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Villar, J. et al.

Jesús Villar, Nuria Cabrera, Milena Casula, Carlos Flores, Francisco Valladares, Mercedes Muros, Lluis Blanch, Arthur S. Slutsky, Robert M. Kacmarek,

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 (V (T)) with no positive end-expiratory pressure (PEEP) versus low V (T) (6 ml/kg) plus 10 cmH(2)O PEEP. MEASUREMENTS AND MAIN RESULTS: Histological evaluation, TLR-2, TLR-4, inhibitory kappaB alpha (IkappaBalpha), interleukin-1 receptor-associated 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 V (T) plus PEEP attenuated sepsis-associated TLR-4 activation, and produced a significant decrease of IRAK-3 gene expression and protein levels, a significant increase of IkappaBalpha, and a decrease in lung gene expression and serum levels of cytokines. High-V (T) MV caused a significant increase of TLR-4 and IRAK-3 protein levels, lung and systemic cytokines, and mortality, and a significant decrease of IkappaBalpha. 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.[1]

References

Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model. Villar, J., Cabrera, N., Casula, M., Flores, C., Valladares, F., Muros, M., Blanch, L., Slutsky, A.S., Kacmarek, R.M. Intensive. Care. Med (2010) [Pubmed]

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