Complement C5a and adrenal cell function: examining a potential mechanism of adrenal dysfunction in sepsis

Abstract

The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production and release. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. Cellular and molecular techniques were utilized to identify the effect of C5a on a cell culture model employing PC12 cells derived from a rat pheochromocytoma (tumour of adrenal medullary chromaffin cells). This thesis identifies impairment of PC12 cell function following septic-level exposure to C5a, as well as an immediate increase in catecholamine release, followed by a decrease in catecholamine biosynthetic enzyme expression and catecholamine secretion. Furthermore, septic-level C5a induces apoptosis in PC12 cells through C5aR-dependent protein kinase signalling. These results provide insight into the regulation of catecholamine biosynthesis and release and the mechanism of adrenal dysfunction in sepsis.