Abstract 9843: Proton Pump Inhibitors Inhibit DDAH and Processes Underlying Idiopathic Pulmonary Fibrosis

Abstract

Rationale: The cardiovascular enzyme dimethylarginine dimethylaminohydrolase (DDAH) has recently been implicated in the progression of idiopathic pulmonary fibrosis (IPF). By degrading asymmetric dimethylarginine (ADMA), an inhibitor of inducible nitric oxide (NO) synthase (iNOS), DDAH releases the brake on a pathway implicated in lung injury and fibrosis. In addition, DDAH promotes the pro-fibrotic activity of the TGFβ pathway. Objectives: We embarked on studies to discover DDAH inhibitors, and to assess the effect of such inhibitors on processes involved in IPF. Methods: We performed high throughput screening (HTS) of over 130,000 small molecules and discovered that the proton pump inhibitors (PPIs) modestly inhibit DDAH. We used cellular and molecular assays to study the effect of the PPIs on DDAH activity by measuring the concentration of ADMA. In addition, we assessed the effect of PPIs on collagen synthesis by IPF lung fibroblasts, and on the survival and proliferation of lung alveolar epithelial cells. Finally, a retrospective analysis of the Stanford University interstitial lung disease (ILD) database was performed to assess the effect of PPIs on transplant-free survival. Results: We found that the PPIs inhibit DDAH activity in biochemical assays, cell culture and in vivo. The resulting increase in ADMA level was mirrored by a reduction in NO production. In addition, the PPIs reduced the production of soluble collagen by primary IPF lung fibroblasts in response to TGFβ and regulated both proliferation and survival of lung alveolar epithelial cells. Retrospective review of the ILD database of 131 IPF patients (of who 85 were on PPIs for > 1 year) revealed a survival advantage (i.e. time to transplant or death when calculated from the time of diagnosis) of the patients on PPIs, including those without symptoms of Gastroesophageal disease (GERD); an indication for which the PPIs are primarily prescribed for, suggesting the involvement of a mechanism other than acid-suppression. Conclusions: Our data reveal a plausible biological explanation for the clinical benefit of the PPIs in IPF. The reported reduction in radiologic fibrosis score and significant survival advantage of IPF patients on PPIs may be due to modulation of the DDAH/NOS pathway.