We found in our study that HS/R activates the TLR4-MyD88-IRAK4 signaling pathway through HMGB1, and further activates p38 MAPK and Akt pathways to initiate PMN NAD(P)H oxidase activation. PMN NAD(P)H oxidase-derived oxidants, in turn, mediate TLR4-TLR2 cross-talk in AMφ and sensitize AMφ response to TLR2 ligands, which act in a positive feedback manner to amplify pulmonary PMN infiltration and inflammation (130) .