Fig. 1.

Role of HMGB1 in the development of acute lung injury (ALI): extracellular high-mobility group box 1 (HMGB1) activates cell membrane TLR2, TLR4 and RAGE receptors. Activation of RAGE receptors leads to triggering of ROS-dependent activation of MAPK pathway. Though, activations of TLR2 and TLR4 by HMGB1 trigger activations of intracellular myeloid differentiation 88 (MyD88), which activates inhibitor of nuclear factor kappa B kinase (IKK-β). Both of IKK-β and mitogen-activated protein kinase (MAPK) stimulate NF-κB signaling pathway. However, extracellular HMGB1 may directly activate NF-κB through phosphatidyl-inositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) independent of TLRs or RAGE receptors leading to release of pro-inflammatory cytokines that result in ALI