Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

430 Scopus citations


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 κB 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.

Original languageEnglish
Pages (from-to)917-928
Number of pages12
JournalJournal of Experimental Medicine
Issue number6
StatePublished - 16 Mar 1998
Externally publishedYes


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