title: Hsp90 regulation of fibroblast activation in pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix (ECM) production. To identify inhibitors that can attenuate fibroblast activation, we queried IPF gene signatures against a library of small-molecule-induced gene-expression profiles and identified Hsp90 inhibitors as potential therapeutic agents that can suppress fibroblast activation in IPF. Although Hsp90 is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in IPF. Here, we found elevated Hsp90 staining in lung biopsies of patients with IPF. Notably, fibroblasts isolated from fibrotic lesions showed heightened Hsp90 ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a small-molecule inhibitor of Hsp90 ATPase activity, attenuated fibroblast activation and also TGF-β-driven effects on fibroblast to myofibroblast transformation. The loss of the Hsp90AB, but not the Hsp90AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of pulmonary fibrosis, suggesting that targeting Hsp90 represents an effective strategy for the treatment of fibrotic lung disease.
authors.affiliation: Division of Pulmonary Medicine.|Department of Biochemistry, National Institute of Nutrition, Hyderabad, Telangana, India.
authors.forename: Vishwaraj
authors.initials: V
authors.lastname: Sontake
authors.affiliation: Division of Biomedical Informatics and.
authors.forename: Yunguan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Pulmonary Medicine.|Department of Biochemistry, National Institute of Nutrition, Hyderabad, Telangana, India.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Kasam
authors.affiliation: Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio USA.
authors.forename: Debora
authors.initials: D
authors.lastname: Sinner
authors.affiliation: Department of Biochemistry, National Institute of Nutrition, Hyderabad, Telangana, India.
authors.forename: Geereddy B
authors.initials: GB
authors.lastname: Reddy
authors.affiliation: Division of Pulmonary Medicine.
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio USA.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, AnnArbor, Michigan, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: Division of Biomedical Informatics and.
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.affiliation: Division of Pulmonary Medicine.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Madala
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts; D034741:RNA, Small Interfering; D059467:Transcriptome; D016212:Transforming Growth Factor beta
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; C112969:HSP90AA1 protein, human; C493165:HSP90AB1 protein, human; D047029:Lactams, Macrocyclic; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; C112765:tanespimycin