Several studies have now shown that nitric oxide (NO), a free radical gas produced endogenously, has profound effects on the function of leukocytes and in the overall host immune response to infection, sepsis and septic shock. In cells, NO is synthesized by three different isoforms of an enzyme named NO synthase (NOS). Two of these isoforms, NOS1 and NOS3 are constitutively expressed, while the third, NOS2, is an inducible (by toxins and cytokines) form of the enzyme. Differing lines of evidence suggest that NOS1 may have a very important role in the pathophysiology of sepsis. The enzyme is constitutively expressed not only in neuronal cells in the brain and spinal cord, but also in the microvasculature and epithelium of the gastrointestinal tract and kidney, bronchial epithelium, myocytes of skeletal muscle, mast cells in skin, and neutrophils. Researchers have shown that, under baseline conditions and during sterile peritonitis, mice congenitally lacking NOS1 (NOS1 knock out, NOS1-KO) have increased leukocyte rolling and adhesion to the endothelium of postcapillary venules and increased leukocyte migration into the peritoneal cavity. The purpose of this study is to investigate the effects of NOS1 on extravascular neutrophil recruitment, bacterial clearance, and inflammatory tissue injury during polymicrobial peritonitis, sepsis, and septic shock. We hypothesize that absence of NOS1, either in genetically engineered mice that congenitally lack the NOS1 gene or in wild type mice (phenotype considered normal) treated with a pharmacologic inhibitor of NOS1, will increase extravascular neutrophil recruitment and improve bacterial clearance and outcome during polymicrobial peritonitis and sepsis. Following cecal ligation and puncture in wild type or NOS1-KO mice randomized to receive a NOS1 inhibitor or placebo, survival, extravascular neutrophil recruitment, microbial clearance, and inflammatory tissue injury will be measured
| Finkel, Julia; Guptill, Virginia; Khaibullina, Alfia et al. (2012) The three isoforms of nitric oxide synthase distinctively affect mouse nocifensive behavior. Nitric Oxide 26:81-8 |
| Cui, Xizhong; Besch, Virginia; Khaibullina, Alfia et al. (2007) Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis. Intensive Care Med 33:1993-2003 |
