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

Abstract

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.

• Authors: Jesús Villar, Nuria Cabrera, Milena Casula, Carlos Flores, Francisco Valladares, Mercedes Muros, Lluis Blanch, Arthur S Slutsky, Robert M Kacmarek
• Journal: Intensive care medicine (Intensive Care Med) Vol. 36 Issue 6 Pg. 1049-57 (Jun 2010) ISSN: 1432-1238 [Electronic] United States
• PMID: 20397011 (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 (blood)
• Disease Models, Animal
• Gene Expression
• Interleukin-1 Receptor-Associated Kinases (genetics, immunology, metabolism)
• Lung Injury (etiology, immunology)
• Male
• Prospective Studies
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Respiration, Artificial (adverse effects)
• Sepsis (complications, etiology)
• Toll-Like Receptor 4 (immunology, metabolism)