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

In this study, we have 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 up-regulated 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 down-regulation 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 generation, mt DNA damage, and apoptosis of lung epithelial cells PF in mice. Thus, PLD may be a novel therapeutic target in ameliorating experimental PF in mice. PMID: 31090437 [PubMed - as supplied by publisher]
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research