Nitric oxide (NO) is normally produced in the endothelium by the constitutive isoform of the NO synthase. This physiological production of NO is important for blood pressure regulation and blood flow distribution. Several lines of evidence suggest that a hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Lipopolysaccarides and cytokines, such as tumor necrosis factor, interleukin-1 and interferon-gamma, have been shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells. Treatment with inhibitors of NO synthesis has been shown to improve hemodynamic variables and survival in several animal models of septic shock. In human septic shock, inhibition of NO synthesis has been shown to alter hemodynamic variables in short-term studies, but it is uncertain whether this treatment has beneficial long-term effects. The aim of this review is to give an overview of the physiological role of NO and to discuss the role of NO in sepsis and the potential therapeutic implications of NO as a target in treatment of human septic shock. A main new aspect of this review is a critical discussion of previous reports measuring plasma nitrite/nitrate during septic shock and an evaluation of the validity of interpreting these data as evidence for a hyperproduction of NO. This review also emphasizes that many septic patients have preexisting endothelial dysfunction and lung diseases, which may contribute to adverse effects by systemic inhibition of NO synthesis. Another new aspect of the present review is a focus on the lack of direct evidence of iNOS expression in human septic shock.

Plasma concentrations of NOx and NT are elevated in primary episodes of septic shock and may also be elevated in secondary septic shock, but too few episodes of recurrent septic shock occurred to allow firm conclusions. Plasma concentrations of NT are elevated in patients with septic shock with normal plasma NOx concentrations, indicating that plasma concentrations of NOx may not always accurately reflect NO production. Reactive nitrogen species may be formed in septic shock, and measuring both NOx and NT may give a better indication of NO production in septic shock than NOx alone. Plasma levels of nitrosothiols did not change during septic shock.

BackgroundScrub typhus, caused by Orientia tsutsugamushi, is endemic in the Asia-Pacific region. Mortality is high if untreated, and even with treatment as high as 10–20%, further knowledge of the immune response during scrub typhus is needed. The current study was aimed at comparing plasma levels of a variety of inflammatory mediators in scrub typhus patients and controls in South India in order to map the broader cytokine profile and their relation to disease severity and clinical outcome.Methodology/Principal FindingsWe examined plasma levels of several cytokines in scrub typhus patients (n = 129) compared to healthy controls (n = 31) and infectious disease controls (n = 31), both in the acute phase and after recovery, by multiplex technology and enzyme immunoassays. Scrub typhus patients were characterized by marked changes in the cytokine network during the acute phase, differing not only from healthy controls but also from infectious disease controls. While most of the inflammatory markers were raised in scrub typhus, platelet-derived mediators such as RANTES were markedly decreased, probably reflecting enhanced platelet activation. Some of the inflammatory markers, including various chemokines (e.g., interleukin-8, monocyte chemoattractant peptide-1 and macrophage inflammatory protein-1β) and downstream markers of inflammation (e.g., C-reactive protein and pentraxin-3), were also associated with disease severity and mortality during follow-up, with a particular strong association with interleukin-8.Conclusions/SignificanceOur findings suggest that scrub typhus is characterized by a certain cytokine profile that includes dysregulated levels of a wide range of mediators, and that this enhanced inflammation could contribute to disease severity and clinical outcome.

In this porcine model of peritoneal sepsis, infusion of L-NMMA increased survival rate and maintained mean arterial pressure without worsening tissue oxygenation. Coronary blood flow, cardiac index, systemic vascular resistance, and urine production were well maintained during L-NMMA treatment.