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

Abstract

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.

• Authors: Jesús Villar, Nuria E Cabrera, Milena Casula, Carlos Flores, Francisco Valladares, Lucio Díaz-Flores, Mercedes Muros, Arthur S Slutsky, Robert M Kacmarek
• Journal: Respiratory research (Respir Res) Vol. 11 Pg. 27 (Mar 03 2010) ISSN: 1465-993X [Electronic] England
• PMID: 20199666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Interleukin-1 Receptor-Associated Kinases

Topics

• Animals
• Cytokines (immunology)
• Disease Models, Animal
• Humans
• Interleukin-1 Receptor-Associated Kinases (immunology)
• Male
• Rats
• Rats, Sprague-Dawley
• Respiration, Artificial (adverse effects)
• Respiratory Tract Infections (complications, metabolism)
• Toll-Like Receptor 4 (immunology)
• Ventilator-Induced Lung Injury (etiology, immunology)