Idiopathic Pulmonary Fibrosis: Novel Concepts of Proton Pump Inhibitors as Antifibrotic Drugs

Abstract

The prevalence of abnormal acid gastroesophageal reflux (GER) is higher in patients with idiopathic pulmonary fibrosis (IPF) than in matched control subjects. Several studies demonstrated that more than one-third of patients with IPF have abnormal esophageal acid exposures. In addition, many of these studies indicate that the majority of patients with IPF have silent reflux with no symptoms of GER. Findings of abnormal reflux persist in a large proportion of patients with IPF placed on antacid therapy such as proton pump inhibitors (PPIs). This seemingly paradoxical observation suggests that either patients with IPF are somehow resistant to PPI-based intervention or PPIs are inherently unable to suppress acid GER. By contrast, patients with IPF who undergo Nissen fundoplication surgery are effectively relieved from the complications of GER, and retrospective studies suggest improved lung function. Retrospective, anecdotal data suggest a beneficial role of PPIs in IPF including stabilization of lung function, reduction in episodes of acute exacerbation, and enhanced longevity. The recent evidence-based guidelines for treatment of IPF approved conditional recommendation of PPIs for all patients with IPF regardless of their GER status. Recently, we have reported that PPIs possess antiinflammatory and antifibrotic activities by directly suppressing proinflammatory cytokines, profibrotic proteins, and proliferation of lung fibroblasts. Our study provides an alternative explanation for the beneficial effect of PPIs in IPF. In this Perspective, we reviewed emerging progress on antifibrotic effect of PPIs using IPF as a disease model. In addition, we summarized surgical and pharmacological interventions for GER and their downstream effect on lung physiology.

Keywords: antireflux surgery; fibrosis; gastroesophageal reflux; lung inflammation; proton pump inhibitors.

Figure 1.

Outpouching of foregut endoderm and respiratory tract tissues during mammalian embryogenesis. The respiratory diverticula that form the lungs and the stomach are highlighted.

Figure 2.

Schematic illustration of the key cellular and molecular events associated with an injured alveolar wall in a genetically predisposed person manifesting pulmonary fibrosis. Note that proton pump inhibitors (PPIs) suppress key events in lung inflammation and fibrosis including (1) release of proinflammatory molecules from injured epithelial cells (43, 47); (2) expression of adhesion molecules and adherence of inflammatory cells into vascular wall (–47); and (3) proliferation of fibroblasts including extracellular matrix deposition (47). The ? indicates “unclear.” EMT = epithelial-to-mesenchymal transition; EndoMT = endothelial-to-mesenchymal transition; FGF = fibroblast growth factor; FVIII = factor VIII; HO1 = heme oxygenase 1; PDGF = platelet-derived growth factor; RBC = red blood cell; TGF-β = transforming growth factor-β; VEGF = vascular endothelial growth factor; VWF = Von Willenbrand factor.

Figure 3.

In a genetically predisposed individual, pulmonary fibrosis/idiopathic pulmonary fibrosis may develop as a result of chronic microaspiration and reflux of gastric contents to the respiratory system. Potential preventative and/or therapeutic mechanism of surgical (e.g., Nissen fundoplication) or pharmacological (e.g., antifibrotic agent or proton pump inhibitor [PPI]) agents is shown. ICAM = intercellular adhesion molecule; TNF = tumor necrosis factor; VCAM = vascular cell adhesion molecule.