Dysregulated phospholipid metabolism leads to lung fibrosis

Currently, Idiopathic pulmonary fibrosis has no FDA-approved drug for the reversal of fibrosis, and this warrants identification of new and novel therapeutic targets. Phospholipase D is one of the most important phospholipid hydrolyzing enzymes in mammalian cells, which generates phosphatidic acid, a key regulator of multiple signaling pathways.

Researchers at the University of Illinois Chicago, led by Vidyani Suryadevara and Viswanathan Natarajan, have identified for the first time that phospholipase D expression was increased in lung tissues from IPF patients and mouse with bleomycin induced pulmonary fibrosis. Their findings were reported in July 2019 in the American Journal of Physiology-Lung Cellular and Molecular Physiology, a journal of the American Physiological Society.

In prior pulmonary fibrosis research, the UIC team found that genetic depletion of phospholipase D led to protection against bleomycin induced inflammation and fibrosis in mice. Epithelial cells are the first to be damaged during lung injury and elevated phospholipase D expression induced by bleomycin in the bronchial alveolar epithelial cells was found to induce mitochondrial reactive oxygen species production. This further led to mitochondrial DNA damage and finally epithelial cell apoptosis, which was found to be reduced when the cells were treated with small molecule inhibitors of phospholipase D.

This study thus identifies phospholipase D as a potential therapeutic target against pulmonary fibrosis and provides a deeper insight into the signaling mechanism(s) in epithelial cells during the development of pulmonary fibrosis. Co-authors of the study are Longshuang Huang, Mark Shaaya, Mounica Bandela and Panfeng Fu of UIC; Seok-Jo Kim, Paul Cheresh and David W. Kamp from Northwestern University; Carol Feghali-Bostwick from Medical University of South Carolina, and Gilbert Di Paolo from Columbia University Medical Center.

The work was supported by grant from a National Heart, Lung, and Blood Institute (P01 HL-098050) and a VA Merit Award (2I01BX000786-05A2).