Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model

Background: Experimental and clinical studies on sepsis have demonstrated activation of the innate immune response following the initial host-bacterial interaction. In addition, mechanical ventilation (MV) can induce a pulmonary inflammatory response. How these two responses interact when present simultaneously remains to be elucidated. We hypothesized that MV modulates innate host response during sepsis by influencing Toll-like receptor (TLR) signaling. Design: Prospective, randomized, controlled animal study. Subjects: Male, septic Sprague- Dawley rats. Interventions: Sepsis was induced by cecal ligation and perforation. At 18 h, surviving animals had the cecum removed and were randomized to spontaneous breathing or two strategies of MV for 4 h: high (20 ml/kg) tidal volume (VT) with no positive end-expiratory pressure (PEEP) versus low VT (6 ml/kg) plus 10 cmH2O PEEP. Measurements and main results: Histological evaluation, TLR-2, TLR-4, inhibitory kappaB alpha (IκBα), interleukin-1 receptorassociated kinase-3 (IRAK-3) gene expression, protein levels and immunohistochemical lung localization, inflammatory cytokines gene expression, and protein serum concentrations were analyzed. MV with low VT plus PEEP attenuated sepsis-associated TLR-4 activation, and produced a signifi-cant decrease of IRAK-3 gene expression and protein levels, a significant increase of IjBa, and a decrease in lung gene expression and serum levels of cytokines. High-VT MV caused a significant increase of TLR-4 and IRAK-3 protein levels, lung and systemic cytokines,and mortality, and a significant decrease of IκBα. Conclusions: Our findings suggest a novel mechanism that could partially explain how MV modulates the innate immune response in the lung by interfering with cellular signaling pathways that are activated in response to pathogens. © 2010 jointly held by Springer and ESICM.