wound Healing versus fibrosis

 J Pathol. 2008 January : 214(2): 199-210. doi: 10.1002/path.2277.

Wound healing versus fibrosis

When epithelial and/or endothelial cells are damaged, they release inflammatory mediators that initiate an anti-fibrinolytic coagulation cascade [5], which triggers blood-clot formation and formation of a provisional ECM. Platelets are exposed to ECM components, triggering aggregation, clot formation and haemostasis. Platelet degranulation also promotes vasodilation and increased blood vessel permeability, while myofibroblasts (activated collagen secreting. a-SMA+ fibroblasts) and epithelial and/or endothelial cells produce MMPs, which disrupt the basement membrane, allowing inflammatory cells to be easily recruited to the site of injury.

Growth factors, cytokines and chemokines are also produced, which stimulates the proliferation and recruitment of leukocytes across the provisional ECM. Some of the early responders include macrophages and neutrophils, which eliminate tissue debris, dead cells and any invading organisms. They also produce cytokines and chemokines, which are mitogenic and chemotactic for endothelial cells, which begin to surround the injured site. They also help form new blood vessels as epithelial/endothelial cells migrate towards the centre of the wound.

During this period, lymphocytes and other cells become activated and begin secreting profibrotic cytokines and growth factors, such as TGFß, IL-13 and PDGF [6-8], which further activate the macrophages and fibroblasts. Activated fibroblasts transform into a-SMA-expressing myofibroblasts as they migrate along the fibrin lattice into the wound. Following activation, the myofibroblasts promote wound contraction, the process in which the edges of the wound migrate towards the centre. Finally, epithelial and/or endothelial cells divide and migrate over the basal layers to regenerate the damaged tissue, which completes the wound-healing process. However, chronic inflammation and repair can trigger an excessive accumulation of ECM components, which leads to the formation of a permanent fibrotic scar.

Collagen turnover and ECM remodelling is regulated by various MMPs and their inhibitors, which include the tissue inhibitors of metalloproteinases (TIMPs). Shifts in synthesis versus catabolism of the ECM regulate the net increase or decrease of collagen within the wound

[9]. Fibrosis occurs when the synthesis of new collagen by myofibroblasts exceeds the rate at which it is degraded, such that the total amount of collagen increases over time.