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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Villar
Jesús
J
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain. jesus.villar54@gmail.com
Cabrera
Nuria E
NE
Casula
Milena
M
Flores
Carlos
C
Valladares
Francisco
F
Díaz-Flores
Lucio
L
Muros
Mercedes
M
Slutsky
Arthur S
AS
Kacmarek
Robert M
RM
D000818:Animals; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D012141:Respiratory Tract Infections / Q000150:complications / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000276:immunology*
D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases