Role of C5a in multiorgan failure during sepsis

In humans with sepsis, the onset of multiorgan failure (MOF), especially in volving liver, lungs, and kidneys, is a well known complication that is ass ociated with a high mortality rate. Our previous studies with the cecal lig ation/puncture (CLP) model of sepsis in rats have revealed a C5a-induced de fect in the respiratory burst of neutrophils. In the current CLP studies, M OF occurred during the first 48 h with development of liver dysfunction and pulmonary dysfunction (falling arterial partial pressure of O-2, rising pa rtial pressure of CO2). In this model an early respiratory alkalosis develo ped, followed by a metabolic acidosis with increased levels of blood lactat e. During these events, blood neutrophils lost their chemotactic responsive ness both to C5a and to the bacterial chemotaxin, fMLP. Neutrophil dysfunct ion was associated with virtually complete loss in binding of C5a, but bind ing of fMLP remained normal. If CLP animals were treated with anti-C5a, ind icators of MOF and lactate acidosis were greatly attenuated. Under the same conditions, C5a binding to blood neutrophils remained intact; in tandem, i n vitro chemotactic responses to C5a and fMLP were retained. These data sug gest that, in the CLP model of sepsis, treatment with anti-C5a prevents dev elopment of MOF and the accompanying onset of blood neutrophil dysfunction. This may explain the protective effects of anti-C5a in the CLP model of se psis.