Nitric oxide synthase is downregulated, while haem oxygenase is increased, in patients with septic shock

Abstract

The vasodilatation characteristic of human septic shock is conventionally attributed to increased nitric oxide production, primarily by extrapolation of animal and human in vitro studies. There are no conclusive studies of human disease, and the cellular source of nitric oxide in human sepsis is not known. Haem oxygenase is upregulated by oxidative stress, but little is known about haem oxygenase expression in human sepsis. Haem oxygenase may modulate nitric oxide production, and may also have a direct effect on vascular tone. Mesenteric arterial smooth muscle (ASM) (obtained during laparotomy) and peripheral blood mononuclear cells (PBMCs) were obtained from patients with early septic shock and from control patients. mRNA levels were determined by real-time RT-PCR. mRNA for inducible and endothelial nitric oxide synthase was reduced in both ASM and PBMCs from septic patients. In contrast, inducible haem oxygenase mRNA was increased in sepsis in both cell types. These results suggest that, rather than being induced, the enzymes which produce nitric oxide are reduced at this time point in human septic shock. Thus many of the in vitro models of sepsis studied to date may not fully replicate human disease. The increase in haem oxygenase expression confirms that these cells have been subjected to oxidative stress in sepsis. The activity of induced haem oxygenase may limit nitric oxide production, while possibly causing vasodilation through production of carbon monoxide.