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Phosphatidylinositol-3-Kinase/Akt regulates bleomycin-induced fibroblast proliferation and collagen production.

Authors
Lu-YJ; Azad-N; Wang-LY; Iyer-AKV; Castranova-V; Jiang-BH; Rojanasakul-Y
Source
Am J Respir Cell Mol Biol 2010 Apr; 42(4):432-441
NIOSHTIC No.
20036690
Abstract
Abnormal repair and dysregulated angiogenesis have been implicated in the pathogenesis of pulmonary fibrosis, but the underlying mechanisms of regulation are not well understood. The present study investigated the role of phosphatidylinositol-3-kinase (PI3K)/Akt in fibrogenesis of human lung fibroblasts and its regulation by reactive oxygen species (ROS). Exposure of lung fibroblasts to bleomycin, a known inducer of fibrosis, resulted in rapid activation of PI3K/Akt and a parallel increase in fibroblast proliferation and collagen production, characteristics of lung fibrosis. Bleomycin had no significant effect on total Akt protein expression but induced phosphorylation of the protein at threonine 308 and serine 473 positions. Inhibition of this phosphorylation by PI3K inhibitors or by dominant-negative Akt (T308A/S473A) expression abrogated the effects of bleomycin on fibroblast proliferation and collagen production, suggesting the role of PI3K/Akt in the fibrogenic process. Activation of PI3K/Akt by bleomycin also led to transcriptional activation and protein expression of hypoxia-inducible factor-la (HIF-1 alpha) and vascular endothelial growth factor, which contributed to the fibroproliferative and collagen-inducing effects of bleomycin. The fibrogenic effects of bleomycin were dependent on ROS generation, particularly superoxide anion and hydrogen peroxide, which were induced by bleomycin. Inhibition of ROS generation by antioxidant enzymes, catalase and superoxide dismutase mimetic MnTBAP, abrogated the fibrogenic effects of bleomycin as well as its induction of PI3K/Akt and HIF-1 alpha activation. Together, our results indicate a novel role of PI3K/Akt in fibrogenesis of human lung fibroblasts and its regulation by ROS, which could be exploited for the treatment of pulmonary fibrosis and related disorders.
Keywords
Dust-exposure; Dust-particles; Fibrogenicity; Fibrous-dusts; Humans; Lung-disorders; Lung-fibrosis; Lung-irritants; Pulmonary-system; Pulmonary-system-disorders; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Author Keywords: collagen; bleomycin; PI3K; Akt; ROS
Contact
Yon Rojanasakul, Ph.D., West Virginia University, Department of Pharmaceutical Sciences, P.O. Box 9530, Morgantown, WV 26506
CODEN
AJRBEL
Publication Date
20100401
Document Type
Journal Article
Email Address
yrojan@hsc.wvu.edu
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Issue of Publication
4
ISSN
1044-1549
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
American Journal of Respiratory Cell and Molecular Biology
State
WV
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