Proposed TLR/NF-κB signaling pathway activation in a non-infectious, high VT mechanical ventilation experimental model. Overdistension induced by high VT mechanical ventilation produces endogenous ligands that are able to activate TLR-4 receptors. Subsequent activation of downstream intracellular adapter proteins, enhanced by the down-regulation of IRAK3 expression, leads to the degradation of Iκβα and activation of NF-κB, which gives rise to the expression of pro-inflammatory cytokines. Abbreviations: TLR-4: Toll-like receptor-4; IRAK: Interleukin-1 receptor-associated kinase; IκBα: Inhibitory kappa B alpha; NF-κB: Nuclear factor kappa B; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha. TRAF: Tumor necrosis factor receptor-associated factor; VT: tidal volume.