The cellular and molecular responses of the lung to oxidative stress involve increased expression of antioxidant enzymes and stress-response genes, including the stress-inducible gone heme oxygenase-1 (HO-1). Heme oxygenase (HO) catalyzes the first and rate-limiting step in the catabolism of home to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and iron. Our laboratory and others have demonstrated that induction of HO-1 provides cytoprotection both in vivo and in vitro against oxidative stress including but not limited to hyperoxia, ischemia-reperfusion, and endotoxin. The mechanism(s) by which HO-1 provides cytoprotection against oxidant-induced tissue injury is poorly understood. Recent studies highlight the possibility that the gaseous molecule CO, a by-product of HO activity, can mediate cytoprotection against oxidant-induced lung injury. Furthermore, we have established that CO mediates protection via the MKK3/p38 mitogen-activated kinase (MAPK) signaling pathway. We hypothesize that CO mediates HO-1 cytoprotection against endotoxic shock and that the reciprocal effects exerted by CO on p38( and p38( MAPK mediate the reciprocal down-regulation of the pro-inflammatory cytokine TNF-( and the upregulation of the anti-inflammatory cytokine IL-10. Furthermore, we hypothesize that a complex interplay between NF-(B and the NF-(B-dependent gone iNOS regulates CO-induced p38 activation and its functional anti-inflammatory and cytoprotective effects. We will test this hypothesis by addressing the following aims: 1) to identify which of the p38 isoforms ((,(,(,() are involved in the anti-inflammatory effects observed with CO. 2) To determine the role of NF-(B activation and the role of the p38 isoforms in this activation. 3) Evaluate the mechanism by which CO-induced activation of p38 provides cytoprotection in endotoxic shock. 4) Evaluate the rote of CO-induced iNOS in the cytoprotection and induction of the anti-inflammatory phenotype.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL071797-03
Application #
6962252
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
2003-08-01
Project End
2007-05-31
Budget Start
2004-12-15
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$289,583
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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