If repair cannot be accomplished by regeneration alone, it occurs by replacement of the injured cells with connective tissue, leading to the formation of a scar, or by a combination of regeneration of some residual cells and scar formation. As discussed earlier, scarring may happen if the tissue injury is severe or chronic and results in damage to parenchymal cells and epithelia as well as to the connective tissue framework, or if nondividing cells are injured. In contrast to regeneration, which involves the restitution of tissue components, scar formation is a response that “patches” rather than restores the tissue. The term scar is most often used in connection to wound healing in the skin, but also may be used to describe the replacement of parenchymal cells in any tissue by collagen, as in the heart after myocardial infarction.
Repair by connective tissue deposition consists of a series of sequential steps that follow tissue injury (
Fig. 3.24
Within minutes after injury, a hemostatic plug comprised of platelets (Chapter 4) is formed, which stops bleeding and provides a scaffold for infiltrating inflammatory cells.
Inflammation. This step is comprised of the typical acute and chronic inflammatory responses. Breakdown products of complement activation, chemokines released from activated platelets, and other mediators produced at the site of injury function as chemotactic agents to recruit neutrophils and then monocytes during the next 6 to 48 hours. As described earlier, these inflammatory cells eliminate the offending agents, such as microbes that may have entered through the wound, and clear the debris. Macrophages are the central cellular players in the repair process—M1 macrophages clear microbes and necrotic tissue and promote inflammation in a positive feedback loop, and M2 macrophages produce growth factors that stimulate the proliferation of many cell types in the next stage of repair. As the injurious agents and necrotic cells are cleared, the http://ebooksmedicine.net
Fig. 3.24 Steps in repair by scar formation: healing of a large wound in the skin. This is an example of healing by second intention. (A) Hemostatic plug and inflammation. (B) Proliferation of epithelial cells; formation of granulation tissue by vessel growth and proliferating fibroblasts. (C) Remodeling to produce the fibrous scar.
inflammation resolves; how this inflammatory flame is extinguished in most situations of injury is still not well  defined.
Cell proliferation. In the next stage, which takes up to 10 days, several cell types, including epithelial cells, endothelial and other vascular cells, and fibroblasts, proliferate and migrate to close the now-clean wound. Each cell type serves unique functions.
Epithelial cells respond to locally produced growth factors and migrate over the wound to cover it.
Endothelial and other vascular cells proliferate to form new blood vessels, a process known as angiogenesis. Because of the importance of this process in physiologic host responses and in many pathologic conditions, it is described in more detail later.
Fibroblasts proliferate and migrate into the site of injury and lay down collagen fibers that form the scar.
The combination of proliferating fibroblasts, loose connective tissue, new blood vessels and scattered chronic inflammatory cells, forms a type of tissue that is unique to healing wounds and is called granulation tissue. This term derives from its pink, soft, granular gross appearance, such as that seen beneath the scab of a skin wound.
Remodeling. The connective tissue that has been deposited by fibroblasts is reorganized to produce the stable fibrous scar. This process begins 2 to 3 weeks after injury and may continue for months or years.