The relationship between gastroesophageal reflux (GER; an indication for which the PPIs are primarily prescribed) and lung fibrosis is well appreciated [
73‐
76]. Studies utilizing esophageal pH monitoring have documented abnormal pH readings in the distal and proximal esophagus of a large proportion of IPF patients [
10,
77,
78]. However, the precise association between GER and IPF is unclear. There are two major hypotheses regarding this relationship. The first hypothesis involves GER as a sequel of IPF. Decreased lung compliance in patients with IPF may lead to increased swings in pleural pressure causing dysfunction of the lower esophageal sphincter and eventually leading to GER [
10,
79]. The alternative hypothesis revolves around chronic microaspiration of small gastric droplets either triggering acute exacerbations or leading to progressive injury and fibrosis [
10,
80]. However, discordance between the high prevalence of GER (200 per 1,000) and the orphan classification of IPF (300 per 1,000,000) [
81,
82], lack of clear evidence demonstrating a causal role of microaspiration in clinical pulmonary fibrosis, the grossly distinct histopathological outcomes between acid-induced lung injury in animals (mainly granulomatous inflammation) and clinical IPF (honeycomb changes without or minimal inflammation) and anatomical differences in the sites of fibrosis are findings that pose questions about a causal relationship [
83,
84].
It has been assumed that the presumed benefit of PPIs in measures of lung function in IPF is due to a reduction in gastric acidity that would reduce potential lung injury due to microaspiration. Although GER commonly accompanies IPF [
10,
76,
85]; and it is believed that anti-reflux strategies may benefit IPF [
70], several reports have indicated the lack of direct and complete association between the progression of GER and IPF [
10,
77,
80,
86‐
88]. Paradoxically, some IPF patients who undergo fundoplication therapy have been initially placed on PPIs and failed to suppress symptoms of reflux such as heartburn and regurgitation despite the PPIs; making them eligible for the surgical procedure (see the question and answer section of ref [
70]). Thus, the use of PPIs may not provide for effective reflux control [
70] and gastric reflux and microaspiration may still persist in IPF patients placed on PPIs [
8,
10,
79,
89]. Furthermore, there is no evidence that the PPI-induced changes in gastric pH would reduce (lung) tissue injury in the event of microaspiration.
In light of our in vitro findings, we chose to focus our analysis of interstitial lung disease (ILD) database on the use of PPIs and potential survival benefit of IPF patients. Intriguingly, we found that the use of PPIs for 12 months or longer was associated with significantly longer transplant-free survival compared to IPF patients who did not take PPIs (Fig.
11). In principle, our finding that the use of PPIs is associated with favorable outcome in IPF is similar to what has been previously reported in the literature. Two retrospective studies have suggested an association between PPI use and improved survival [
7,
8]. Moreover, deterioration in lung function has been correlated with poor adherence to PPI therapy [
7]. In a case series of 4 IPF patients, Raghu et al. [
7] observed clinical improvement in IPF patients on PPI therapy. Recently, Lee and colleagues [
8] conducted a retrospective analysis of 204 IPF patients from two ILD databases. Ninety-eight (98) of their patients were on some form of pharmacological anti-reflux therapy as follows: PPIs = 84, H
2-blockers = 12 and combined PPI and H
2-blocker = 2. The use of anti-reflux medications (composed of 87% of patients taking PPIs) was associated with longer survival. In our study, we also observed survival benefit including in patients that did not have any history of GER or GER-related symptoms (Fig.
11b; Additional file
1: Table S4). In light of this, it is interesting to note that esomeprazole regulated the gene expression and plasma levels of MMP7 (Figs.
4,
8b) since clinical studies have shown that elevated level of MMP7 (Matrilysin) is associated with increased lung fibrosis and independently predicts survival in IPF [
90,
91]. Meanwhile, the reduced baseline radiologic fibrosis noted by Lee et al. [
8] suggest that PPIs may possess an anti-fibrotic effect, given our present in vitro and preclinical findings, however, the retrospective nature of the clinical data does not allow such a firm conclusion. Furthermore, a recent analysis of IPF patients who participated in clinical trials and were prospectively followed by the IPF clinical research network (IPFnet) showed a slower rate of forced vital capacity (FVC) decline in IPF patients on anti-reflux therapy (of whom over 90% were on PPIs) [
9]. Surprisingly, the use of anti-reflux therapy was also associated with fewer episodes of acute exacerbations compared to IPF patients who did not take these medications [
9]. Intriguingly, we discovered that esomeprazole significantly upregulated the expression and rat plasma levels of chitinase 3-like 1 (CHI3L1) protein (Fig.
8). A recent study reported that the lung expression and plasma levels of endogenous CHI3L1 is reduced in IPF patients with episodes of acute exacerbation compared to IPF patients in a stable condition [
92]. Therefore, if our data is translated to humans, induction of CHI3L1 by PPIs might have been responsible, at least in part, for the reported incidences of fewer acute exacerbations associated with the use of PPIs in patients with respiratory diseases including IPF [
9] and chronic obstructive pulmonary disease (COPD) [
43].