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

• Published in: American journal of physiology. Lung cellular and molecular physiology 2008-05, Vol.294 (5), p.L891-L901
• Main Authors: Milam, Jami E, Keshamouni, Venkateshwar G, Phan, Sem H, Hu, Biao, Gangireddy, Srinivasa R, Hogaboam, Cory M, Standiford, Theodore J, Thannickal, Victor J, Reddy, Raju C
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic; Bleomycin; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Division - drug effects; Cell Division - physiology; Cells, Cultured; Chromans - pharmacology; Cyclin D; Cyclins - genetics; Disease Models, Animal; Fibroblasts - drug effects; Fibroblasts - pathology; Fibrosis; Gene Expression - physiology; Humans; Hypoglycemic Agents - pharmacology; Ligands; Phenotype; PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; Promoter Regions, Genetic - physiology; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - pathology; Rats; Rats, Inbred F344; Thiazolidinediones - pharmacology; Transforming Growth Factor beta1 - pharmacology; Troglitazone
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00333.2007

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-gamma (PPAR-gamma) 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-gamma as a potential therapeutic target for fibrotic lung diseases remains undefined. In the present study, we show expression of PPAR-gamma in fibroblasts obtained from normal human lungs and lungs of patients with idiopathic interstitial pneumonias. Treatment of lung fibroblasts and myofibroblasts with PPAR-gamma agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR-gamma agonists, including a constitutively active PPAR-gamma construct (VP16-PPAR-gamma), inhibit the ability of transforming growth factor-beta1 to induce myofibroblast differentiation and collagen secretion. PPAR-gamma 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-gamma is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR-gamma ligands as novel therapeutic agents for fibrotic lung diseases.