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Christian Hierholzer^*, Brian Harbrecht^*, John M. Menezes^*, John Kane^*, John MacMicking^**, Carl F. Nathan^**, Andrew B. Peitzman^*, Timothy R. Billiar^*, and David J. Tweardy^,,||

From the ^* Department of Surgery, the Department of Medicine, the Department of Molecular Genetics and Biochemistry, and the ^|| University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and the ^** Beatrice & Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York 10021

Resuscitation from hemorrhagic shock induces profound changes in the physiologic processes of many tissues and activates inflammatory cascades that include the activation of stress transcriptional factors and upregulation of cytokine synthesis. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that the inducible nitric oxide synthase (iNOS) is expressed during hemorrhagic shock. We postulated that nitric oxide production from iNOS would participate in proinflammatory signaling. Using the iNOS inhibitor N⁶-(iminoethyl)-L-lysine or iNOS knockout mice we found that the activation of the transcriptional factors nuclear factor B and signal transducer and activator of transcription 3 and increases in IL-6 and G-CSF messenger RNA levels in the lungs and livers measured 4 h after resuscitation from hemorrhagic shock were iNOS dependent. Furthermore, iNOS inhibition resulted in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide is essential for the upregulation of the inflammatory response in resuscitated hemorrhagic shock and participates in end organ damage under these conditions.

The present address of J. MacMicking is Laboratory of Immunology, HHMI, The Rockefeller University, 1230 York Ave., New York 10021.

Abbreviations used: ALT, alanine aminotransferase; EMSA, electrophoretic mobility shift assay; G-CSF, granulocyte colony-stimulating factor; hSIE, high-affinity serum-inducible element; iNOS, inducible NO synthase; L-NIL, N⁶-(iminoethyl)-L-lysine; MAP, mean arterial blood pressure; MPO, myeloperoxidase; mRNA, messenger RNA; NF, nuclear factor; NO, nitric oxide; p, protein; RT-PCR, reverse transcriptase PCR; SIF, serum-inducible factor; stat, signal transducer and activator of transcription.

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