Complement dependency of cardiomyocyte release of mediators during sepsis

Atefi, Gelareh; Zetoune, Firas S.; Herron, Todd J.; Jalife, José; Bosmann, Markus; Al-Aref, Rami; Sarma, J. Vidya; Ward, Peter A.

doi:10.1096/fj.11-183236

Cited by 52 publications

(47 citation statements)

References 30 publications

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“…C5a is a major cardio-depressant (41). CLP sepsis in rodents induces expression of C5aR on cardiomyocytes and increased generation of C5a causes dysfunction of cardiomyocytes (42).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

Keshari

Silasi‐Mansat

Popescu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9. RA101295 reduced the E. coliinduced "oxidative burst," as well as leukocyte activation, without affecting host phagocytosis of E. coli. RA101295 treatment reduced plasma LPS content in E. coli-challenged baboons, implying reduced complement-mediated bacteriolysis, whereas treated animals showed slightly improved bacterial clearance during the bacteremic stage compared with controls. Treatment with RA101295 also improved consumptive coagulopathy and preserved endothelial anticoagulant and vascular barrier functions. RA101295 abolished sepsis-induced surges in proinflammatory cytokines and attenuated systemic circulatory and febrile responses, likely reflecting decreased systemic levels of LPS and C5a. Overall, RA101295 treatment was associated with significant organ protection and markedly reduced mortality compared with nontreated controls (four of five animals survived in a 100% lethal model). We therefore conclude that inhibition of C5 cleavage during the bacteremic stage of sepsis could be an important therapeutic approach to prevent sepsis-induced inflammation, consumptive coagulopathy, and subsequent organ failure and death. complement | coagulation | sepsis | Escherichia coli | organ failure

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“…C5a is a major cardio-depressant (41). CLP sepsis in rodents induces expression of C5aR on cardiomyocytes and increased generation of C5a causes dysfunction of cardiomyocytes (42).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

Keshari

Silasi‐Mansat

Popescu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…C5a-C5a receptor interaction has previously been shown to be centrally involved in sepsis-induced cardiomyocyte dysfunction and heart failure (Niederbichler et al, 2006;Atefi et al, 2011). Recent data show that complement may be a pivotal regulator of sterile inflammatory processes in the heart as well, and Iyer et al showed that C5a receptor antagonism with the cyclic peptide antagonist PMX53 inhibited hypertension-induced myocardial fibrosis and stiffness (Iyer et al, 2011).…”

Section: Pathogenic Role Of Complement In Heart Failure Developmentmentioning

confidence: 99%

A vital role for complement in heart disease

Lappegård

Garred

Jonasson

et al. 2014

Molecular Immunology

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Heart diseases are common and significant contributors to worldwide mortality and morbidity. During recent years complement mediated inflammation has been shown to be an important player in a variety of heart diseases. Despite some negative results from clinical trials using complement inhibitors, emerging evidence points to an association between the complement system and heart diseases. Thus, complement seems to be important in coronary heart disease as well as in heart failure, where several studies underscore the prognostic importance of complement activation. Furthermore, patients with atrial fibrillation often share risk factors both with coronary heart disease and heart failure, and there is some evidence implicating complement activation in atrial fibrillation. Moreover, Chagas heart disease, a protozoal infection, is an important cause of heart failure in Latin America, and the complement system is crucial for the protozoa-host interaction. Thus, complement activation appears to be involved in the pathophysiology of a diverse range of cardiac conditions. Determination of the exact role of complement in the various heart diseases will hopefully help to identify patients that might benefit from therapeutic complement intervention.

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“…A total of 100 l of each diluted sample was placed on Trypticase soy agar plates with 5% sheep blood (Becton, Dickinson GmbH, Heidelberg, Germany) separately and incubated at 37°C for 24 h under aerobic conditions, and colonies were counted after 24 h of incubation. Bacterial counts are expressed as the number of CFU (ϫ10 5 ) per milliliter of blood and number of CFU (ϫ10 3 ) per gram of tissue. Statistics.…”

Section: Regulatory T Cellsmentioning

confidence: 99%

“…Systemic inflammation is characterized by increased plasma levels of high-mobility group box 1 (HMGB1) and interleukin 6 (IL-6), which are both well-known predictors of clinical outcome in patients with severe sepsis (3,4). IL-17 is rapidly formed in response to bacterial infections and triggers synthesis of other proinflammatory compounds, such as IL-1, IL-6, and IL-8, collectively resulting in neutrophil accumulation (5,6). On the other hand, the septic insult disturbs the immune system, which becomes incapable of mounting effective host defense responses against invading microbes due to macrophage and T-cell dysfunction.…”

mentioning

confidence: 99%