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Tyrosine Nitration and Mitogen-Activated Protein Kinase Activation in Asbestosis-Induced Pulmonary Fibrosis*

Elliott Kagan, MB, BCh; Akitaka Iwagaki, MD; Nonghoon Choe, DVM, PhD; Ping Zhang, PhD; Yi-Zhe Wang, PhD; James C. Bonner, PhD
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*From the Department of Pathology (Drs. Kagan, Iwagaki, and Choe), Uniformed Services University of the Health Sciences, Bethesda, MD; and Laboratory of Pulmonary Pathobiology (Drs. Zhang, Wang, and Bonner), National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Correspondence to: Elliott Kagan, MB, BCh, Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814-4799



Chest. 2001;120(1_suppl):S26-S27. doi:10.1378/chest.120.1_suppl.S26
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Generation of reactive nitrogen species with nitrotyrosine formation has been implicated in the pathogenesis of pulmonary fibrosis. We have shown previously that asbestos inhalation induced nitrotyrosine formation, a marker of peroxynitrite production, in the rat lung. To determine whether asbestos inhalation may induce mitogen-activated protein kinase (MAPK) activation and whether such activation may be associated with peroxynitrite production, lung lysates from crocidolite and chrysotile asbestos-exposed rats and from sham-exposed rats were immunoprecipitated with antinitrotyrosine antibody and captured proteins were subjected to Western blotting with anti-phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 antibodies. Both types of asbestos inhalation induced greater phosphorylation of stress-activated protein kinase/c-Jun NH(2)-terminal kinase, ERK-1/2, and p38 kinase than was noted after sham exposure. Phosphorylated of ERK-1/2 activity coimmunoprecipitated with nitrotyrosine. Moreover, immunoprecipitated phosphorylated of ERK-1/2 from both crocidolite-exposed and chrysotile-exposed rats demonstrated significantly greater functional MAPK activity using Elk1 substrate than was noted after sham exposure. Lung sections from rats exposed to crocidolite or chrysotile (but not from sham-exposed rats) demonstrated strong immunoreactivity for nitrotyrosine, phosphorylation of ERK-1/2, phosphorylation of stress-activated protein kinase/c-Jun NH(2)-terminal kinase, and phosphorylation of p38 in alveolar macrophages and bronchiolar epithelium. Normal rat lung myofibroblasts treated with 1 mM of peroxynitrite or H2O2 demonstrated activation of Raf, MAPK/ERK kinase, and ERK. Whereas H2O2-induced ERK activation was abrogated by the epidermal growth factor-receptor tyrosine kinase inhibitor, AG1478, by the Raf inhibitor, forskolin, and by the MAPK/ERK kinase inhibitor, PD98059, peroxynitrite-induced ERK activation was inhibited exclusively by PD98059. Conceivably, peroxynitrite formation, in association with upregulated MAPK activation, may modulate downstream signaling events that have relevance to the induction of asbestos-related pulmonary fibrosis.

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