Intensive Care Medicine

, Volume 36, Issue 6, pp 1049–1057

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

  • Jesús Villar
  • Nuria Cabrera
  • Milena Casula
  • Carlos Flores
  • Francisco Valladares
  • Mercedes Muros
  • Lluis Blanch
  • Arthur S. Slutsky
  • Robert M. Kacmarek
Experimental

DOI: 10.1007/s00134-010-1799-3

Cite this article as:
Villar, J., Cabrera, N., Casula, M. et al. Intensive Care Med (2010) 36: 1049. doi:10.1007/s00134-010-1799-3

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 (VT) with no positive end-expiratory pressure (PEEP) versus low VT (6 ml/kg) plus 10 cmH2O PEEP.

Measurements and main results

Histological evaluation, TLR-2, TLR-4, inhibitory kappaB alpha (IκBα), 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 VT 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 IκBα, and a decrease in lung gene expression and serum levels of cytokines. High-VT MV caused a significant increase of TLR-4 and IRAK-3 protein levels, lung and systemic cytokines, and mortality, and a significant decrease of IκBα.

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.

Keywords

Acute lung injury Sepsis Positive-pressure ventilation Cytokine Toll-like receptor 

Supplementary material

134_2010_1799_MOESM1_ESM.doc (90 kb)
Supplementary material 1 (DOC 89.5 kb).

Copyright information

© Copyright jointly held by Springer and ESICM 2010

Authors and Affiliations

  • Jesús Villar
    • 1
    • 2
    • 3
  • Nuria Cabrera
    • 1
    • 2
  • Milena Casula
    • 1
    • 2
  • Carlos Flores
    • 1
    • 4
  • Francisco Valladares
    • 1
    • 5
  • Mercedes Muros
    • 1
    • 6
  • Lluis Blanch
    • 1
    • 7
  • Arthur S. Slutsky
    • 3
    • 8
    • 9
  • Robert M. Kacmarek
    • 10
    • 11
  1. 1.CIBER de Enfermedades RespiratoriasInstituto de Salud Carlos IIIMadridSpain
  2. 2.Research Unit, Multidisciplinary Organ Dysfunction Evaluation Research NetworkHospital Universitario Dr. NegrinLas Palmas de Gran CanariaSpain
  3. 3.Keenan Research Center, Li Ka Shing Knowledge InstituteSt. Michael’s HospitalTorontoCanada
  4. 4.Research UnitHospital Universitario N.S. de CandelariaTenerifeSpain
  5. 5.Department of Anatomy, Pathology and HistologyUniversity of La LagunaTenerifeSpain
  6. 6.Department of Clinical BiochemistryHospital Universitario N.S. de CandelariaTenerifeSpain
  7. 7.Critical Care CenterSabadellSpain
  8. 8.Interdepartmental Division of Critical Care MedicineUniversity of TorontoTorontoCanada
  9. 9.King Saud UniversityRiyadhSaudi Arabia
  10. 10.Department of Respiratory CareMassachusetts General HospitalBostonUSA
  11. 11.Department of AnesthesiaHarvard Medical SchoolBostonUSA