TGF-β is a potent fibrogenic agent; ECM deposition depends on the balance among fibrogenic agents, matrix metalloproteinases (MMPs) that digest ECM, and the tissue inhibitors of MMPs (TIMPs).
Tissue repair may be impaired by a variety of factors that reduce the quality or adequacy of the reparative process. Factors that interfere with healing may be extrinsic (e.g., infection) or intrinsic to the injured tissue, and systemic or local:
Infection is one of the most important causes of delayed healing; it prolongs inflammation and potentially increases the local tissue injury.
Diabetes is a metabolic disease that compromises tissue repair for many reasons (Chapter 24), and is an important systemic cause of abnormal wound healing.
Nutritional status has profound effects on repair; protein malnutrition and vitamin C deficiency, for example, inhibit collagen synthesis and retard healing.
Glucocorticoids (steroids) have well-documented anti-inflammatory effects, and their administration may result in weak scars because they inhibit TGF-β production and diminish fibrosis. In some instances, however, the anti-inflammatory effects of glucocorticoids are desirable. For example, in corneal infections, glucocorticoids may be prescribed (along with antibiotics) to reduce the likelihood of opacity due to collagen deposition.
Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart (dehisce).
Poor perfusion, resulting either from arteriosclerosis and diabetes or from obstructed venous drainage (e.g., in varicose veins), also impairs healing.
Foreign bodies such as fragments of steel, glass, or even bone impede healing.
The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of cells capable of proliferating; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function. Injury to tissues composed of nondividing cells must inevitably result in scarring; such is the case with healing of a myocardial infarct.
The location of the injury and the character of the tissue in which the injury occurs also are important. For example, in inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities), small exudates may be resorbed and digested by the proteolytic enzymes of leukocytes, resulting in resolution of the inflammation and restoration of normal tissue architecture. However, when the exudate is too large to be fully resorbed it undergoes organization, a process during which granulation tissue grows into the exudate, and a fibrous scar ultimately forms.
Clinical Examples of Abnormal Wound Healing and Scarring
Complications in tissue repair can arise from abnormalities in any of the basic components of the process, including deficient scar formation, excessive formation of the repair components, and formation of contractures.
Defects in Healing: Chronic Wounds
These are seen in numerous clinical situations, as a result of local and systemic factors. The following are some common examples.
Fig. 3.27A ) develop most often in elderly people as a result of chronic venous hypertension, which may be caused by severe varicose veins or congestive heart failure. Deposits of iron pigment (hemosiderin) are common, resulting from red cell breakdown, and there may be accompanying chronic inflammation. These ulcers fail to heal because of poor delivery of oxygen to the site of the ulcer.
Fig. 3.27B ) develop in individuals with atherosclerosis of peripheral arteries, especially associated with diabetes. The ischemia results in atrophy and then necrosis of the skin and underlying tissues. These lesions can be quite painful.