32) and healthy volunteers. The study was approved by the Independent Local Ethics Committee of the University of Ulm. Blood was obtained upon admission to the ER and 4 h, 12 h, 24 h, 48 h, 120 h and 240 h after trauma. Key players of complement and coagulation on the leukocyte cell surface were analyzed by flow cytometry in comparison to expression profiles in healthy volunteers.
All leukocytes showed significantly increased expression of PAI-1 during later time points after trauma, possibly accounting for decreased fibrinolysis and enhanced risk of thrombosis. TCC was significantly incorporated in monocyte membranes at increased amounts early after trauma, returning to base line levels on days 5 and 10. A similar expression pattern was observed for thrombomodulin, an essential regulator of protein C activation. TCC levels on monocytes positively correlated with thrombomodulin expression and negatively with platelet counts.
The data are indicative of so far unknown interactions between complement and coagulation on a cellular level and the potential role of leukocyte surface molecules in the development of coagulopathy after trauma.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
In sepsis myocardial dysfunction is correlated with high mortality rates. Damage associated molecular patterns are released from cells during sepsis. Furthermore, the complement activation product C5a resulted in murine cardiomyocyte in defective contractility and relaxation, suggesting that interaction of C5a with its receptors is involved in the development of septic cardiomyopathy. We hypothesized that during sepsis interaction of C5a with its receptors contribute to cardiac dysfunction.
Sepsis was induced by cecal ligation and puncture (CLP) procedure. The isolation of adult rat or mouse cardiomyocytes was performed using a Langendorff perfusion system. Intracellular calcium ([Ca2+]i) and reactive oxygen species (ROS) were measured by flow cytometry using cell permeable dyes. Cardiac hemodynamic function in mice was determined with echocardiograms.
Absence of C5a receptors resulted in a significant decrease in plasma histone levels during sepsis, indicating a linkage between complement and histone appearance. In isolated rodent cardiomyocytes presence of C5a or histones resulted in time- and dose-dependent increases in [Ca2+]i and ROS. After infusion of FITC-labeled histones intravenously in wild type mice heart homogenates contained histones. Echocardiographic parameters showed improved cardiac function after CLP in absence of C5a receptors or in presence of histone neutralizing antibody.
The current studies indicate that addition of C5a or extracellular histones to CMs are associated with buildup of [Ca2+]i and ROS. Cardiac dysfunction during sepsis was correlated with presence of both C5a receptors and extracellular histones. Collectively, these alterations may explain at least in part, the cardiomyopathy in sepsis.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
During systemic inflammatory conditions, such as sepsis, the immune system is uniquely challenged. Studies indicate that excessive complement activation is associated with impaired neutrophil function although the mechanism is marginally characterised. As a balanced cytosolic pH regulation is essential for cellular function, the effect of complement activation on neutrophil pH and resulting functional changes was investigated.
Isolated human neutrophils were incubated with C5a and analyzed for intracellular pHi by flow cytometry. For evaluation of sepsis-induced changes, neutrophil pHi was determined in experimental cecal-ligation and puncture- (CLP) induced murine sepsis and in patients with septic shock (ethical approval 163/2003). Results were analyzed using one-way ANOVA followed by Student Newman-Keuls-test.
C5a significantly increased pHi in neutrophils in a dose- and time-dependent manner, whereas C3a failed to alter pHi. C5a was found to induce the sodium-hydrogen exchanger-1 (NHE-1) by C5a-receptor interaction with subsequent intracellular Ca2+ release and activation of PKC and calmodulin. This C5a-induced alkalinisation resulted in exocytosis of lactoferrin and myeloperoxidase from healthy human neutrophils and was almost normalised by inhibition of NHE-1. In vivo, CLP-induced sepsis also increased neutrophil pHi, which could be mitigated by pretreatment with a C5a-receptor antagonist. Similarly, pHi was significantly elevated in neutrophils from patients with sepsis (n = 10) compared to healthy volunteers (n = 10).
These results suggest that excessive complement activation via C5a leads to a NHE-1-mediated shift of pHi and subsequent neutrophil functions during septic shock. Therefore, targeted inhibition of the C5a-C5aR interaction may balance the pHi homeostasis of neutrophils regulating crucial cellular functions during sepsis.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Acute and chronic lung disease up-regulate purinergic receptor (P2XR4, P2XR7) expression. P2XR7 deletion or blockade attenuated pulmonary hyper-inflammation, but P2XR4 up-regulation compensated for P2XR7 deletion. Therefore, we tested the hypotheses that P2XR4 deletion may attenuate post-traumatic acute lung injury (ALI) after cigarette smoke (CS) exposure-induced COPD.
After 3-4 weeks of CS exposure, anesthetized wild type or P2XR4-ko mice (n = 8 each) underwent pressure wave-induced blunt chest trauma followed by 4 hours of lung-protective mechanical ventilation, fluid resuscitation and noradrenaline to maintain blood pressure > 55mmHg. Lung mechanics, gas exchange, hemodynamics, metabolism and acid-base status were measured together with lung histology,immune-histochemistry, and western blotting.
P2XR4-ko mice showed higher lung compliance and lower PaO2/FiO2 ratios, which coincided with higher P2XR7 expression, aggravated histological damage and immune-cell infiltration and HO-1 expression. In contrast, P2XR4 deletion was associated with less impairment of systemic hemodynamics, glucose homeostasis and acid-base status.
After CS exposure, genetic P2XR4 deletion aggravated post-traumatic ALI and hyper-inflammation, but attenuated impairment of systemic hemodynamics and metabolism, possibly due to preserved liver metabolic capacity resulting from less alveolar hypoxia-induced right ventricular re-modelling.
Supported by Ministry of Science, Research and the Arts of Baden-Württemberg (Az:32-729.55-0/239-5/32-7533.-6-10/15/1) (Boehringer Ingelheim Ulm University BioCenter).
[Show abstract][Hide abstract] ABSTRACT: Activation of both the complement and coagulation cascade after trauma and subsequent local and systemic inflammatory response represent a major scientific and clinical problem. After severe tissue injury and bone fracture, exposure of innate immunity to damaged cells and molecular debris is considered a main trigger of the posttraumatic danger response. However, the effects of cellular fragments (e.g., histones) on complement activation remain enigmatic. Furthermore, direct effects of "broken" bone and cartilage surfaces on the fluid phase response of complement and its interaction with key cells of connective tissues are still unknown. Here, we summarize data suggesting direct and indirect complement activation by extracellular and cellular danger associated molecular patterns. In addition, key complement components and the corresponding receptors (such as C3aR, C5aR) have been detected on "exposed surfaces" of the damaged regions. On a cellular level, multiple effects of complement activation products on osteoblasts, osteoclasts, chondrocytes and mesenchymal stem cells have been found.In conclusion, the complement system may be activated by trauma-altered surfaces and is crucially involved in connective tissue healing and posttraumatic systemic inflammatory response.
Advances in Experimental Medicine and Biology 08/2015; 865:43-55. DOI:10.1007/978-3-319-18603-0_3 · 1.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: After severe blunt chest trauma, the development of an acute lung injury (ALI) is often associated with severe or even lethal complications. Especially in multiple injured patients after blunt chest trauma ALI/ARDS [acute respiratory distress syndrome (ARDS)] is frequent. However, in the initial posttraumatic phase, inflammatory clinical signs are often not apparent and underlying changes in gene-expression profile are unknown.
Therefore, inflammation in lung tissue following blunt chest trauma was characterized in a well-defined bilateral lung injury model. Using DNA microarrays representing 9240 genes, the temporal sequence of blunt chest trauma-induced gene-expression patterns in lung tissue was examined.
The results suggest an activation of a highly complex transcriptional program in response to chest trauma. Chest trauma led to elevated expression levels of inflammatory and coagulatory proteins (such as TNFα receptor, IL-1α, IL-1β, C3, NF-κB and plasminogen activator). However, upregulation of proteins was found, usually incoherent of exerting effects in blunt thoracic trauma (pendrin, resistin, metallothionein and glucocorticoid-induced leucine zipper). Furthermore, significant downregulation was observed as early as 10 min after trauma for cytokines and complement factors (LCR-1, C4) as well as for intracellular signaling molecules (inhibitory protein phosphatase) and ion-channels (voltage-dependent Ca(2+) channel).
Taken together, the provided global perspective of the inflammatory response following blunt chest trauma could provide a molecular framework for future research in trauma pathophysiology.
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100 % O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.
PLoS ONE 08/2015; 10(7):e0132810. DOI:10.1371/journal.pone.0132810 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational "wet" and in silico synthetic approaches and an array of biophysical, structural, and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogs that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
European Journal of Clinical Investigation 02/2015; 45(4). DOI:10.1111/eci.12419 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Blunt chest trauma causes pulmonary and systemic inflammation. It is still a matter of debate whether the long-term course of this inflammatory response is associated with persistent impairment of lung function. We hypothesized that an increase of inflammatory biomarkers may still be present at later time points after blunt chest trauma, eventually despite normalized lung mechanics and gas exchange. Anesthetized, spontaneously breathing male C57BL/6J mice underwent a blast wave induced blunt chest trauma or sham procedure. 12 and 24 hours later, blood gases and lung mechanics were measured together with blood, bronchoalveolar lavage (BAL), and tissue cytokine concentrations (multiplex cytokine kit), heme oxygenase-1 (HO-1), activated Caspase-3, Bcl-xL, and Bax expression (western blotting), nuclear factor-κB activation (electrophoretic mobility shift assay), nitrotyrosine formation, and purinergic (P2XR4 and P2XR7) receptor expression (immunohistochemistry). Histological damage was assessed by HE and PAS staining. High-resolution respirometry allowed assessing mitochondrial respiration in diaphragm biopsies. Chest trauma significantly increased tissue and BAL cytokine levels, associated with a significant increase of HO-1, purinergic receptor expression, and tissue nitrotyrosine formation. In contrast, lung mechanics, gas exchange, and histological damage did not show any significant difference between sham and trauma groups. Activation of the immune response remains present at later time points after murine blunt chest trauma. Discordance of the increased local inflammatory response and preserved pulmonary function may be explained by a dissociation of the immune response and lung function, such as previously suggested after experimental sepsis.
[Show abstract][Hide abstract] ABSTRACT: Multipotent mesenchymal stromal cells (MSC) exert immune-modulatory effects and support tissue regeneration in various local trauma models. In case of a polytrauma, high amounts of danger-associated molecular patterns are released, leading to a systemic increase of inflammatory mediators. The influence of such a complex inflammatory microenvironment on human MSC is mainly unknown so far. Therefore, we investigated the effects of a defined serum-free polytrauma "cocktail" containing ILͳbeta, IL6, IL8 and the anaphylatoxins C3a and C5a, in concentrations corresponding to those measured in the blood of polytrauma patients, on human MSC in vitro. The polytrauma cocktail induced directed migration of MSC with C3a representing its major soluble chemoattractive agent. Furthermore, the polytrauma cocktail and IL1beta upregulated the expression of MMP1 indicating a potential role of IL1beta to enhance MSC migration in the tissue context. COX2, PTGES and TSG6 were also found to be upregulated upon stimulation with the polytrauma cocktail or IL1beta, but not through other single factors of the polytrauma cocktail in pathophysiologically relevant concentrations. An RNA expression array of 84 inflammation-related genes revealed that both the polytrauma cocktail and IL1beta induced C3, CSF1, TLR3 and various chemokines without major qualitative or quantitative differences. These results indicate that IL1beta is a crucial mediator of the polytrauma cocktail in terms of immune-modulation and MMP1 expression. Thus, upon encountering the primary sterile, inflammatory milieu of a polytrauma, endogenous or systemically transfused MSC might be able to migrate to sites of injury, secrete TSG6 and PGE2 and to influence macrophage biology as observed in local trauma models.
PLoS ONE 01/2015; 10(1):e0116772. DOI:10.1371/journal.pone.0116772 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent experimental research has either focused on the role of accidental hypothermia as part of the lethal triad after trauma or tried to elucidate the effects of therapeutically induced hypothermia on the posttraumatic course. Induced hypothermia seems to reduce the mortality in experimental models of trauma-haemorrhage. As potential mechanisms, a decrease of cellular metabolism, beneficial effects on haemodynamic function and an attenuation of the inflammatory response have been described. However, negative side effects of hypothermia have to be considered, such as impairment of the coagulatory function and immunosuppressive effects. Furthermore, the optimal strategy for the induction of hypothermia (magnitude, duration, timing, cooling rate, etc.) and subsequent rewarming remains unclear. Nevertheless, this piece of information is essential before considering hypothermia as a treatment strategy for severely injured patients. This review aims to elaborate the differences between accidental and induced hypothermia and to summarize the current knowledge of the potential therapeutic use of induced hypothermia suggested in porcine models of trauma-haemorrhage.
[Show abstract][Hide abstract] ABSTRACT: Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.
The Journal of Immunology 04/2014; 192(11). DOI:10.4049/jimmunol.1400341 · 4.92 Impact Factor