Ventilation-induced chemokine and cytokine release is associated with activation of nuclear Factor-kappa B and is blocked by steroids

Recent clinical trials have shown that the survival of patients with acute respiratory distress syndrome (ARDS) is improved by ventilation with reduce d volumes. These studies suggested that overinflation of the lungs causes o veractivation of the immune system. The present study investigated the hypo thesis that ventilation with increased tidal volumes results in early respo nses similar to those caused by stimulation with one of the major risk fact ors for ARDS: bacterial lipopolysaccharide (LPS). We therefore compared the effects of ventilation (-10 cm H2O or -25 cm H2O end-inspiratory pressure) and LPS (50 mug/ml) on nuclear factor (NF)-kappaB activation, chemokine re lease, and cytokine release in isolated perfused lungs obtained from BALB/C mice. We found that both LPS and ventilation with -25 cm H2O (overventilat ion; OV) caused translocation of NF-kappaB, which was abolished by pretreat ment with the steroid dexamethasone. Furthermore, both treatments resulted in similar increases in perfusate levels of alpha -chemokines (macrophage i nflammatory protein; [MIP]-2; KC), beta -chemokines (macrophage chemotactic protein-1; MlP-1 alpha), and cytokines (tumor necrosis factor-alpha, inter leukin-6), which were largely prevented by dexamethasone pretreatment. In L PS-resistant C3H/HeJ mice, only OV, and not LPS, caused translocation of NF -KB and release of MIP-2. We conclude that OV evokes early inflammatory res ponses similar to those evoked by LPS (i.e., NF-kappaB translocation and re lease of proinflammatory mediators). The NF-kappaB translocation elicited b y OV appears to be independent of Toll-like receptor 4 and not due to LPS c ontamination introduced by the ventilator. Our data further suggest that st eroids might be considered as a subsidiary treatment during artificial mech anical ventilation.