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Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model
Jesús Villar1, Nuria Cabrera, Milena Casula
1CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.com
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.
Insights
Mechanical ventilation (MV) during sepsis modulates the innate immune response by influencing Toll-like receptor (TLR) signaling. Low tidal volume with PEEP reduces inflammation, while high tidal volume increases it, impacting sepsis outcomes.
Area of Science:
- Immunology
- Critical Care Medicine
- Pulmonology
Background:
- Sepsis triggers innate immune responses, involving Toll-like receptor (TLR) signaling.
- Mechanical ventilation (MV) can independently induce pulmonary inflammation.
- The interaction between sepsis-induced inflammation and MV requires further investigation.
Purpose of the Study:
- To investigate how mechanical ventilation (MV) modulates the innate immune response during sepsis.
- To examine the role of Toll-like receptor (TLR) signaling in MV-modulated sepsis response.
Main Methods:
- A prospective, randomized, controlled animal study using male Sprague-Dawley rats.
- Sepsis induced via cecal ligation and perforation.
- Animals randomized to spontaneous breathing or MV with either high tidal volume (20 ml/kg) or low tidal volume (6 ml/kg) plus PEEP (10 cmH2O) for 4 hours.
Main Results:
- Low tidal volume MV with PEEP attenuated sepsis-associated TLR-4 activation, decreased IRAK-3, increased IkappaBalpha, and reduced lung and serum cytokine levels.
- High tidal volume MV significantly increased TLR-4 and IRAK-3 protein levels, lung and systemic cytokines, and mortality, while decreasing IkappaBalpha.
- Histological evaluation, gene expression, and protein analyses were performed.
Conclusions:
- Mechanical ventilation strategies significantly impact the innate immune response during sepsis.
- Low tidal volume with PEEP may mitigate sepsis-induced inflammation by modulating TLR signaling pathways.
- High tidal volume ventilation exacerbates inflammation and increases mortality in a sepsis model.
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