Compartmentalised inducible nitric-oxide synthase activity in septic shock Original Research Article

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 α (TNFα) and interleukin 1β (IL-1β). In two patients, iNOS activity was also assessed in peripheral blood mononuclear cells (PBMC) incubated with microorganisms causing the sepsis, or in macrophages isolated from suppurating peritoneal fluid incubated with IL-1β. 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 inflammed 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 skin. Compared with normal areas, putrescent areas of arteries showed increased iNOS expression (1280-fold [598–3153]; p<0·01). Compared with normal areas, TNFα and IL-1β 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 TNFα and IL-1β. PBMCs and tissue macrophages can be a cellular source for iNOS.