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Am J Physiol Lung Cell Mol Physiol 297: L912-L919, 2009. First published September 4, 2009; doi:10.1152/ajplung.00148.2009
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Peroxisome proliferator-activated receptor-{gamma} ligands induce heme oxygenase-1 in lung fibroblasts by a PPAR{gamma}-independent, glutathione-dependent mechanism

Heather E. Ferguson,1,3 Thomas H. Thatcher,2 Keith C. Olsen,2 Tatiana M. Garcia-Bates,3,4 Carolyn J. Baglole,1,3 R. M. Kottmann,2 Emily R. Strong,2 Richard P. Phipps,1,3,4 and Patricia J. Sime1,2,3,4

Departments of 1 Environmental Medicine, ; 2Medicine, ; 3Lung Biology and Disease Program, ; 4Immunology and Microbiology, University of Rochester, Rochester, New York

Submitted 4 May 2009 ; accepted in final form 2 September 2009

Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPAR{gamma} ligands 15d-PGJ2 and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPAR{gamma} independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-PGJ2 contain an {alpha}/β unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPAR{gamma} ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-PGJ2 and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-PGJ2 or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-PGJ2 and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPAR{gamma} ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses.

2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; myofibroblast; N-acetyl cysteine


Address for reprint requests and other correspondence: P. J. Sime, Dept. of Medicine, Univ. of Rochester, 601 Elmwood Ave., Box 692, Rochester, NY 14642 (e-mail: Patricia_Sime{at}urmc.rochester.edu).






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