Overventilation-induced airspace acidification promotes Pseudomonas pneumonia

Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection in critically ill patients. Local pH variations affect bacterial growth. This study investigated the role and mechanisms of airspace acidification by mechanical ventilation (MV) in Pseudomonas aeruginosa (PA)-induced VAP to test the hypothesis that overventilation-induced airspace acidification promotes Pseudomonas aeruginosa adhesion and increases susceptibility to pneumonia. Mice were subjected to high (HVt:34 mL·kg −1 ) or low (LVt:9 mL·kg −1 ) tidal volume MV and intratracheally infected with PA. Relative airspace acidification was estimated via fluorescence microscopy in murine lungs ex vivo . Bacterial growth and adhesion on cyclically stretched A549 and human alveolar epithelial cells was examined. Upon PA infection, HVt mice showed significantly increased alveolo-capillary permeability, elevated lung and blood leukocyte counts, and higher bacterial load in lungs and extrapulmonary organs as compared to LVt controls. HVt MV increased airspace acidification signal in lungs ex vivo and significantly decreased pulmonary expression of Na + /H + exchanger 1 (NHE1). Inhibition of NHE1 significantly enhanced PA growth on alveolar epithelial cells in vitro and increased pulmonary bacterial loads in LVt-MV mice in vivo. In a novel murine VAP model, key characteristics of PA-VAP were replicated. HVt MV induced mild VILI with acidification of airspace lining fluid, increasing susceptibility to PA pneumonia. NHE1-dependent pH regulation was identified as a mechanistic contributor to ventilation-associated airspace acidification and subsequent pulmonary infection susceptibility, representing a candidate target for therapeutic modulation in PA-VAP.