Inflammations of the respiratory tract are associated with production of various reactive oxygen metabolites as well as increased production of nitric oxide (NO). Interactions between NO and inflammatory oxidants results in formation of more reactive nitrogen species, such as nitrogen dioxide (NO2), peroxynitrite (ONOO-) or nitryl halides, which are proposed to significantly contribute to cell and tissue injury in the lung. These reactive nitrogen species can induce specific modifications in proteins, such as nitration and nitrosation products, which may represent unique modulatory mechanisms of protein and enzyme function. Specifically, nitration of tyrosine residues represents an irreversible modification that is likely to alter enzyme function, and 3- nitrotyrosine has been detected in a wide variety of diseased and inflamed tissues, indicating the local formation of NO-derived reactive nitrogen species. These reactive nitrogen species have also been demonstrated to be capable of inducing protein cross-linking via dityrosine, and increased dityrosine content has been detected in tissues subjected to inflammation. However, it has not yet been established to what extent functional alterations caused by tyrosine nitration or dimerization may contribute to decreases in lung function in association with inflammation. Chemical studies have shown that tyrosine nitration may interfere with tyrosine phosphorylation pathways, and preliminary studies from our laboratory have indicated that exposure of epithelial cells that overexpress epidermal growth factor receptors (EGFR) to reactive nitrogen oxides causes irreversible cross-linking of this receptor tyrosine kinase, which is hypothesized to involve intermolecular dityrosine cross-links. As ligand-induced receptor dimerization is involved in activation of a variety of receptors for growth factors, cytokines and hormones, covalent oxidative receptor cross-linking may significantly alter activation and turnover of EGFR and other growth factor receptors, and thereby affect processes such as wound repair or tumor growth, conditions accompanied by increased expression of EGFR and increased production of growth factors. We hypothesize that (irreversible) protein modications by NO-derived reactive nitrogen species may significantly alter growth factor mediated signaling by nitrating critical tyrosine residues or by inducing irreversible cross-linking of growth factor receptors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060812-04
Application #
6390014
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
1998-09-21
Project End
2002-04-30
Budget Start
2001-07-01
Budget End
2002-04-30
Support Year
4
Fiscal Year
2001
Total Cost
$71,124
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618