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. 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. Several 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. 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. We are investigating the effects of NOS1 on extravascular neutrophil recruitment, bacterial clearance, and inflammatory tissue injury during polymicrobial peritonitis, sepsis, and septic shock. We have shown that although NOS1-KO animals have reported increased migration of neutrophils in the setting of chemical peritonitis, in the setting of live bacterial peritonitis, genetic deficiency of NOS1 is detrimental and increases mortality. In addition, we found that 7-nitroindazole, a specific inhibitor of NOS1, had opposite effects in wild type animals compared to NOS1-KO. We are studying the mechanism whereby NOS1 impacts on survival, leukocyte trafficking, and bacterial clearance during sepsis and septic shock
| 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 |
