Targeting pepsin provides superior protection to acid suppression in reflux‐associated airway inflammation and lung dysfunction

Gastro-oesophageal reflux disease is a prevalent condition associated with extra-oesophageal manifestations, such as pulmonary inflammation. Pepsin, an essential gastric enzyme, has been implicated in pulmonary complications owing to its inflammatory effects. Although acid-suppressive therapies, such as proton pump inhibitors, reduce gastric acidity, they do not prevent reflux episodes, microaspiration or the harmful effects of pepsin. This study evaluated the effects of pepsin inhibition by pepstatin on inflammation and pulmonary dysfunction in a murine model of reflux. Male Swiss mice were anaesthetized with ketamine and xylazine and subjected to a surgical procedure involving pyloric stenosis and complete stenosis of the gastric fundus to induce reflux. The mice were divided into four groups: sham, reflux, reflux + pepstatin and reflux + omeprazole. Treatments were administered daily for 28 days. The evaluated parameters included oesophageal and pulmonary wet weights, myeloperoxidase activity, cytokine levels [interleukin (IL)-6, IL-10 and keratinocyte chemoattractant], histopathological alveolitis scores, functional analyses of spirometry and tracheal contractility. The reflux group exhibited significant oesophageal and pulmonary oedema, increased myeloperoxidase activity, elevated levels of IL-6 and keratinocyte chemoattractant, reduced IL-10, severe alveolitis, impaired pulmonary function and tracheal hyper-reactivity. Pepstatin treatment significantly reduced inflammatory and functional alterations in the reflux model. In contrast, omeprazole was less effective at controlling inflammation and improving pulmonary function. These findings suggest that pepsin inhibition might reduce pulmonary inflammation and help to preserve lung function in a murine reflux model. Targeting pepsin, rather than solely suppressing gastric acidity, shows promise in mitigating reflux-related extra-oesophageal complications.