title: PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis.
abstract: 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.
authors.affiliation: Univ. of Michigan, Division of Pulmonary and Critical Care Medicine, 109 Zina Pitcher Pl., 4062 BSRB, Ann Arbor, MI 48109-2200, USA.
authors.forename: Jami E
authors.initials: JE
authors.lastname: Milam
authors.forename: Venkateshwar G
authors.initials: VG
authors.lastname: Keshamouni
authors.forename: Sem H
authors.initials: SH
authors.lastname: Phan
authors.forename: Biao
authors.initials: B
authors.lastname: Hu
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Gangireddy
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Raju C
authors.initials: RC
authors.lastname: Reddy
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008024:Ligands; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D045162:Thiazolidinediones / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D000903:Antibiotics, Antineoplastic; D002839:Chromans; D056741:Cyclin D; D016213:Cyclins; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D000077288:Troglitazone; C039671:ciglitazone