The role of Toll-like receptors(TLRs)in pathogen recognition has been expeditiously advanced in recent years.However,investigations into the function of TLRs in non-infectious tissue injury have just begun.Previously,we andothers have demonstrated that fragmented hyaluronan(HA)accumulates during tissue injury.CD44 is required to clearHA during tissue injury,and impaired clearance of HA results in unremitting inflammation.Additionally,fragmentedHA stimulates the expression of inflammatory genes by inflammatory cells at the injury site.Recently,we identified thatHA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines andcytokines.In a non-infectious lung injury model,mice deficient in both TLR2 and TLR4 show an impaired transepithelialmigration of inflammatory cells,increased tissue injury,elevated lung epithelial cell apoptosis,and decreased survival.Lung epithelial cell overexpression of high molecular mass HA protected mice against acute lung injury and apoptosis,in part through TLR-dependent basal activation of NF-κB.The exaggerated injury in TLR2 and TLR4 deficient miceappears to be due to impaired HA-TLR interactions on epithelial cells.These studies identify that host matrix componentHA and TLR interactions provide signals that initiate inflammatory responses,maintain epithelial cell integrity,andpromote recovery from acute lung injury. The role of Toll-like receptors (TLRs) in pathogen recognition has been expeditiously advanced in recent years. Despite, investigations into the function of TLRs in non-infectious tissue injury have just begun. Previously, we andothers have demonstrated that fragmented hyaluronan (HA CD44 is required to clear HA during tissue injury, and impaired clearance of HA results in unremitting inflammation. Additionally, fragmented HA stimulates the expression of inflammatory genes by inflammatory cells at the injury site. Recently, we identified that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines andcytokines. In a non-infectious lung injury model, mice deficient in both TLR2 and TLR4 show an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis, and decreased survival .Lung epithelial cell overexpression of high molecular mass HA protected mice against acu te lung injury and apoptosis, in part through TLR-dependent basal activation of NF-κB. The exaggerated injury in TLR2 and TLR4 deficient mice due to be due to impaired HA-TLR interactions on epithelial cells. Contact provide signals that starting epithelial cell integrity, andpromote recovery from acute lung injury.