Contributions of ATP12A, a non-gastric proton pump alpha subunit, to the pathogenesis of idiopathic pulmonary fibrosis

• Published in: Physiology (Bethesda, Md.) Vol. 38; no. S1
• Main Authors: Li, Xiaopeng, Abdelgied, Mohamed, Uhl, Katie, Chen, Oliver, Schultz, Chad, Tripp, Kaylie, Peraino, Angela, Paithankar, Shreya, Chen, Bin, Tamae Kakazu, Maximiliano, Castillo Bahena, Alicia, Jager, Tara, Lawson, Cameron, Chesla, Dave, Pestov, Nikolay, Modyanov, Nikolai, Prokop, Jeremy, Neubig, Richard, Uhal, Bruce, Girgis, Reda
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5789924

Abstract only Background: Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to the thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H + , K + -ATPase, which functions to acidify the airway surface liquid (ASL) and impairs mucociliary transport function in cystic fibrosis patients. Hypothesis: We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Methods: ATP12A expression level was evaluated by immunohistochemical staining and RNAscope in situ hybridization in normal and IPF human distal lungs. Primary human small airway culture model was used to elucidate the potential roles of ATP12A in the activation of latent TGF-beta activation. Viral vector mediated ATP12A overexpression was used in the bleomycin-induced lung fibrosis mouse model. A potassium-competitive proton pump blocker, vonoprazan was used to block ATP12A functions both in vitro and in vivo. Results: Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. Potassium competitive proton pump blocker vonoprazan decreased airway surface liquid (ASL) pH and TGF-β1 activation in IPF small airway epithelial cells. In addition, overexpression of the ATP12A protein in mouse lungs worsened the Bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan. Conclusion: Those data support that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF. This work was funded by the National Institutes of Health (HL153165-01A1 to X.L.), the Cystic Fibrosis Foundation (LI19XX0), Cystic Fibrosis Research Institute, and Spectrum Health-MSU Alliance Corporation funds. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.