Abstract
BackgroundMechanical stress induced by injurious ventilation leads to pro-inflammatory cytokine production and lung injury. The extracellular-signal-regulated-kinase, ERK1/2, participates in the signaling pathways activated upon mechanical stress in the lungs to promote the inflammatory response. Tumor progression locus 2 (Tpl2) is a MAP3kinase that activates ERK1/2 upon cytokine or TLR signaling, to induce pro-inflammatory cytokine production. The role of Tpl2 in lung inflammation, and specifically in the one caused by mechanical stress has not been investigated. The aim of the study was to examine if genetic or pharmacologic inhibition of Tpl2 could ameliorate ventilator-induced lung injury.MethodsAdult male wild-type and Tpl2-deficient mice were ventilated with normal or high tidal volume for 4 h. Additional wild-type mice were treated with a Tpl2 inhibitor either before or 30 min after initiation of high tidal ventilation. Non-ventilated mice of both genotypes served as controls. The development of lung injury was evaluated by measuring lung mechanics, arterial blood gases, concentrations of proteins, IL-6, and MIP-2 in bronchoalveolar lavage fluid (BALF) and by lung histology. Data were compared by Kruskal-Wallis non-parametric test and significance was defined as p < 0.05.ResultsMechanical ventilation with normal tidal volume induced a mild increase of IL-6 in BALF in both strains. High tidal volume ventilation induced lung injury in wild-type mice, characterized by decreased lung compliance, increased concentrations of proteins, IL-6 and MIP-2 in BALF, and inflammatory cell infiltration on histology. All indices of lung injury were ameliorated in Tpl2-deficient mice. Wild-type mice treated with the Tpl2 inhibitor, either prior of after the initiation of high tidal volume ventilation were protected from the development of lung injury, as indicated by preserved lung compliance and lower BALF concentrations of proteins and IL-6, than similarly ventilated, untreated wild-type mice.ConclusionsGenetic and pharmacologic inhibition of Tpl2 is protective in a mouse model of ventilator-induced lung injury, ameliorating both high-permeability pulmonary edema and lung inflammation.
Highlights
Mechanical stress induced by injurious ventilation leads to pro-inflammatory cytokine production and lung injury
wild type (WT) and TPL2−/−mice do not differ at baseline and after mechanical ventilation with normal tidal volume (VT) Control WT and Tumor progression locus 2 (Tpl2)−/−mice had no differences on histological appearance, lung compliance, and concentrations of proteins, IL-6 and macrophage inflammatory protein 2 (MIP-2) in bronchoalveolar lavage fluid (BALF)
After 240 min of mechanical ventilation with normal VT, WT, and Tpl2−/−, the mice had no differences in all indices of lung injury studied, inspiratory capacity (Figure 2), arterial oxygen (Figure 3), and concentration of proteins (Figure 4) and IL-6 (Figure 5) in BALF
Summary
Mechanical stress induced by injurious ventilation leads to pro-inflammatory cytokine production and lung injury. Tumor progression locus 2 (Tpl2) is a MAP3kinase that activates ERK1/2 upon cytokine or TLR signaling, to induce pro-inflammatory cytokine production. The cellular responses to increased stress and strain result in alveolar barrier disruption and activation of inflammation, inducing or exacerbating acute lung injury (ALI). Either in vivo or in vitro, impairs barrier properties of alveolar epithelial and endothelial cells [1,2,3]. Both alveolar epithelial and endothelial cells have been shown to produce pro-inflammatory cytokines when subjected to deformation [4,5]. Alveolar macrophages are activated by cyclic stretch [6], and have been shown to mediate inflammation, and barrier dysfunction [6,7,8]
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