ESSENTIAL ROLE OF INDUCED NITRIC-OXIDE IN THE INITIATION OF THE INFLAMMATORY RESPONSE AFTER HEMORRHAGIC-SHOCK

Resuscitation from hemorrhagic shock induces profound changes in the p hysiologic processes of many tissues and activates inflammatory cascad es that include the activation of stress transcriptional factors and u pregulation of cytokine synthesis. This process is accompanied by acut e organ damage (e.g., lungs and liver). We have previously demonstrate d that the inducible nitric oxide synthase (iNOS) is ex-pressed during hemorrhagic shock. We postulated that nitric oxide production from iN OS would participate in proinflammatory signaling. Using the INOS inhi bitor N-6-(iminoethyl)-L-lysine or iNOS knockout mice we found that th e activation of the transcriptional factors nuclear factor KB and sign al transducer and activator of transcription 3 and increases in IL-6 a nd G-CSF messenger RNA levels in the lungs and livers measured 4 h aft er resuscitation from hemorrhagic shock were INOS dependent. Furthermo re, iNOS inhibition resulted in a marked reduction of lung and Liver i njury produced by hemorrhagic shock. Thus, induced nitric oxide is ess ential for the upregulation of the inflammatory response in resuscitat ed hemorrhage shock and participates in end organ damage under these c onditions.