Increased susceptibility to Pseudomonas aeruginosa pneumonia in overventilated lungs is caused by airspace acidification

Abstract

Rationale: Ventilator-associated pneumonia(VAP) is the most frequent nosocomial infection in critically ill patients. Local pH variations affect bacterial growth. Whether airway acidification contributes to the pathogenesis and pathophysiology of Pseudomonas aeruginosa(PA) -induced VAP is currently unknown.

Objectives: To investigate the role and mechanisms of airspace acidification by mechanical ventilation(MV) in PA-induced VAP.

Methods: C57BL/6J mice were subjected to high(HVt:34mL/kg) or low(LVt:9mL/kg)tidal volume MV for 4h. PA was instilled via the tracheal tube, and animals were allowed to recover from sedation and breathespontaneously for 24h following extubation. Fluorescence microscopy was applied to determine alveolar pH in ex vivo perfused and ventilated murine lungs, and bacterial growth and adhesion on cyclically stretched A549 and human airway epithelial cells.

Results: Upon PA infection, HVt mice showed increased alveolo-capillary permeability, elevated lung and blood leukocyte counts, and a higher bacterial load in lungs and extrapulmonary organs as compared to LVt controls. HVt MV induced acidification of alveolar lining fluid(ALF) in lungs and decreased pulmonary expression of Na+/H+exchanger1(NHE1). Inhibition of NHE1 enhanced growth of PA in vitro on epithelial cells and increased pulmonary bacterial loads in LVt-MV mice in vivo.

Conclusion: In a novel murine VAP model, key characteristics of PA-VAP were replicated. HVt MV induced mild VILI with acidification of airway lining fluid, increasing susceptibility to PA pneumonia. NHE1 was identified as critical factor for MV-induced airspace acidification, and thus as possible target to combat PA-VAP.