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.
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16 March 1998
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March 16 1998
Essential Role of Induced Nitric Oxide in the Initiation of the Inflammatory Response after Hemorrhagic Shock
Christian Hierholzer,
Christian Hierholzer
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
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Brian Harbrecht,
Brian Harbrecht
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
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John M. Menezes,
John M. Menezes
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
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John Kane,
John Kane
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
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John MacMicking,
John MacMicking
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
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Carl F. Nathan,
Carl F. Nathan
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
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Andrew B. Peitzman,
Andrew B. Peitzman
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
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Timothy R. Billiar,
Timothy R. Billiar
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
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David J. Tweardy
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
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Christian Hierholzer,
Brian Harbrecht,
John M. Menezes,
John Kane,
John MacMicking,
Carl F. Nathan,
Andrew B. Peitzman,
Timothy R. Billiar,
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
Address correspondence to David J. Tweardy, W1052 Biomedical Science Tower, University of Pittsburgh Cancer Institute, 200 Lothrop St., Pittsburgh, PA 15213. Phone: 412-624-0344; Fax: 412-624-7737; E-mail: [email protected]
The present address of J. MacMicking is Laboratory of Immunology, HHMI, The Rockefeller University, 1230 York Ave., New York 10021.
Received:
October 17 1997
Revision Received:
December 12 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (6): 917–928.
Article history
Received:
October 17 1997
Revision Received:
December 12 1997
Citation
Christian Hierholzer, Brian Harbrecht, John M. Menezes, John Kane, John MacMicking, Carl F. Nathan, Andrew B. Peitzman, Timothy R. Billiar, David J. Tweardy; Essential Role of Induced Nitric Oxide in the Initiation of the Inflammatory Response after Hemorrhagic Shock . J Exp Med 16 March 1998; 187 (6): 917–928. doi: https://doi.org/10.1084/jem.187.6.917
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