title: Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 (PAI-1), a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung fibrosis as compared to young mice. Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-β1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-β1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-β1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung fibrosis in part by protecting fibroblasts from apoptosis.
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Wen-Tan
authors.initials: WT
authors.lastname: Huang
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Hasina
authors.initials: H
authors.lastname: Akhter
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: MacEwen
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Antony
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Victor John
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA. Electronic address: rliu@uab.edu.
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Liu
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D005347:Fibroblasts / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000209:etiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; D001761:Bleomycin
keywords: Aging; Fibroblast apoptosis; Idiopathic pulmonary fibrosis; Plasminogen activator inhibitor 1