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Role of C5a in Multiorgan Failure During Sepsis¹

Markus Huber-Lang^*, Vidya J. Sarma^*, Kristina T. Lu^*, Stephanie R. McGuire^*, Vaishalee A. Padgaonkar^*, Ren-Feng Guo^*, Ellen M. Younkin^*, Robin G. Kunkel^*, Jiabing Ding, Richard Erickson, John T. Curnutte and Peter A. Ward^2,*

^* Department of Pathology University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Immunology, Genentech, South San Francisco, CA 94080

In humans with sepsis, the onset of multiorgan failure (MOF), especially involving liver, lungs, and kidneys, is a well known complication that is associated with a high mortality rate. Our previous studies with the cecal ligation/puncture (CLP) model of sepsis in rats have revealed a C5a-induced defect in the respiratory burst of neutrophils. In the current CLP studies, MOF occurred during the first 48 h with development of liver dysfunction and pulmonary dysfunction (falling arterial partial pressure of O₂, rising partial pressure of CO₂). In this model an early respiratory alkalosis developed, followed by a metabolic acidosis with increased levels of blood lactate. During these events, blood neutrophils lost their chemotactic responsiveness both to C5a and to the bacterial chemotaxin, fMLP. Neutrophil dysfunction was associated with virtually complete loss in binding of C5a, but binding of fMLP remained normal. If CLP animals were treated with anti-C5a, indicators of MOF and lactate acidosis were greatly attenuated. Under the same conditions, C5a binding to blood neutrophils remained intact; in tandem, in vitro chemotactic responses to C5a and fMLP were retained. These data suggest that, in the CLP model of sepsis, treatment with anti-C5a prevents development of MOF and the accompanying onset of blood neutrophil dysfunction. This may explain the protective effects of anti-C5a in the CLP model of sepsis.

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