the complement anaphylatoxin c5a induces apoptosis in adrenomedullary cells during experimental sepsis补充过敏毒素c5a adrenomedullary细胞在凋亡实验败血症.pdfVIP

The Complement Anaphylatoxin C5a Induces Apoptosis in Adrenomedullary Cells during Experimental Sepsis 1 1 1 1 1 Michael A. Flierl , Daniel Rittirsch , Anthony J. Chen , Brian A. Nadeau , Danielle E. Day , J. Vidya 1 2 1 Sarma , Markus S. Huber-Lang , Peter A. Ward * 1 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 2 Department of Trauma, Hand and Reconstructive Surgery, University of Ulm Medical School, Ulm, Germany Abstract Sepsis remains a poorly understood, enigmatic disease. One of the cascades crucially involved in its pathogenesis is the complement system. Especially the anaphylatoxin C5a has been shown to have numerous harmful effects during sepsis. We have investigated the impact of high levels of C5a on the adrenal medulla following cecal ligation and puncture (CLP)- induced sepsis in rats as well as the role of C5a on catecholamine production from pheochromocytoma-derived PC12 cells. There was significant apoptosis of adrenal medulla cells in rats 24 hrs after CLP, as assessed by the TUNEL technique. These effects could be reversed by dual-blockade of the C5a receptors, C5aR and C5L2. When rats were subjected to CLP, levels of C5a and norepinephrine were found to be antipodal as a function of time. PC12 cell production of norepinephrine and dopamine was significantly blunted following exposure to recombinant rat C5a in a time-dependent and dose-dependent manner. This impaired production could be related to C5a-induced initiation of apoptosis as defined by binding of Annexin V and Propidium Iodine to PC12 cells. Collectively, we describe a C5a-dependent induction of apoptotic events in cells of