Neutralizing the effects of the C5a protein fragment may represent a new therapeutic approach to preventing sepsis-related heart failure, researchers claim. Work in mice and rats by a University of Michigan team showed that injecting sepsis-induced mice with a C5a-neutralizing antibody significantly reduced detrimental cytokine activity. Moreover, in mice bred to lack C5a receptors, the induction of sepsis resulted in little or no spontaneous release of cytokines from heart cells. The research is published in The FASEB Journal, in a paper titled, “Complement dependency of cardiomyocyte release of mediators during sepsis.”
Severe sepsis affects about 750,000 people in the U.S. every year, and up to 50% of these patients die, which is more than the combined number of U.S. deaths from prostate cancer, breast cancer, and AIDS every year, according to NIH figures quoted by Peter A. Ward, M.D., and colleagues at the University Medical School’s department of pathology.
The team says it has recently shown that antibody-induced blockade of C5a, C5a receptors, or IL-17A greatly reduces the harmful outcomes of sepsis. To further investigate the potential to block sepsis-related cytokine release, the researchers first demonstrated that normal isolated cardiomyocytes from young rats responded in vitro to C5a by releasing IL-6 and TNFα. They then showed that adding anti-C5a or IL-17A neutralizing antibodies to mouse cardiomyocytes taken from sepsis-induced animals reduced the spontaneous release of cardiosuppressive cytokines and chemokines in vitro. Importantly, a non-neutralizing C5a antibody had no such effects, they note. Cardiomyocytes from engineered mice lacking the C5a receptor also showed little or no spontaneous in vitro release of cytokines and chemokines.
The overall findings suggest that in sepsis, cardiomyocytes interact with the complement-derived C5a anaphylatoxin to result in the release of cardiosuppressive cytokines, Dr. Ward notes. “These data suggest that cardiomyocytes from septic mice release suppressive cytokines in a C5a-, C5aR-, and IL-17A-dependent manner, followed by mediator reactivity with receptors on cardiomyocytes, resulting in defective contractility and relaxation,” the authors write.
“Now that we know that C5a is at least partly responsible, antibodies to C5a promise to get to the heart of the problem,” Dr. Ward concludes.