Phosphatidylinositol-3-Kinase/Akt Regulates Bleomycin-Induced Fibroblast Proliferation and Collagen Production

Details

• Personal Author:
  Azad N ; Castranova, Vincent ; Iyer AKV ; Jiang BH ; Lu YJ ; Rojanasakul Y ; Wang LY
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Dust Irritants Lung Lung Diseases Occupational Health Respiratory Hypersensitivity Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Akt Author Keywords: Collagen Bleomycin Dust-exposure Dust-particles Fibrogenicity Fibrous-dusts Humans Lung-disorders Lung-fibrosis Lung-irritants PI3K Pulmonary-system Pulmonary-system-disorders Respiratory-hypersensitivity Respiratory-irritants Respiratory-system-disorders ROS

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• ISSN:
  1044-1549
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  432-441
• Volume:
  42
• Issue:
  4
• NIOSHTIC Number:
  nn:20036690
• Citation:
  Am J Respir Cell Mol Biol 2010 Apr; 42(4):432-441
• Contact Point Address:
  Yon Rojanasakul, Ph.D., West Virginia University, Department of Pharmaceutical Sciences, P.O. Box 9530, Morgantown, WV 26506
• Email:
  yrojan@hsc.wvu.edu
• Federal Fiscal Year:
  2010
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  American Journal of Respiratory Cell and Molecular Biology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:435c0f21214af24ece8e1287814c9cb0065997cc9822b9cbf5eecd6ef97ab3da550ec75847d01260b5c8788e52ff9439905834b34f2074e6e9af670e5f6ff52a
• Download URL:
  https://stacks.cdc.gov/view/cdc/188011/cdc_188011_DS1.pdf
• File Type:
  [PDF - 992.56 KB ]