Targeting ATP12A, a Nongastric Proton Pump a Subunit, for Idiopathic Pulmonary Fibrosis Treatment

Idiopathic pulmonary fibrosis (IPF) is a pathological condition of unknown etiology that 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 lung disease. The ATP12A gene encodes the a-subunit of the nongastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in patients with cystic fibrosis. It is hypothesized that the ATP12A protein may play a role in the pathogenesis of IPF. The authors' studies demonstrate that ATP12A protein is overexpressed in distal small airways from the lungs of patients with IPF compared with normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened bleomycin induced experimental pulmonary fibrosis. This was prevented by a potassium competitive proton pump blocker, vonoprazan. These data support the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has potential as a novel therapeutic strategy in IPF treatment.

Automated summary

Idiopathic pulmonary fibrosis (IPF) is a pathological condition with unknown cause that leads to lung injury and fibrotic response, resulting in thickening of alveolar walls and obliteration of alveolar space. Small airway disease and mucus accumulation are prominent in IPF lungs, similar to cystic fibrosis lung disease. Overexpression of the ATP12A protein in distal small airways of IPF patients and in mouse lungs exacerbates pulmonary fibrosis, which can be prevented by vonoprazan, a potassium competitive proton pump blocker. Inhibiting ATP12A protein may serve as a novel therapeutic strategy for IPF.