Role of S-nitrosohemoglobin in Sepsis

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DESCRIPTION (provided by applicant): Septic shock is a leading cause of mortality in hospitalized patients and is defined as the systemic inflammatory response to infection. This disease is characterized by hypotension and inflammatory damage to organs including the lung and which ultimately leads to multiple organ failure and death. Nitric oxide (NO) has a critical role in this disease with NO produced from iNOS receiving much attention. However, the role of NO in sepsis remains unclear with both detrimental and beneficial roles reported. An important regulator of NO function in the vasculature is Hemoglobin (Hb). Recent insights into the reactions between NO and Hb have shown that in addition to reactions with the heme, NO also interacts with a critical cysteine residue forming S-nitrosohemoglobin (SNOHb). SNOHb can elicit NO dependent effects and has been investigated principally in the context of physiological regulation of blood flow. The potential role of SNOHb in pathology has not been considered however. Recent studies show that SNOHb is elevated during endotoxemia and in this proposal, the novel concept that SNOHb mediates endotoxin induced hypotensive and inflammatory responses, by modulating production of different redox congeners of NO is put forward. The biological role of redox derivatives of NO, including nitroxyl anion (N0-) in disease remains largely unexplored although functions in promoting vasodilatation and stimulation of inflammatory responses have been suggested. Preliminary data presented herein suggest that SNOHb dependent vasorelaxation occurs via formation of N0- and vasorelaxing effects of red blood cells purified from endotoxin treated rats are demonstrated. These observations have led to the hypothesis that systemic hypotension and inflammation observed in sepsis are mediated by SNOHb. This hypothesis will be tested by pursuit of the following specific aims: 1) Determine the mechanism of SNOHb formation in endotoxic shock; 2) Determine the vasodilatory mechanisms of SNOHb; and 3) Investigate the role of SNOHb as a mediator of inflammatory damage in the lung. Accomplishment of these aims will yield novel insights into both the molecular mechanisms by which NO impacts upon the pathogenesis of septicemia and on possible therapeutic strategies to treat this inflammatory disease.