PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis.
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.
Milam
Jami E
JE
Univ. of Michigan, Division of Pulmonary and Critical Care Medicine, 109 Zina Pitcher Pl., 4062 BSRB, Ann Arbor, MI 48109-2200, USA.
Keshamouni
Venkateshwar G
VG
Phan
Sem H
SH
Hu
Biao
B
Gangireddy
Srinivasa R
SR
Hogaboam
Cory M
CM
Standiford
Theodore J
TJ
Thannickal
Victor J
VJ
Reddy
Raju C
RC
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
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