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.

Gastro-oesophageal reflux and idiopathic pulmonary fibrosis: in search of evidence

“…Evidence obtained from asymmetrical fibrosis further support the contribution of GOR to disease progression [10]. These data support the hypothesis that treating GOR may influence IPF behaviour, and many mechanisms have been proposed to explain a potential benefit of GOR treatment in IPF [11].…”

Idiopathic Pulmonary Fibrosis in Switzerland: Diagnosis and Treatment

“…One prospective observational study showed reduced disease progression regarding FVC and exacerbations [100] , while a new post hoc evaluation of clinical studies on IPF shows increased numbers of overall and pulmonary infections in advanced IPF patients treated with antacids compared to those not treated with antacids [101] . Furthermore, patients with antacid treatment at baseline receiving nintedanib seemed to do worse than those without antacid treatment [99] . Promising surgical interventions to inhibit acid as well as anti-acid reflux with Nissen fundoplication in IPF are currently studied in an ongoing clinical trial (WRAP-IPF) [99] .…”

“…Nevertheless, gastroesophageal reflux is considerably prevalent in patients with IPF. Anti-reflux treatment, however, has been controversially discussed [99] . One prospective observational study showed reduced disease progression regarding FVC and exacerbations [100] , while a new post hoc evaluation of clinical studies on IPF shows increased numbers of overall and pulmonary infections in advanced IPF patients treated with antacids compared to those not treated with antacids [101] .…”

“…Promising surgical interventions to inhibit acid as well as anti-acid reflux with Nissen fundoplication in IPF are currently studied in an ongoing clinical trial (WRAP-IPF) [99] . Current international guidelines recommend conditional treatment with proton pump inhibitors regardless of patients' gastroesophageal reflux status [2] , which is controversially discussed [99] .…”

Pharmacotherapy for idiopathic pulmonary fibrosis: current landscape and future potential

“…However, there are significant concerns regarding the design of that study, and the results must be interpreted with caution [11]. While recent perspectives on the topic discuss the potential and prospects of the antifibrotic properties of proton pump inhibitors (PPIs), several questions regarding the use of PPIs and antiacid treatment need to be answered [11,12]. In a recent retrospective study, the safety of laparoscopic antireflux surgery in patients with IPF demonstrating abnormal acid gastro-oesophageal reflux (GOR), and a trend to slow the rate of decline in FVC over a year were demonstrated [13].…”