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Neutrophils (PMN) represent a first line of defense in innate immunity via their ability to generate H2O2, which is the main oxygen-dependent bactericidal pathway to clear bacteria. There is abundant evidence that sepsis causes alteration of PMN function and excessive activation of complement. In rats developing sepsis after cecal ligation/puncture (CLP), blood PMN demonstrated a reduced binding capacity for C5a, loss of chemotactic activity, impaired phagocytosis and defective respiratory burst, the latter being due to the inability to assemble NADPH-oxidase and generate H2O2. Defective assembly of NADPH oxidase was found in PMN obtained from CLP rats, as defined by an inability to translocate p47phox from the cytosol of PMN to the cell membrane. When PMN were exposed to C5a (for in vitro simulation of complement activation during sepsis), a progressive C5a - induced (time- and dose-dependent) failure of PMN function (chemotaxis, phagocytosis, H2O2-generation) was found. The oxidative burst defects were associated with failure in phosphorylation of p47phox as well as absence of phosphorylation of p42/p44 mitogen activated protein kinase (MAPK). Development of PMN dysfunction during sepsis was prevented by in vivo blockade of C5a in CLP rats, which was associated with a significantly improved survival rate. Thus, during CLP-induced sepsis at least two acquired defects in cell signalling occur, resulting in a key loss of innate immune function (bactericidal activity). These studies provide the molecular basis for the dysfunction of innate immunity during experimental sepsis and suggest a possible therapeutic approach for …