Previous studies have proposed that a major cause of shock in sepsis is expression of the enzyme inducible nitric oxide synthase (iNOS). Bacterial products and cytokines induce iNOS expression. Excess NO can cause vasodilation and failure of the pressor response, weaken the heart, interfere with cell oxygen utilization, and damage tissue, all of which are hallmarks of septic shock. A key part of the evidence for the role of iNOS is the reversal of shock by NOS inhibitors. However, these agents lack specificity. The same agents can inhibit not only harmful NOS but also NOS whose action may be beneficial. To test whether selective iNOS inhibition could be beneficial, the investigator has """"""""knocked out"""""""" the iNOS gene in the mouse. The iNOS knock out mice, which are otherwise normal, were protected against hypotension and from the lethal effects of LPS. However, in mice with a preexisting systemic inflammation, LPS caused liver damage, neutrophil margination and death as readily in the iNOS deficient as wild type mice. Thus there appears to be more than one final common pathway to lethality in septic shock: one involving iNOS mediated cardiovascular collapse, and another that remains to be determined. In the iNOS deficient mice, since one route to LPS lethality is blocked, the other lethality producing route can be studied. The investigator will evaluate in the context of iNOS deficiency the effect of interventions of MAb against TNFa, neutrophil adhesive molecules, an antagonist of PAF, and an inhibitor of phosphatidic acid generation. The investigator will also study a previously untested intervention, the specific and total ablation of the phagocytic respiratory burst by using mice deficient in phagocyte oxidase component, phox91, the mice doubly deficient in phox 91 and iNOS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053921-04
Application #
2900869
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1996-04-01
Project End
2000-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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