Decreased arginine de novo synthesis as cause of multiple organ failure during sepsis: mechanistic studies in experimental and human sepsis
09 / 2007 - 09 / 2010
Sepsis is an exaggerated inflammatory response to an infection leading to dysfunction of multiple organs. Mortality due to multiple organ failure (MOF) ranges from 40-70%. The incidence of sepsis in the Netherlands has been estimated to be 25-30% of all intensive care patients. Until recently, global hypotension and perfusion disturbances were thought to be the main pathophysiological features of sepsis and MODS. Exaggerated production of nitric oxide (NO) by the inducible enzyme NO synthase (NOS-2) was seen as a key factor in the pathophysiology, since NO causes vasodilatation resulting in hypotension. Despite the ability to treat these global perfusion abnormalities, mortality rates remain high. Recent data showed the importance of regional disturbances of microcirculation in the liver and gut in the development of MODS. Disturbances in NO production and its precursor arginine play an important role in the disregulation of the microcirculation. Interestingly, it was recently found that decreased endogenous NOS (NOS-1 and NOS-3) induced NO production in liver and gut is essential and not increased NOS-2 induced NO production. Decreased NO production by endogenous NOS leads to local vasoconstriction, which results in reduced perfusion and function of liver and gut. Recently our group was the first to show severely depressed arginine de novo synthesis (arginine production from citrulline) during sepsis, which resulted in limited availability of arginine. Septic patients with a decreased arginine de novo synthesis have an increased mortality rate. The underlying mechanisms of this decreased arginine de novo synthesis have not been investigated before. This present research proposal addresses the hypothesis that decreased arginine de novo synthesis leads to decreased NO synthesis, which consequently compromises organ perfusion and function.Both experimental studies using knock-out mice models and human studies in sepsis will address the effects of and the mechanisms underlying this reduced arginine de novo synthesis. Our research group has extensive experience in the application of stable isotope and perfusion techniques both in human and animal studies to address this issue. This research proposal may finally result in therapeutic options directed at modulation of de novo arginine synthesis.