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To address the role of Toll-like receptor 4 signaling in mediating neutrophil recruitment and lung injury induced by lipopolysaccharide challenge coupled to lung hyperinflation, using Toll-like receptor 4 knockout (tlr4−/−) mice. Infiltration of polymorphonuclear neutrophils into the lung is an important feature of ventilator-induced lung injury associated with pneumonia, but the mechanisms involved in neutrophil recruitment are poorly understood.Experimental animal model.University laboratory.tlr4−/− and wild-type C57BL/6 mice.Wild-type or tlr4−/− mice were challenged by intratracheal instillation of lipopolysaccharide (0.3 mg/kg) for 2 hrs and then subjected to normal (7 mL/kg) or high (28 mL/kg) tidal volume ventilation for another 2 hrs. In other studies, neutrophils from wild-type or tlr4−/− mice were pretreated with lipopolysaccharide for 30 mins and then infused into the isolated lung preparation for 30 mins as the lungs were ventilated with 25 cm H2O peak inspiratory pressure.Lipopolysaccharide-challenged wild-type mice ventilated with a 28 mL/kg tidal volume exhibited 12-fold increase in neutrophil sequestration, 6-fold increase in bronchoalveolar lavage albumin concentration, and 1.6-fold increase in lung water content compared with unchallenged mice exposed to normal tidal volume ventilation. However, tlr4−/− mice showed negligible neutrophil sequestration, microvascular barrier breakdown, or edema formation. Mechanical ventilation alone or combined with lipopolysaccharide caused activation of circulating neutrophils and pulmonary endothelium in wild-type mice, whereas this was prevented in tlr4−/− mice.High tidal volume ventilation during pneumonia/sepsis induces lung neutrophil sequestration and injury via the Toll-like receptor 4-dependent signaling pathway. The results suggest an important role of Toll-like receptor 4 in the mechanism of lung neutrophil sequestration and acute lung injury when pneumonia/sepsis is coupled to lung hyperinflation.