The Journal of Experimental Medicine
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Published online 27 December 2005 doi:10.1084/jem.20051207
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 53-61
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ARTICLE

 An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction

Andreas D. Niederbichler2, Laszlo M. Hoesel1, Margaret V. Westfall2, Hongwei Gao1, Kyros R. Ipaktchi2, Lei Sun1, Firas S. Zetoune1, Grace L. Su3, Saman Arbabi2, J. Vidya Sarma1, Stewart C. Wang2, Mark R. Hemmila2, and Peter A. Ward1

1 Department of Pathology, 2 Department of Surgery, and 3 Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109

CORRESPONDENCE: Peter A. Ward: pward{at}umich.edu

Defective cardiac function during sepsis has been referred to as "cardiomyopathy of sepsis." It is known that sepsis leads to intensive activation of the complement system. In the current study, cardiac function and cardiomyocyte contractility have been evaluated in rats after cecal ligation and puncture (CLP). Significant reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro. These defects were prevented in CLP rats given blocking antibody to C5a. Both mRNA and protein for the C5a receptor (C5aR) were constitutively expressed on cardiomyocytes; both increased as a function of time after CLP. In vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and CLP cardiomyocytes, but to a consistently greater degree in cells from CLP animals. These data suggest that CLP induces C5aR on cardiomyocytes and that in vivo generation of C5a causes C5a–C5aR interaction, causing dysfunction of cardiomyocytes, resulting in compromise of cardiac performance.

Abbreviations used: ANOVA, analysis of variance; C5aR, C5a receptor; CLP, cecal ligation and puncture; CT, cycle threshold; rr, recombinant rat.

A.D. Niederbichler and L.M. Hoesel contributed equally to this work.


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