Porth's Essentials of Pathophysiology, 4e

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Cell Proliferation and Tissue Regeneration and Repair

C h a p t e r 4

in two phases: emigration and proliferation of fibroblasts into the site of injury, and deposition of extracellular matrix by these cells. The recruitment and proliferation of fibroblasts is mediated by a number of growth factors including FGF-2 and TGF- β . These growth factors are released from endothelial cells and from inflammatory cells that are present at the site of injury. As healing progresses, the number of proliferating fibroblasts and formation of new vessels decrease and there is increased synthesis and deposition of collagen. Collagen synthesis is important to the development of strength in the healing wound site. Ultimately, the gran- ulation tissue scaffolding evolves into a scar composed of largely inactive spindle-shaped fibroblasts, dense col- lagen fibers, fragments of elastic tissue, and other ECM components. As the scar matures, vascular degeneration eventually transforms the highly vascular granulation tissue into a pale, largely avascular scar. Maturation and Remodeling of the FibrousTissue The transition from granulation to scar tissue involves shifts in the modification and remodeling of the ECM. The outcome of the repair process is, in part, a bal- ance between previously discussed ECM synthesis and degradation. The rate of collagen synthesis diminishes until it reaches equilibrium with collagen degradation. The degradation of collagen and other ECM proteins is achieved through a family of metalloproteinases, which require zinc for their activity. The metallopro- teinases are produced by a variety of cell types (fibro- blasts, macrophages, synovial cells, and some epithelial cells), and their synthesis and secretion are regulated by growth factors, cytokines, and other agents. 10,11 Their synthesis may be suppressed pharmacologically by corticosteroids. Metalloproteinases are typically released as inactive precursors that require activation by enzymes, such as proteases, that are present at sites of injury. Cutaneous Wound Healing Thus far, this chapter has focused on general aspects of tissue repair and wound healing. The following section specifically addresses healing of skin wounds (cutane- ous wound healing). This is a process that involves both epithelial cell regeneration and connective tissue scar formation, and thus is illustrative of general principles that apply to all tissues. Healing by Primary and Secondary Intention Depending on the extent of tissue loss, wound closure and healing occur by primary or secondary intention (Fig. 4-6). A sutured surgical incision is an example of healing by primary intention. Larger wounds (e.g., burns and large surface wounds) that have a greater loss of tissue and contamination heal by secondary intention. Healing by secondary intention is slower than healing by primary intention and results in the formation of larger

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formation of capillary buds, and proliferation of endothe- lial cells, followed by fusion and remodeling of the endo- thelial cells into capillary tubes. Several growth factors induce angiogenesis, but the most important are VEGF and basic FGF-2. In angiogenesis, VEGF stimulates both proliferation and motility of endothelial cells, thus initiat- ing the process of capillary sprouting. FGF-2 participates in angiogenesis mainly by stimulating the proliferation of endothelial cells. During angiogenesis, new blood vessels are leaky because of incompletely formed interendothe- lial cell junctions and because VEGF increases vascu- lar permeability. This leakiness explains the edematous appearance of granulation tissue and accounts in part for the swelling that may persist in healing wounds long after the acute inflammation has subsided. Emigration of Fibroblasts and Deposition of Extracellular Matrix Scar formation builds on the granulation tissue frame- work of new vessels and loose ECM. The process occurs FIGURE 4-5. Granulation tissue. (A) A foot covered by granulation tissue. (B) A photomicrograph of granulation tissue shows the thin-walled vessels (arrows) embedded in a loose connective tissue matrix containing mesenchymal cells and occasional inflammatory cells. (From Sephal GC, Davidson JM. Repair, regeneration, and fibrosis. In: Rubin R, Strayer DS, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer Health | Lippincott Williams &Wilkins; 2012:94.)