Enhancement of the endotoxin recognition pathway by ventilation with a large tidal volume in rabbits

Ventilation with a small tidal volume (V_t) is associated with better clinical outcomes than with a large V_t particularly in critical settings, including acute lung injury. To determine whether V _t influences the lipopolysaccaharide (LPS) recognition pathway, we studied CD 14 expression in rabbit lungs and the release of TNF-α by cultured alveolar macrophages after 240 min of ventilation with a large (20 ml/kg) vs. a small (5 ml/kg) V_t. We also applied small or large V_t to lungs instilled with 50 μg/kg of LPS. The alveolar macrophages collected after large V_t ventilation revealed a 20-fold increase in LPS-induced TNF-α release compared with those collected after small V_t ventilation, whereas TNF-α was undetectable without LPS stimulation. In animals ventilated with a large V_t, the expression of CD14 mRNA in whole lung homogenates and the expression of CD14 protein on alveolar macrophages, assessed by immunohistochemistry, were both significantly increased in the absence of LPS stimulation. A large V _t applied to LPS-instilled lungs increased the pulmonary albumin permeability and TNF-α release into the plasma. These results suggest that mechanical stress caused by a large V_t sensitizes the lungs to endotoxin, a phenomenon that may occur partially via the upregulation of CD14.