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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/L891    most recent 00333.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Google Scholar Articles by Milam, J. E. Articles by Reddy, R. C. PubMed PubMed Citation Articles by Milam, J. E. Articles by Reddy, R. C.

PPAR- agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis

¹Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, and ²Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan

Submitted 19 August 2007 ; accepted in final form 26 December 2007

Pulmonary fibrosis is characterized by alterations in fibroblast phenotypes resulting in excessive extracellular matrix accumulation and anatomic remodeling. Current therapies for this condition are largely ineffective. Peroxisome proliferator-activated receptor- (PPAR-) is a member of the nuclear hormone receptor superfamily, the activation of which produces a number of biological effects, including alterations in metabolic and inflammatory responses. The role of PPAR- as a potential therapeutic target for fibrotic lung diseases remains undefined. In the present study, we show expression of PPAR- in fibroblasts obtained from normal human lungs and lungs of patients with idiopathic interstitial pneumonias. Treatment of lung fibroblasts and myofibroblasts with PPAR- agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR- agonists, including a constitutively active PPAR- construct (VP16-PPAR-), inhibit the ability of transforming growth factor-β1 to induce myofibroblast differentiation and collagen secretion. PPAR- agonists also inhibit fibrosis in a murine model, even when administration is delayed until after the initial inflammation has largely resolved. These observations indicate that PPAR- is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR- ligands as novel therapeutic agents for fibrotic lung diseases.

troglitazone; ciglitazone; transforming growth factor

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				M. G. Belvisi and D. J. Hele Peroxisome Proliferator-Activated Receptors as Novel Targets in Lung Disease Chest, July 1, 2008; 134(1): 152 - 157. [Abstract] [Full Text] [PDF]