Methionine aminopeptidase-2 as a selective target of myofibroblasts in pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive, scarring lung disease characterized by fibroblast accumulation and deposition of collagen. Factors that promote growth and/or survival of fibroblasts are potential therapeutic targets. Methionine aminopeptidase 2 (MetAP2), a member of the aminopeptidase family of proteases, has been implicated in cell proliferation in a variety of cell types, but its expression and function in the lung is not known. By immunohistochemistry, MetAP2 was expressed in many cell types, including fibroblasts, in IPF lungs. Fumagillin, an irreversible inhibitor of the enzymatic activity of MetAP2, attenuated collagen deposition in the bleomycin model of acute lung injury in mice. Treatment with fumagillin caused a selective reduction in the numbers of bromodeoxyuridine (BrdU)-positive myofibroblasts, but not type II alveolar epithelial cells, macrophages, or B- and T-lymphocytes in the lungs of bleomycin-treated mice. Incubation of primary rat lung fibroblasts with either fumagillin or with short interfering RNA that targeted MetAP2 led to reduced proliferation, as assessed by incorporation of BrdU. The profibrotic growth factor, platelet-derived growth factor, increased expression of MetAP2 in rat lung fibroblasts. We propose that MetAP2 plays a role in the proliferation of fibroblasts and myofibroblasts in fibrotic lung diseases and may serve as a novel pharmacologic target in IPF.
Kass
Daniel
D
Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. dk371@columbia.edu
Bridges
Robert Stone
RS
Borczuk
Alain
A
Greenberg
Steven
S
D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000963:Antimetabolites / Q000378:metabolism; D001761:Bleomycin / Q000378:metabolism / Q000633:toxicity; D001973:Bromodeoxyuridine / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003510:Cyclohexanes / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009130:Muscle, Smooth / Q000166:cytology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000963:Antimetabolites; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D001761:Bleomycin; C026211:fumagillin; D003094:Collagen; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D001973:Bromodeoxyuridine