Hyaluronan (HA) is a massive sugar polymer in the extracellular matrix. Under physiologic conditions, HA exists as a high-molecular-weight polymer (>106 D) and undergoes dynamic regulation resulting in accumulation of lower molecular weight species (10-500 kD) after tissue injury. HA fragments can trigger innate immune responses in a manner that overlaps with both Grampositive and Gram-negative organism recognition pathways (132) . It has been demonstrated that fragmented HA accumulates during tissue injury (133) (134) (135) . 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 (136) . Recently, Jiang et al. demonstrated that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines and cytokines. In a noninfectious lung injury model, mice deficient in both TLR2 and TLR4 showed an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis and decreased survival (132) . Lung epithelial cell overexpression of high molecular mass HA protected mice against ALI and apoptosis, in part through TLR-dependent basal activation of NF-κB. The exaggerated injury in TLR2-and TLR4-deficient mice appears to be due to impaired HA-TLR interactions on epithelial cells. These studies demonstrate that host-matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from ALI (136) .