Factors Modulating Repair PDF

25 FACTORS MODULATING REPAIR ILOs By the end of this lecture, students will be able to 1. Apply steps of repair to healing in simple and complicated surgical wounds and parenchymal organs. 2. Delineate factors that influence tissue repair and abnormalities in tissue repair Fac...

25 FACTORS MODULATING REPAIR ILOs By the end of this lecture, students will be able to 1. Apply steps of repair to healing in simple and complicated surgical wounds and parenchymal organs. 2. Delineate factors that influence tissue repair and abnormalities in tissue repair Factors That Influence Tissue Repair 1. Nutritional status of the host. 2. Metabolic status (diabetes mellitus delays healing). 3. Circulatory status or vascular adequacy. 4. Hormones (e.g., glucocorticoids can impede the inflammatory and reparative process). 5. Size and location: Well-vascularized tissues heal faster; inflammation in tissue spaces (e.g., peritoneal cavity) develops exudates that can either resolve or undergo organization. 6. Type of tissue: Labile and stable tissues have better tissue regeneration, whereas permanent tissues form only scar. 7. Local factors that delay healing include infections, ischemia, mechanical forces (e.g., motion or wound tension), and foreign bodies. Selected Clinical Examples of Tissue Repair and Fibrosis Healing of Skin Wounds A. Healing by First Intention (or Primary Union): Healing by first intention (or primary union) occurs when injury involves only the epithelial layer. Repair is mainly by epithelial regeneration. In a clean, uninfected surgical incision approximated by surgical sutures there is only focal disruption of the basement membrane and relatively minimal cell death. Steps of wound healing by first intention: 1. Wounding activates coagulation pathways; the clot (containing fibrin, fibronectin, and complement proteins) stops the bleeding and acts as a scaffold for migrating cells. As dehydration occurs, a scab is formed. 2. Within 24 hours, neutrophils arrive at the incision margin, releasing proteolytic enzymes that begin to clear the debris. 3. Within 24 to 48 hours, epithelial cells from both edges have migrated and proliferated along the dermis, depositing basement membrane components as they progress. Page 1 of 4  4. By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space, with collagen fibers evident at the incision margins. 5. By day 5, neovascularization reaches its peak with ongoing migration of fibroblasts, which are producing ECM proteins. The epidermis recovers its normal thickness as differentiation of surface cells yields a mature epidermal architecture with surface keratinization. 6. During the second week, there is continued collagen accumulation and fibroblast proliferation, but leukocyte infiltrate, edema, and vascularity are diminished. 7. By 4 weeks, scar is well formed with few inflammatory cells. Although the epidermis is essentially normal, dermal appendages destroyed in the line of the incision are permanently lost. B. Healing by Second Intention (or Secondary Union): Healing by second intention (or secondary union) happens when tissue loss is more extensive (e.g., large wounds, abscesses, ulceration, and ischemic necrosis [infarction]). repair involves a combination of regeneration and scarring. The inflammatory reaction is more intense, and there is abundant granulation tissue, with subsequent increased ECM accumulation and formation of a large scar, followed by myofibroblast wound contraction. Steps of wound healing by second intention: 1. In wounds causing large tissue deficits, inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed. 2. Much larger amounts of granulation tissue are formed. 3. The original granulation tissue scaffold is eventually converted into a pale, avascular scar; although the epidermis recovers its normal thickness and architecture, dermal appendages are permanently lost. 4. Wound contraction generally occurs in large surface wounds; within 6 weeks, large skin defects can be contracted to 5% to 10% of their original size. Wound Strength After suture removal at 1 week, wound strength is approximately 10% of that of unwounded skin. Tensile strength progressively increases through collagen synthesis during the first 2 months of healing, and at later times from structural modifications of collagen fibers (cross-linking, increased fiber size). Wound strength reaches approximately 70% to 80% of normal by 3 months but usually does not substantially improve beyond that point. Page 2 of 4 Fibrosis in Parenchymal Organs Fibrosis in parenchymal organs denotes abnormal deposition of collagen in the setting of chronic (often inflammatory) diseases. The basic mechanisms of fibrosis are the same as those of scar formation (largely driven by TGF-β). Fibrosis can cause substantial organ dysfunction and even organ failure (e.g., liver cirrhosis, fibrosing diseases of the lung [idiopathic pulmonary fibrosis, and drug- or radiation-induced pulmonary fibrosis], end-stage kidney disease, and constrictive pericarditis). Abnormalities in Tissue Repair Deficient scar formation: Inadequate granulation tissue or collagen deposition and remodeling can lead to either wound dehiscence or ulceration. This occurs most frequently after abdominal surgery and is a result of increased abdominal pressure, such as may occur with vomiting, coughing, or ileus. Excessive repair: Exuberant granulation tissue (proud flesh): characterized by the formation of excessive amounts of granulation tissue, which protrudes above the level of the surrounding skin and blocks reepithelialization. Excessive granulation must be removed by cautery or surgical excision to permit restoration of epithelial continuity. Hypertrophic scar: Excessive collagen accumulation forms a raised hypertrophic scar. These often grow rapidly and contain abundant myofibroblasts, but they tend to regress over several months. Hypertrophic scars generally develop after thermal or traumatic injury that involves the deep layers of the dermis. Keloid: Progression beyond the original area of injury without subsequent regression is termed a keloid. Certain individuals seem to be predisposed to keloid formation, particularly those of African descent. Desmoids (aggressive fibromatosis): incisional scars or traumatic injuries may be followed by exuberant proliferation of fibroblasts and other connective tissue elements that may recur after excision. Formation of contractures: Although wound contraction is a normal part of healing, an exaggerated process is designated a contracture. It will cause wound deformity (e.g., producing hand claw deformities or limit joint mobility). Contractures are commonly seen after serious burns and can compromise the movement of joints. Defects in Healing: Chronic Wounds: 1. Venous leg ulcers: develop most often in elderly people as a result of chronic venous hypertension, which may be caused by severe varicose veins or Page 3 of 4  congestive heart failure. These ulcers fail to heal because of poor delivery of oxygen to the site of the ulcer. 2. Arterial ulcers: 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. 3. Pressure sores: are areas of skin ulceration and necrosis of underlying tissues caused by prolonged compression of tissues against a bone, for example, in bedridden, immobile elderly individuals with numerous morbidities. The lesions are caused by mechanical pressure and local ischemia. 4. Diabetic ulcers: affect the lower extremities, particularly the feet. Tissue necrosis and failure to heal are the result of small vessel disease causing ischemia, neuropathy, systemic metabolic abnormalities, and secondary infections. Histologically, these lesions are characterized by epithelial ulceration and extensive granulation tissue in the underlying dermis References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 4 of 4