A hallmark of tissue injury and repair is the turnover of extracellular matrix components. This review focuses on the role of the
glycosaminoglycan hyaluronan in tissue injury and repair. Both the synthesis and degradation of extracellular matrix are critical contributors to tissue repair and remodeling. Fragmented
hyaluronan accumulates during tissue injury and functions in ways distinct from the native
polymer. There is accumulating evidence that
hyaluronan degradation products can stimulate the expression of inflammatory genes by a variety of immune cells at the injury site. CD44 is the major cell-surface
hyaluronan receptor and is required to clear
hyaluronan degradation products produced during
lung injury; impaired clearance of
hyaluronan results in persistent
inflammation. However,
hyaluronan fragment stimulation of inflammatory gene expression is not dependent on CD44 in inflammatory macrophages. Instead,
hyaluronan fragments utilize both
Toll-like receptor (TLR) 4 and TLR2 to stimulate inflammatory genes in macrophages.
Hyaluronan also is present on the cell surface of lung alveolar epithelial cells and provides protection against tissue damage by interacting with TLR2 and TLR4 on these parenchymal cells. The simple repeating structure of
hyaluronan appears to be involved in a number of important aspects of noninfectious tissue injury and repair that are dependent on the size and location of the
polymer as well as the interacting cells. Thus, the interactions between the endogenous matrix component
hyaluronan and its signaling receptors initiate inflammatory responses, maintain structural cell integrity, and promote recovery from tissue injury.