Compartmentalised inducible nitric-oxide synthase activity in septic shock

Background Previous experimental studies support a role for inducible nitric-oxide synthase (iNOS) in the pathogenesis of severe sepsis. The aim of the study was to characterise iNOS activity in different tissues in patients with septic shock. Methods 13 consecutive patients with septic shock caused by cellulitis were enrolled. Skin, muscle, fat, and artery samples were obtained from normal, inflamed, and putrescent areas to measure iNOS activity, and concentrations of tumour necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta), In two patients, iNOS activity was also assessed in peripheral blood mononuclear cells (PRMC) incubated with microorganisms causing the sepsis, or in macrophages isolated from suppurating peritoneal fluid incubated with IL-1 beta. Findings: Compared with normal and inflamed areas, iNOS activity was increased in putrescent areas for muscle (71-fold [95% CI 20-259] vs normal areas, 69-fold [19-246] vs inflamed areas; p<0.01 for each) and for fat (68-fold [23-199] and 49-fold [18-137], respectively; p<0.01), but not for shin. Compared with normal areas, putrescent areas of arteries showed increased iNOS expression (1280-fold [598-3153]; p<0.01). Compared with normal areas, TNF alpha and IL-1 beta were increased in putrescent areas of arteries (223-fold and 41-fold, respectively; p<0.01 for each). PBMCs and tissue macrophages expressed iNOS. Plasma nitrite/nitrate concentrations inversely correlated with mean arterial pressure and systemic vascular resistance. Interpretation: In human septic shock we found that iNOS activity is compartmentalised at the very site of infection and parallels expression of TNF alpha and IL-1 beta. PBMCs and tissue macrophages can be a cellular source for iNOS.