steps: (1) migration and proliferation of fibroblasts into the site of injury and (2) deposition of ECM proteins produced by these cells. The recruitment and activation of fibroblasts to syn- thesize connective tissue proteins are driven by many growth factors, including PDGF, FGF-2 (described earlier), and TGF-b. The major source of these factors is inflamma- tory cells, paicularly macrophages, which are present at sites of injury and in granulation tissue. Sites of inflamma- tion are also rich in mast cells, and in the appropriate chemotactic milieu, lymphocytes may be present as well. Each of these cell types can secrete cytokines and growth factors that contribute to fibroblast proliferation and activation. As healing progresses, the number of proliferating fibroblasts and new vessels decreases; however, the fibro- blasts progressively assume a more synthetic phenotype, so there is increased deposition of ECM. Collagen synthe- sis, in paicular, is critical to the development of strength in a healing wound site. As described later, collagen syn- thesis by fibroblasts begins early in wound healing (days 3 to 5) and continues for several weeks, depending on the size of the wound. Net collagen accumulation, however, depends not only on increased synthesis but also on diminished collagen degradation (discussed later). Ulti- mately, the granulation tissue evolves into a scar composed of largely inactive, spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM com- ponents (Fig. 2-30, B). As the scar matures, there is proA A gressive vascular regression, which eventually transforms the highly vascularized granulation tissue into a pale, largely avascular scar. Growth Factors Involved in ECM Deposition and Scar Formation Many growth factors are involved in these processes, including TGF-b, PDGF, and FGF. Because FGF also is involved in angiogenesis, it was described earlier. Here we briefly describe the major propeies of TGF-b and PDGF. * Transforming growth factor-b (TGF-b) belongs to a family of homologous polypeptides (TGF-b1, -b2, and -b3) that includes other cytokines such as bone morphogenetic proteins. The TGF-b1 isoform is widely distributed and is usually referred to as TGF-b. The active factor binds to two cell surface receptors with serine-threonine kinase activity, triggering the phosphorylation of transcription factors called Smads. TGF-b has many and often oppo- site effects, depending on the cell type and the metabolic state of the tissue. In the context of inflammation and repair, TGF-b has two main functions: TGF-b stimulates the production of collagen, fibro- nectin, and proteoglycans, and it inhibits collagen degradation by both decreasing proteinase activity and increasing the activity of tissue inhibitors of pro- teinases known as TIMPs (discussed later on). TGF-b is involved not only in scar formation after ref Robbins 9/e p83