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.


METHODS
Prospective, randomized, controlled animal study.


METHODS
Male, septic Sprague-Dawley rats.


METHODS
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.


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.
Villar
Jesús
J
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.com
Cabrera
Nuria
N
Casula
Milena
M
Flores
Carlos
C
Valladares
Francisco
F
Muros
Mercedes
M
Blanch
Lluis
L
Slutsky
Arthur S
AS
Kacmarek
Robert M
RM
D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D015870:Gene Expression; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055370:Lung Injury / Q000209:etiology* / Q000276:immunology; D008297:Male; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D018805:Sepsis / Q000150:complications* / Q000209:etiology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases
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