Steven D. Nathan, MD
Medical Director, Lung Transplant Program
Advanced Lung Disease Program
Inova Fairfax Hospital
Falls Church, Virginia

Ghebremariam YT, Cooke JP, Gerhart W, Griego C, Brower JB, Doyle-Eisele M, Moeller BC, Zhou Q, Ho L, de Andrade J, Raghu G, Peterson L, Rivera A, Rosen GD. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. J Transl Med. 2015;13:249.

The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. The authors investigated the mechanisms of action with cell experiments, in mice treated with bleomycin, and through observations of patients with IPF.

The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor β (TGFβ), fibronectin and matrix metalloproteinases (MMPs).

Esomeprazole mitigated the inflammatory and fibrotic responses in a murine model of acute lung injury. Retrospective analysis of two ILD databases demonstrated that IPF patients on PPIs had prolonged transplant-free survival over controls (median survival of 3.4 vs 2 years).

The authors suggest that PPIs may have a protective function in IPF by directly modulating the disease process and that they may have other clinical utility in the treatment of extra-intestinal inflammatory and/or fibrotic diseases.

Expert Commentary
This study expands our knowledge of the cytokine effects of PPI treatment and supports observational evidence for the therapeutic benefits of PPIs in patients with IPF. The high concentration (50 microM) required to elicit in vitro effects is recognized by the authors and underlines the need for investigation of other PPI compounds, as well as randomized controlled trials in patients with IPF to solidify the use of PPIs as antifibrotic or anti-inflammatory agents.