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

^* 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

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.

Footnotes

Abbreviations: ERK = extracellular signal-regulated kinase; MAPK = mitogen-activated protein kinase

Supported by National Institutes of Health grant HL-54196 and the National Institute of Environmental Health Sciences.

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Kagan, E. Articles by Bonner, J. C. Search for Related Content PubMed Articles by Kagan, E. Articles by Bonner, J. C.