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C5a-Blockade Improves Burn-Induced Cardiac Dysfunction¹

Laszlo M. Hoesel^2,*, Andreas D. Niederbichler^2,, Julia Schaefer^*, Kyros R. Ipaktchi, Hongwei Gao, Daniel Rittirsch^*, Matthew J. Pianko^*, Peter M. Vogt^¶, J. Vidya Sarma^*, Grace L. Su, Saman Arbabi^||, Margaret V. Westfall, Stewart C. Wang, Mark R. Hemmila and Peter A. Ward^3,*

^* Department of Pathology, Department of Surgery, and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Biochemistry and Molecular Biology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202; ^¶ Department of Plastic and Reconstructive Surgery, Hannover Medical School, Hannover, Germany; and ^|| Department of Surgery, University of Washington, Seattle, WA 98195

We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the American College of Surgeons C. James Carrico Faculty Research Fellowship for the Study of Trauma and Critical Care (to M.R.H.) and by National Institutes of Health Grants GM54911 (to S.C.W.), GM61656 (to P.A.W.), GM29507 (to P.A.W.), and HL-31963 (to P.A.W.).

² These authors contributed equally to the work.

³ Address correspondence and reprint requests to Dr. Peter A. Ward, Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, Michigan 48109-0602. E-mail: pward{at}umich.edu

⁴ Abbreviations used in this paper: CM, cardiomyocyte; C_T, cycle threshold; LVP, left ventricular pressure; LVP_max, maximum LVP; LVP_mean, mean LVP; LVP_min, minimum LVP; MIF, migration inhibitory factor.