Cytotoxicity and Induction of Inflammation by Pepsin in Acid in Bronchial Epithelial Cells

Abstract

Introduction. Gastroesophageal reflux has been associated with chronic inflammatory diseases and may be a cause of airway remodelling. Aspiration of gastric fluids may cause damage to airway epithelial cells, not only because acidity is toxic to bronchial epithelial cells, but also since it contains digestive enzymes, such as pepsin. Aim. To study whether pepsin enhances cytotoxicity and inflammation in airway epithelial cells, and whether this is pH-dependent. Methods. Human bronchial epithelial cells were exposed to increasing pepsin concentrations in varying acidic milieus, and cell proliferation and cytokine release were assessed. Results. Cell survival was decreased by pepsin exposure depending on its concentration (F = 17.4) and pH level of the medium (F = 6.5) (both P < 0.01). Pepsin-induced interleukin-8 release was greater at lower pH (F = 5.1; P < 0.01). Interleukin-6 induction by pepsin was greater at pH 1.5 compared to pH 2.5 (mean difference 434%; P = 0.03). Conclusion. Pepsin is cytotoxic to bronchial epithelial cells and induces inflammation in addition to acid alone, dependent on the level of acidity. Future studies should assess whether chronic aspiration causes airway remodelling in chronic inflammatory lung diseases.

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

“…For example, Johnston and colleagues (24) performed electron microscopy study and demonstrated that airway epithelial cells uptake pepsin by receptor-mediated endocytosis. Once internalized, pepsin is known to induce cytotoxicity, inflammatory response (e.g., up-regulation of IL-6 and IL-8), and airway remodeling (18). In addition, endotoxins are often found in gastric juice likely due to lysis of bacteria in the stomach (25).…”

Airway Pepsin Levels in Otherwise Healthy Surgical Patients Receiving General Anesthesia With Endotracheal Intubation

“…Toward a more causal mechanism, an increasing number of investigators have independently developed their own pepsin assays and successfully identifi ed pepsin in the airways of a variety of lung pathologies: lung transplant patients, 28,29 interstitial lung disease, 30 pediatric patients, 10 and the critically ill. 6,11 Recognizing that pepsin itself is directly cytotoxic not just to the esophagus but also to the respiratory epithelium, 31 it may help to fi nally link the relationship between refl ux and lung pathology and explain why gastric acid-suppressive therapies have largely been ineffective in the treatment of presumed pulmonary manifestations of refl ux. 27,32 Unfortunately, controls in these airway pepsin studies have not consistently been reported, and, to our knowledge, only one study has tried to specifi cally examine for the presence of airway pepsin in a controlled setting using a qualitative pepsin assay in normal adults.…”

The role of gastro-esophageal reflux (GER) in systemic sclerosis and lung fibrosis

“…In addition to the well reported clinical association between GER in SSc and lung involvement (18)(19)(20), data from animal models and in vitro analysis have provided a biologic rationale supporting the role of microaspiration in the genesis and/or progression of ILD. Pepsin and bile acids have a citotoxic effect on epithelial cells and can induce a pro-inflammatory response including expression of cytokines and chemokines (21)(22)(23). In a rat model of chronic aspiration, interstitial pneumonitis changes followed the instillation into the airways of either whole gastric or neutralized gastric fluid, but not of hydrochloric acid (24).…”