Role of phospholipase D in bleomycin-induced mitochondrial reactive oxygen species generation, mitochondrial DNA damage, and pulmonary fibrosis

Vidyani Suryadevara, Longshuang Huang, Seok Jo Kim, Paul Cheresh, Mark Shaaya, Mounica Bandela, Panfeng Fu, Carol Feghali-Bostwick, Gilbert Di Paolo, David W. Kamp, Viswanathan Natarajan*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is a pernicious lung disease characterized by alveolar epithelial apoptosis, dysregulated repair of epithelial injury, scar formation, and respiratory failure. In this study, we identified phospholipase D (PLD)-generated phosphatidic acid (PA) signaling in the development of pulmonary fibrosis (PF). Of the PLD isoenzymes, the protein expression of PLD2, but not PLD1, was upregulated in lung tissues from IPF patients and bleomycin challenged mice. Both PLD1 (Pld1-/-)-and PLD2 (Pld2-/-)-deficient mice were protected against bleomycin-induced lung inflammation and fibrosis, thereby establishing the role of PLD in fibrogenesis. The role of PLD1 and PLD2 in bleomycin-induced lung epithelial injury was investigated by infecting bronchial airway epithelial cells (Beas2B) with catalytically inactive mutants of PLD (hPLD1-K898R or mPld2-K758R) or downregulation of expression of PLD1 or PLD2 with siRNA. Bleomycin stimulated mitochondrial (mt) superoxide production, mtDNA damage, and apoptosis in Beas2B cells, which was attenuated by the catalytically inactive mutants of PLD or PLD2 siRNA. These results show a role for PLD1 and PLD2 in bleomycin-induced generation of mt reactive oxygen species, mt DNA damage, and apoptosis of lung epithelial cells in mice. Thus, PLD may be a novel therapeutic target in ameliorating experimental PF in mice.

Original languageEnglish (US)
Pages (from-to)L175-L187
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume317
Issue number2
DOIs
StatePublished - Aug 2019

Keywords

  • Epithelial cell apoptosis
  • Mitochondrial DNA damage
  • Mitochondrial ROS
  • Phosphatidic acid
  • Phospholipase D
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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