Abstract
BackgroundMechanical ventilation augments lung inflammation resulting from exposure to microbial products. The objective of this study was to test the hypothesis that ventilator-associated immune modulation requires MyD88-dependent signaling. Because MyD88 is a critical adapter protein utilized for pro-inflammatory signaling by all Toll-like receptors (TLRs), with the exception of TLR3, as well as by the IL-1 and IL-18 receptors, MyD88 dependence would implicate generation of an endogenous soluble ligand recognized by one or more of these receptors during mechanical ventilation and would provide an opportunity for a potential future therapeutic intervention.MethodsWe compared the effect of mechanical ventilation on lung inflammation and permeability between poly(I:C) exposed mice with or without expression of MyD88. Poly(I:C) is a synthetic ligand for TLR3, the only MyD88-independent TLR, allowing isolation of the effect of MyD88 deletion on ventilator-augmentation of lung inflammation. Lung inflammation was assessed by cytokine concentration in lung tissue homogenate and polymorphonuclear cell (PMN) number in bronchoalveolar lavage fluid (BALF). Lung permeability was assessed by total protein, IgM, and intravenously injected FITC-dextran concentrations in BALF.ResultsWe found that MyD88 was required for mechanical ventilation augmentation of TLR3-induced lung inflammation and permeability. Because TLR4 is the most commonly reported receptor for endogenous ligands generated during tissue injury, we performed a second experiment comparing wildtype and TLR4-/- mice. We found that mechanical ventilation increased TLR3-mediated inflammation and permeability independent of TLR4.ConclusionThese data support the hypothesis that mechanical ventilation with moderate tidal volumes generates an endogenous ligand(s) recognized by MyD88-dependent receptor(s) other than TLR4, and that this mechanism can contribute to the development of ventilator-associated lung inflammation and injury. Identification of these ligands and/or receptors could lead to new pharmacological treatments for ARDS.
Highlights
Mechanical ventilation augments lung inflammation resulting from exposure to microbial products
Because TLR4 is the most commonly implicated myeloid differentiation factor 88 (MyD88)-dependent receptor for damage-associated endogenous ligands, we evaluated the role of TLR4-dependent signaling during mechanical ventilation by measuring the inflammatory response of wild-type (WT) and TLR4-/mice to a TLR3 ligand (Figure 1B)
We hypothesized that mechanical ventilation with a tidal volume of 10 mL/kg generates endogenous ligands, either classical cytokines and/or damage-associated molecular patterns (DAMPs), which are recognized by MyD88-dependent transmembrane receptors, resulting in amplification of the inflammatory response from concurrently administered poly(I:C), a TLR3 ligand
Summary
Mechanical ventilation augments lung inflammation resulting from exposure to microbial products. A second retrospective study by Jia et al identified tidal volume magnitude as an independent risk factor for the subsequent development of ALI in mechanically ventilated patients without preexisting lung injury [6]. Augmented lung inflammation and injury with mechanical ventilation occurs with a variety of non-microbial insults such as hyperoxia [13,14] and intra-tracheal acid instillation [15]. These data suggest that ventilation with a strategy that does not independently cause clinically significant inflammation or injury may amplify the host response to pro-inflammatory stimuli, such as bacterial or viral infection, resulting in the development of acute lung injury
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