Experimental

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 VillarAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIResearch Unit, Multidisciplinary Organ Dysfunction Evaluation Research Network, Hospital Universitario Dr. NegrinKeenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital Email author 
  • , Nuria CabreraAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIResearch Unit, Multidisciplinary Organ Dysfunction Evaluation Research Network, Hospital Universitario Dr. Negrin
  • , Milena CasulaAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIResearch Unit, Multidisciplinary Organ Dysfunction Evaluation Research Network, Hospital Universitario Dr. Negrin
  • , Carlos FloresAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIResearch Unit, Hospital Universitario N.S. de Candelaria
  • , Francisco ValladaresAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIDepartment of Anatomy, Pathology and Histology, University of La Laguna
  • , Mercedes MurosAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIDepartment of Clinical Biochemistry, Hospital Universitario N.S. de Candelaria
  • , Lluis BlanchAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIICritical Care Center
  • , Arthur S. SlutskyAffiliated withKeenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s HospitalInterdepartmental Division of Critical Care Medicine, University of TorontoKing Saud University
  • , Robert M. KacmarekAffiliated withCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIDepartment of Respiratory Care, Massachusetts General HospitalDepartment of Anesthesia, Harvard Medical School

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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 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 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 IκBα, 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 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