Markus Huber-Lang

Universität Ulm, Ulm, Baden-Württemberg, Germany

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Publications (153)524.32 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca(2+)]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nacht-, LRR-, and PYD-domains-containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca(2+)]i, as well as defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.-Kalbitz, M., Grailer, J. J., Fattahi, F., Jajou, L., Herron, T. J., Campbell, K. F., Zetoune, F. S., Bosmann, M., Sarma, J. V., Huber-Lang, M., Gebhard, F., Loaiza, R., Valdivia, H. H., Jalife, J., Russell, M. W., and Ward, P. A. Role of extracellular histones in the cardiomyopathy of sepsis. © FASEB.
    The FASEB Journal 02/2015; 29(5). DOI:10.1096/fj.14-268730 · 5.48 Impact Factor
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    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 · 2.83 Impact Factor
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    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.
    Shock 02/2015; 43(2):140-7. DOI:10.1097/SHK.0000000000000277 · 2.73 Impact Factor
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    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
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    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.
    01/2015; 20(1):70. DOI:10.1186/s40001-015-0164-y
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    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.
    12/2014; 2(1):16. DOI:10.1186/2197-425X-2-16
  • Shock (Augusta, Ga.) 06/2014; 41(6):554-5. DOI:10.1097/SHK.0000000000000166 · 2.73 Impact Factor
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    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 · 5.36 Impact Factor
  • M Weiss · Z Gueldue · M Georgieff · F Gebhard · M Huber-Lang · M Schneider
    Critical Care 03/2014; 18(Suppl 1):P228. DOI:10.1186/cc13418 · 5.04 Impact Factor
  • 14th European Meeting on Complement in Human Disease; 12/2013
  • S. Denk · D. Rittirsch · H. Barth · J. Sarma · P. Ward · M. Huber-Lang
    Molecular Immunology 12/2013; 56(3):247. DOI:10.1016/j.molimm.2013.05.028 · 3.00 Impact Factor
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    ABSTRACT: There is increasing evidence that complement may play a role in bone development. Our previous studies demonstrated that the key complement receptor C5aR was strongly expressed in the fracture callus not only by immune cells but also by bone cells and chondroblasts, indicating a function in bone repair. To further elucidate the role of complement in bone healing, this study investigated fracture healing in mice in the absence of the key complement molecules C3 and C5. C3(-/-) and C5(-/-) as well as the corresponding wildtype mice received a standardized femur osteotomy, which was stabilized using an external fixator. Fracture healing was investigated after 7 and 21 days using histological, micro-computed tomography and biomechanical measurements. In the early phase of fracture healing, reduced callus area (C3(-/-): -25%, p=0.02; C5(-/-): -20% p=0.052) and newly formed bone (C3(-/-): -38%, p=0.01; C5(-/-): -52%, p=0.009) was found in both C3- and C5-deficient mice. After 21 days, healing was successful in the absence of C3, whereas in C5-deficient mice fracture repair was significantly reduced, which was confirmed by a reduced bending stiffness (-45%; p=0.029) and a smaller callus volume (-17%; p=0.039). We further demonstrated that C5a was activated in C3(-/-) mice, suggesting cleavage via extrinsic pathways. Our results suggest that the activation of the terminal complement cascade in particular may be crucial for successful fracture healing.
    PLoS ONE 11/2013; 8(11):e81341. DOI:10.1371/journal.pone.0081341 · 3.23 Impact Factor
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    Wolfgang Ochsner · Sandra Geiler · Markus Huber-Lang
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    ABSTRACT: Study Goals: It is known that the manifold limitations of oral and practical examinations can be improved by specific training. With the help of an online survey, our present study analyzes the effects that can be achieved by the training conducted at the University of Ulm for examiners in the final medical examination, the long-lasting impact of the training, and differences among participant subgroups. Method: All 367 participants in the training at Ulm (2007- 2012) were contacted via email. Sixty-three persons responded to the survey that included 28 items concerning demographic data, effectiveness, and sustainability. Results: Six main effects of the training were identified (meaning effects rated with a grade of 1 or 2 on a 6-point scale by two thirds of the participants, with 1="applicable" and 6="not applicable"; cumulated percentage of answers of 1 or 2 in parentheses): Conscious handling of strengths and weaknesses of oral examinations (71%),Knowledge of factors contributing to the reliability of oral/practical examinations (76%),Knowledge of factors contributing to the validity of oral/practical examinations (75%),Improvement of competence in task construction (68%),Improvement of competence in respect to examination formalities (75%),Implementation of the concept of "structured oral examinations" (a priori planning of examination subjects, tasks, levels of expectation and grading criteria) (86%). The responses of participants trained more than two years ago were not significantly different from the answers given by recently trained persons. This is an argument for the sustainability of the training effects. Furthermore, participants without relevant prior experience in oral/practical examinations profited significantly more from the trainings, especially in the areas of stress reduction, confidence in grading, and competence in critical discrimination of grading. Conclusion: The positive and sustained effects of the examiner training argue for continuing the training program, especially for inexperienced examiners. Expansion of the successful training program to include the first medical exam should be considered.
    08/2013; 30(3):Doc36. DOI:10.3205/zma000879
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    ABSTRACT: Complement factor C5a is a potent pro-inflammatory mediator that contributes to the pathogenesis of numerous inflammatory diseases. Here we describe the discovery of NOX-D20, a PEGylated biostable mirror-image mixed (L-)RNA/DNA aptamer (Spiegelmer) that binds to mouse and human C5a with picomolar affinity. In vitro, NOX-D20 inhibited C5a-induced chemotaxis of a CD88-expressing cell line and efficiently antagonized the activation of primary human polymorphonuclear leukocytes by C5a. Binding of NOX-D20 to the C5a moiety of human C5 did not interfere with the formation of the terminal membrane attack complex. In sepsis, for which a specific interventional therapy is currently lacking, complement activation and elevated levels of C5a are suggested to contribute to multi-organ failure and mortality. In the model of polymicrobial sepsis induced by cecal ligation and puncture, NOX-D20 attenuated inflammation and organ damage, prevented the breakdown of the vascular endothelial barrier, and improved survival. Our study suggests NOX-D20 as a new therapeutic candidate for the treatment of sepsis.Molecular Therapy (2013); doi:10.1038/mt.2013.178.
    Molecular Therapy 07/2013; 21(12). DOI:10.1038/mt.2013.178 · 6.43 Impact Factor
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    ABSTRACT: The majority of injury combinations in multiply injured patients entail the chest, abdomen and extremities. Numerous pig models focus on the investigation of posttraumatic pathophysiology, organ performance monitoring and on potential treatment options. Depending on the experimental question, previous authors have included isolated insults (controlled or uncontrolled hemorrhage, chest trauma) or a combination of these injuries (hemorrhage with abdominal trauma, chest trauma, traumatic brain injury and/or long bone fractures).Combined trauma models in pigs can provide a high level of clinical relevance, when they are properly designed and mimicking the clinical situation. However, most of these models focus on the first hours after trauma, to assess the acute sequel of traumatic hemorrhage. However, hemorrhagic shock and the associated mass transfusion are also major causes for organ failure and mortality in the later clinical course. Thus, most models lack information on the pathomechanisms during the late posttraumatic phase. Studying new therapies only during the early phase is also not reflective of the clinical situation. Therefore, a longer observation period is required to study the effects of therapeutic approaches during intensive care treatment when using animal models. These long-term studies of combined trauma models will allow the development of valuable therapeutic approaches relevant for the later posttraumatic course. This review summarizes the existing porcine models and outlines the need for long term models in order to provide real effective novel therapeutics for multiple injured patients to improve organ function and clinical outcome.
    Shock (Augusta, Ga.) 07/2013; DOI:10.1097/SHK.0b013e3182a3cd74 · 2.73 Impact Factor
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    Wolfgang Oechsner · Sandra Geiler · Markus Huber-Lang
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    ABSTRACT: Oral examinations have been a crucial format in ancient and modern assessment to evaluate and guarantee quality of medical education and thereby to secure patient safety. To achieve a high level of quality in the oral part of the final examination of medical students, a training program for oral examiners at the Medical Faculty of Ulm (Germany) has been established since 2007.However, little is known about the attitude of the examiners in regard to the impact of this training program and of oral examinations as instruments to ensure patient safety. All 367 academic clinicians from operative and non-operative disciplines, attending the one-day examiner training program at the University of Ulm between 2007 and 2012 have been asked to answer an online survey (EvaSys 5.0). Focus of the survey was to find out in which respect the examiners profited from the trainings, if the training effects were discipline-dependent, and to which degree the oral examinations could contribute to patient safety. Statistical analysis was performed using the t-test for independent samples. Results were considered statistically significant when p < 0.05. A total of 63 participants answered the survey, but in 4 cases the questionnaire was not fully completed (with single items missing). More than half of the study participants (n = 34/59; 58%) have experienced (at least sometimes or rarely) candidates that they deemed incompetent and perhaps even dangerous to the patients' health who nevertheless passed the oral exam successfully. The majority of participants were convinced that oral examinations using concrete clinical cases could significantly contribute to patient safety, if grading is based on clear criteria and if examinations as well as grading are performed more critically. The impact of the training program was rated significantly stronger by surgeons than by non-surgeons in several categories. These categories included "strengths and weaknesses of oral examinations", "reliability", "validity", "competence in grading", "critical grading", and "departmental improvements" concerning oral examinations. In respect to patient safety, it seems crucial to prevent incompetent candidates from passing the oral examination. The present study indicates the importance to continue and to develop our examiner trainings, with main emphasis on concrete clinical problems and a criteria-based critical grading system for oral examinations. Since the impact of the training was particularly high for colleagues from the operative disciplines, the training program should be offered especially in surgical departments.
    Patient Safety in Surgery 07/2013; 7(1):22. DOI:10.1186/1754-9493-7-22
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    ABSTRACT: Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way. Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the µM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro. These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax.
    PLoS ONE 06/2013; 8(6):e66099. DOI:10.1371/journal.pone.0066099 · 3.23 Impact Factor
  • Markus Huber-Lang · Anna Kovtun · Anita Ignatius
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    ABSTRACT: The complement system, as part of innate immunity, is activated immediately after trauma in response to various pathogen- and danger-associated molecular patterns (PAMPs and DAMPs), and helps to eliminate microorganisms and damaged cells. However, recent data indicate an extended role of complement far beyond pure "killing", which includes regulation of the cytokine/chemokine network, influencing physiological barriers, interaction with the coagulation cascade, and even involvement with bone metabolism and repair. Complement-induced hyper-activation and dysfunction reveal the dark side of this system, leading to complications such as sepsis, multiple-organ dysfunction, delayed fracture healing, and unfavorable outcome. Thus, the present review focuses on less known regulatory roles of the complement system after trauma and during fracture healing, rather than on its bacterial and cellular "killing functions". In particular, various complement crosstalks after trauma, including the coagulation cascade and apoptosis system, appear to be crucially involved early after trauma. Long-term effects of complement on tissue regeneration after fracture and bone turnover are also considered, providing new insights into innate immunity in local and systemic complement-driven effects after trauma.
    Seminars in Immunology 06/2013; 25(1):73-78. DOI:10.1016/j.smim.2013.05.006 · 6.12 Impact Factor
  • Peter Radermacher · Markus Huber-Lang · Christoph Thiemermann
    Shock (Augusta, Ga.) 04/2013; 39(4):404-5. DOI:10.1097/SHK.0b013e31828b247b · 2.73 Impact Factor
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    ABSTRACT: During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.
    The Journal of Immunology 03/2013; 190(8). DOI:10.4049/jimmunol.1200534 · 5.36 Impact Factor

Publication Stats

3k Citations
524.32 Total Impact Points


  • 2003–2015
    • Universität Ulm
      • • Centre of Surgery
      • • Clinic of Trauma, Hand, Plastic and Reconstructive Surgery
      Ulm, Baden-Württemberg, Germany
  • 2014
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 2012
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 1999–2008
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2005
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2000
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany