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Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model.
Intensive Care Med. 2010 Jun; 36(6):1049-57.IC

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.

Links

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Authors+Show Affiliations

Villar J
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.com
Cabrera N
No affiliation info available
Casula M
No affiliation info available
Flores C
No affiliation info available
Valladares F
No affiliation info available
Muros M
No affiliation info available
Blanch L
No affiliation info available
Slutsky AS
No affiliation info available
Kacmarek RM
No affiliation info available

MeSH

AnimalsCytokinesDisease Models, AnimalGene ExpressionInterleukin-1 Receptor-Associated KinasesLung InjuryMaleProspective StudiesRandom AllocationRatsRats, Sprague-DawleyRespiration, ArtificialSepsisToll-Like Receptor 4

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20397011

Citation

Villar, Jesús, et al. "Mechanical Ventilation Modulates Toll-like Receptor Signaling Pathway in a Sepsis-induced Lung Injury Model." Intensive Care Medicine, vol. 36, no. 6, 2010, pp. 1049-57.
Villar J, Cabrera N, Casula M, et al. Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model. Intensive Care Med. 2010;36(6):1049-57.
Villar, J., Cabrera, N., Casula, M., Flores, C., Valladares, F., Muros, M., Blanch, L., Slutsky, A. S., & Kacmarek, R. M. (2010). Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model. Intensive Care Medicine, 36(6), 1049-57. https://doi.org/10.1007/s00134-010-1799-3
Villar J, et al. Mechanical Ventilation Modulates Toll-like Receptor Signaling Pathway in a Sepsis-induced Lung Injury Model. Intensive Care Med. 2010;36(6):1049-57. PubMed PMID: 20397011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model. AU - Villar,Jesús, AU - Cabrera,Nuria, AU - Casula,Milena, AU - Flores,Carlos, AU - Valladares,Francisco, AU - Muros,Mercedes, AU - Blanch,Lluis, AU - Slutsky,Arthur S, AU - Kacmarek,Robert M, Y1 - 2010/04/16/ PY - 2009/08/02/received PY - 2010/01/22/accepted PY - 2010/4/17/entrez PY - 2010/4/17/pubmed PY - 2010/9/9/medline SP - 1049 EP - 57 JF - Intensive care medicine JO - Intensive Care Med VL - 36 IS - 6 N2 - 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. SN - 1432-1238 UR - https://www.unboundmedicine.com/medline/citation/20397011/Mechanical_ventilation_modulates_Toll_like_receptor_signaling_pathway_in_a_sepsis_induced_lung_injury_model_ L2 - https://dx.doi.org/10.1007/s00134-010-1799-3 DB - PRIME DP - Unbound Medicine ER -