Abstract: TLR4 mediates I/R injury involving endogenous ligands. Interaction of TLR4 with endogenous ligands provides a critical link between tissue damage and activation of the innate immune response.In the early onset of liver, kidney, heart,or lung I/R injury,endogenous ligands are secreated from several kinds of cells , and they are recognized by TLR4. Interaction of TLR4 with endogenous ligands,such as HMGB1 ,seems to be the most important trigger of inflammation and initiates signaling cascades leading to inflammatory and immune responses.Blocking the interaction of TLR4 with endogenous ligands may be useful in clinical settings associated with inflammation and cellular necrosis caused by ischemic insults.