With time, the connective tissue is degraded and the scar shrinks. The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases (MMPs), so called because they are dependent on metal ions (e.g., zinc) for their enzymatic activity. MMPs are produced by a variety of cell types (fibroblasts, macrophages, neutrophils, synovial cells, and some epithelial cells), and their synthesis and secretion are regulated by growth factors, cytokines, and other agents. They include interstitial collagenases, which cleave fibrillar collagen (MMP-1, -2, and -3); gelatinases (MMP-2 and 9), which degrade amorphous collagen and fibronectin; and stromelysins (MMP-3, -10, and -11), which degrade a variety of ECM constituents, including proteoglycans, laminin, fibronectin, and amorphous collagen. Neutrophil elastase, cathepsin G, plasmin, and other serine proteinases can also degrade ECM but are less important in wound remodeling than the MMPs. In addition, activated collagenases can be rapidly inhibited by specific tissue inhibitors of metalloproteinases (TIMPs), produced by most mesenchymal cells. Thus, a balance of MMPs and TIMPs regulates the size and nature of the scar.
Granulation tissue is characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries in a loose extracellular matrix, often with admixed inflammatory cells, mainly macrophages (
Fig.3.26A ).This tissue progressively invades the site of injury; the amount of granulation tissue that is formed depends on the size of the tissue deficit created by the wound and the intensity of inflammation.
scar or fibrosis in tissues is composed of largely inactive, spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components (
Fig. 3.26B ). Pathologists often use special stains to identify different protein constituents of scars and fibrotic tissues.The trichrome stain detects collagen fibers, and the elastin stain identifies delicate fibers of elastin, which is the major component of pliable elastic tissue. (The trichrome actually contains three stains—hence its name—that stain red cells orange, muscle red, and collagen blue.) Another extracellular matrix protein that makes up the connective tissue stroma of normal organs and is present in early scars is reticulin, which is composed of type III collagen, and it too can be identified with a special stain.
REPAIR BY SCAR FORMATION progressively assume a more synthetic phenotype, and hence there is increased deposition of ECM. Collagen synprogressively assume a more synthetic phenotype, and hence there is increased deposition of ECM. Collagen syn • Repair occurs by deposition of connective tissue and scar formation if the injured tissue is not capable of regeneration or if the structural framework is damaged and cannot support regeneration.
Fig. 3.26 (A) Granulation tissue showing numerous blood vessels, edema, and a loose extracellular matrix containing occasional inflammatory cells. Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this point. (B) Trichrome stain of mature scar, showing dense collagen (stained blue) and scattered vascular channels.
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The main steps in repair by scarring are clot formation, inflammation, angiogenesis and formation of granulation tissue, migration and proliferation of fibroblasts, collagen synthesis, and connective tissue remodeling.
Macrophages are critical for orchestrating the repair process, by eliminating offending agents and producing cytokines and growth factors that stimulate the proliferation of the cell types involved in repair.