Macrophage Involvement in Wound Repair, Remodeling, and Fibrosis

The process of wound repair has as its ultimate goal the restoration of normal aseptic-tissue structure and function following injury. Although injury can take many forms, e.g., surgical trauma, burns, immunologically mediated injury, and so forth, the general sequence of events that are activated in response to injury and that lead to successful wound repair show striking similarity irrespective of the initial injurious insult. The sequence comprises (1) the activation of the coagulation system, leading to a cessation of blood flow and the formation of a provisional matrix; (2) the local generation of a variety of soluble chemotactic factors formed from preformed plasma proteins that attract inflammatory cells to the site of injury; (3) the sequential influx of neutrophils and monocytes, leading to wound sterilization; (4) the debridement of damaged connective tissue matrix; (5) the initiation of neovascularization; and (6) the stimulation of mesenchymal cell proliferation and connective tissue matrix remodeling. However, while in many tissues and situations, this generalized sequence of events leads to the restoration of normal tissue structure and functions, in some tissues, such as in adult skin, repair is invariably associated with scarring caused as a result of abundant collagen synthesis by fibroblasts that proliferate and differentiate within the provisional matrix. While this is generally acceptable in the case of the skin, excessive tissue fibrosis during repair of other tissues, for example, as a consequence of injury to the lung or liver parenchyma, results in a dramatic and frequently fatal loss of function as a consequence of scarring. Thus, understanding what distinguishes these two outcomes may allow treatment strategies to be developed to ameliorate tissue fibrosis in susceptible or “at-risk” individuals.