Figure 6. TLR4-MyD88 signaling pathway following VILI.

Two pathways are involved referring as TLR4-MyD88 pathway and TLR4-TRIF pathway. Upon binding to endogenous activators (e.g., oxidized phospholipids, high mobility group box1, fragmented hyaluronan, heat shock proteins), the adaptor molecule MyD88, which is associated with TIRAP, is recruited to the TLR4 complex. Binding of MyD88 promotes association with IRAKs and TRAF6. The complex IRAKs/TRAF6 dissociates from the receptor and then interacts with another complex,TAK1. TAK1 results in phosphorylation and degradation of IκBα, consequent release of NF-κB, translocation of NF-κB into the nucleus, and transcription of pro-inflammatory genes inducing cytokine production. In the meantime, TAK1 also leads to activation of MAPK such as ERK that activates AP-1 transcription factor, which induces the transcription of inflammatory cytokines. In addition to MyD88, other adaptor proteins such as TRIF, which is associated with TRAM, mediate induction of IRF3, which in turn phosphorylates IκBα, leading to release of NF-κB to the nucleus. Unregulated proinflammatory cytokines may predispose VILI. TLR4 = Toll/interleukin-1 like receptor 4; MyD88 = myeloid differentiation factor 88; TIRAP = Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein; TRIF = Toll/Interleukin-1 receptor-domain containing adaptor-inducing interferon-beta; TRAM = TRIF-related adaptor molecule; RIP1 = receptor interacting protein-1; IRAKs = interleukin (IL)-1 receptor-associated kinases; IRF3 = interferon regulatory factor 3; TRAF6 = tumor necrosis factor receptor associated factor 6; TAK1 = transforming growth factor activated kinase 1; MAPK = mitogen-activated protein kinases; ERK = extracellular signal-regulated kinases; AP1 = activator protein 1; IκBα = inhibitor of κB alpha; VILI = ventilator-induced lung injury.