title: Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts.
abstract: Transforming growth factor-β (TGF-β) is central during the pathogenesis of pulmonary fibrosis, in which the plasminogen activator inhibitor-1 (PAI-1) also has an established role. TGF-β is also known to be the strongest inducer of PAI-1. To investigate the link between PAI-1 and TGF-β in fibrotic processes, we evaluated the effect of SK-216, a PAI-1-specific inhibitor, in TGF-β-dependent epithelial-mesenchymal transition (EMT) and fibroblast to myofibroblast differentiation. In human alveolar epithelial A549 cells, treatment with TGF-β induced EMT, whereas co-treatment with SK-216 attenuated the occurrence of EMT. The inhibition of TGF-β-induced EMT by SK-216 was also confirmed in the experiment using murine epithelial LA-4 cells. Blocking EMT by SK-216 inhibited TGF-β-induced endogenous production of PAI-1 and TGF-β in A549 cells as well. These effects of SK-216 were not likely mediated by suppressing either Smad or ERK pathways. Using human lung fibroblast MRC-5 cells, we demonstrated that SK-216 inhibited TGF-β-dependent differentiation of fibroblasts to myofibroblasts. We also observed this inhibition by SK-216 in human primary lung fibroblasts. Following these in vitro results, we tested oral administration of SK-216 into mice injected intratracheally with bleomycin. We found that SK-216 reduced the degree of bleomycin-induced pulmonary fibrosis in mice. Although the precise mechanisms underlying the link between TGF-β and PAI-1 regarding fibrotic process were not determined, PAI-1 seems to act as a potent downstream effector on the pro-fibrotic property of TGF-β. In addition, inhibition of PAI-1 activity by a PAI-1 inhibitor exerts an antifibrotic effect even in vivo. These data suggest that targeting PAI-1 as a downstream effector of TGF-β could be a promising therapeutic strategy for pulmonary fibrosis.
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Keitaro
authors: K
authors: Omori
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Noboru
authors: N
authors: Hattori
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Tadashi
authors: T
authors: Senoo
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Yusuke
authors: Y
authors: Takayama
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Takeshi
authors: T
authors: Masuda
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Taku
authors: T
authors: Nakashima
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Hiroshi
authors: H
authors: Iwamoto
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Kazunori
authors: K
authors: Fujitaka
authors: Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Hironobu
authors: H
authors: Hamada
authors: Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Nobuoki
authors: N
authors: Kohno
mesh_terms: D000368:Aged; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D001761:Bleomycin / Q000031:analogs & derivatives / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D003998:Dicarboxylic Acids / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D058628:Myofibroblasts / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D001583:Benzoxazoles; D003998:Dicarboxylic Acids; D017395:Plasminogen Activator Inhibitor 1; C000589255:SK-216; D016212:Transforming Growth Factor beta; D001761:Bleomycin; C025703:bleomycetin