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Phospholipase D Regulates GSK3β Mediated Epithelial to Mesenchymal Transition and Akt Mediated Cell Death Leading to Pulmonary Fibrosis
Author(s) -
Suryadevara Vidyani,
Royston Thomas J.,
Natarajan Viswanathan
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.656.2
Subject(s) - pld2 , protein kinase b , bleomycin , epithelial–mesenchymal transition , pulmonary fibrosis , cancer research , phospholipase d , idiopathic pulmonary fibrosis , pi3k/akt/mtor pathway , signal transduction , microbiology and biotechnology , chemistry , fibrosis , biology , medicine , lung , phosphatidic acid , pathology , biochemistry , downregulation and upregulation , phospholipid , chemotherapy , membrane , gene
Idiopathic pulmonary fibrosis (IPF) is a pernicious lung disease characterized by scar formation and respiratory failure. This is due to dysregulated repair of the epithelial injury in the lung, which involves epithelial apoptosis and also epithelial to mesenchymal transition (EMT), thereby leading to the deposition of the extracellular matrix in the lung. Our previous studies have established a role for phospholipase D (PLD) as genetic deletion of PLD2 in mice conferred protection against bleomycin induced PF. PLD2 −/− mice exhibited less inflammation on day 7 and less pulmonary fibrosis on day 21 post‐bleomycin challenge compared to wild type mice. This study aims at understanding how PLD regulates GSK3β mediated EMT and Akt mediated apoptosis. GSK3β and Akt are known to be involved in crucial signaling pathways that regulate cell death and survival. To elucidate the role of PLD signaling in epithelial injury, Beas2B cells were pre‐incubated with either PLD1 (VU0155069‐ 250nM), PLD2 (VU0364739‐500nM) or PLD1 +PLD2 inhibitors prior to bleomycin challenge. Bleomycin challenge enhanced phosphorylation of GSK3β at Ser9 leading to its inactivation, which was reversed by inhibition of PLD1 and PLD2. Also, activated Akt as shown by enhanced phosphorylation at Ser473 was reversed upon PLD1 and PLD2 inhibition. Inhibition of PLD1 and PLD2 was necessary to attenuate bleomycin mediated apoptosis of Beas2B cells as evidenced by cleavage of Caspase‐3 and PARP. The results presented here suggest that PLD regulates bleomycin‐induced pulmonary fibrosis by modulating apoptosis and EMT via Akt/GSK3β signaling in the epithelial cells, and targeting PLD may be beneficial. Support or Funding Information This work is supported by National Institutes of Health grant P01 HL 98050 to VN.