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 adrenal medulla in vivo and
pheochromocytoma PC12 cells in vitro. These data suggest that experimental
sepsis induces apoptosis of adrenomedullary cells, which are responsible for the bulk of endogenous
catecholamines.
Septic shock may be linked to these events. Since blockade of both
C5a receptors virtually abolished adrenomedullary apoptosis in vivo, C5aR and C5L2 become promising targets with implications on future
complement-blocking strategies in the clinical setting of
sepsis.