title: 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.
  
  
  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.
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.com
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
authors.forename: Nuria
authors.initials: N
authors.lastname: Cabrera
authors.forename: Milena
authors.initials: M
authors.lastname: Casula
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.forename: Francisco
authors.initials: F
authors.lastname: Valladares
authors.forename: Mercedes
authors.initials: M
authors.lastname: Muros
authors.forename: Lluis
authors.initials: L
authors.lastname: Blanch
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kacmarek
mesh_terms: 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*
chemical_list: D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases
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