Mechanical ventilation modulates TLR4 and IRAK-3 in a non-infectious, ventilator-induced lung injury model

• Published in: Respiratory research 2010-03, Vol.11 (1), p.27-27, Article 27
• Main Authors: Villar, Jesús, Cabrera, Nuria E, Casula, Milena, Flores, Carlos, Valladares, Francisco, Díaz-Flores, Lucio, Muros, Mercedes, Slutsky, Arthur S, Kacmarek, Robert M
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Artificial respiration; Care and treatment; Cytokines - immunology; Disease Models, Animal; Gene expression; Genes; Genetic aspects; Health aspects; Humans; Interleukin-1 Receptor-Associated Kinases - immunology; Interleukins; Lung diseases; Male; Rats; Rats, Sprague-Dawley; Respiration, Artificial - adverse effects; Respiratory Tract Infections - complications; Respiratory Tract Infections - metabolism; Risk factors; Toll-Like Receptor 4 - immunology; Tumor necrosis factor; Ventilator-Induced Lung Injury - etiology; Ventilator-Induced Lung Injury - immunology
• ISSN: 1465-993X; 1465-9921; 1465-993X
• DOI: 10.1186/1465-9921-11-27

Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury. Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (VT) (20 ml/kg) and low VT (6 ml/kg). Histological evaluation, TLR2, TLR4, IRAK3 gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (IkappaBalpha), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL6) gene expression in the lungs and TNF-alpha and IL-6 protein serum concentrations were analyzed. High VT mechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of IRAK3 lung gene expression and protein levels, a significant decrease of IkappaBalpha, and a higher lung expression and serum concentrations of pro-inflammatory cytokines. The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the over-expression and release of pro-inflammatory cytokines during ventilator-induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections.