Tissue Repair, cellular Growth, fibrosis and wound healing

Repair of tissue involve two distinct processes: Regeneration, replacement of functional, differentiated cells. Replacement by connective tissue or fibroplasia. both processes are determined by largely similar mechanisms involving cell growth and differentiation and cell-matrix interaction.

Control of normal cell growth Size of a population of cells in adult tissue is determined by rates of cell proliferation, differentiation and death by apoptosis. Cell proliferation can be stimulated by injury, mechanical forces acting on tissue, or cell death.

Cell cycle and proliferative potential Cells are divided into three groups based on proliferative capacity: Continuously dividing cells (labile cells); as surface epithelial cells, bone marrow and hemopoietic cells. Quiescent (stable) cells: with low turnover but capable of rapid division in response to stimuli as liver, kidney, and smooth muscles. Non dividing (permanent cells) which cant undergo division in potential life-for example; neurons, skeletal and cardiac muscles.

Three general schemes of intercellular signaling important in regulation of cell proliferation: Autocrine signaling: cells response to signaling substances that they themselves secrete. Paracrine signaling: a cell produces substances that affect only a target cell in close proximity. Endocrine signaling: hormones are synthesized by cells of endocrine organs and act on target cells distant from site of synthesis

Cell surface receptors Cell growth initiated by binding of signaling agents to specific receptor frequently located on the plasma membrane. Receptors with intrinsic kinase activity. Receptors without intrinsic kinase activity. G-linked receptors.

Signal transduction system It is process by which extracellular signals are detected and converted into intracellular signals. Mitogen-activated protein (MAP) kinase pathway. Phosphpoionsitide-3-kinase pathway. Inositol-lipid pathway. Cyclic adenosine monophosphate (cAMP) pathway. JAK/STAT pathway.

Cell cycle G1 (presynthetic) phases. S (DNA) synthesis phases. G (premitotic) phases. M (mitotic) phases. Quiescent cells are in physiological state called G0. Two types of molecular controls regulate the passage of cells through specific phases of cell cycle. Cascade of protein phosphorylation pathway involving cyclins and cyclin-dependent pathway. Set of check points that moniter completion of molecular evens, some times delay progression to next cycle.

Extracellular matrix and cell matrix interaction. Extracellular matrix (ECM) markedly influence cell growth and function. ECM consist of fibrous structural proteins(e.g ; collagen) and adhesive glycoprotein embedded in gel of proteoglycans and hyaluronan. adhesive glycoprotein and integrins link the ECM with specific integral cell membrane protein.

Repair of connective tissue (fibrosis) Repair involve the replacement of lost cells and tissue by connective tissue which in time produces fibrosis and scarring. Connective tissue repair is systematic processes by which unregenerated damage is replaced by fibrosis and scarring. The initial response to a wound consist of the formation of granulation tissue.

Four component of this process. Formation of new blood vessels (angiogenesis), spanning the wound. Migration and proliferation of fibroblasts filling and bridging the wound. Deposition of ECM. Maturation and reorganization of fibrous tissue into scar, also known as remodeling.

Angiogenesis Critical for chronic inflammation, formation of collateral circulation and tumor growth. Proteolytic degradation of basement membrane of parent vessels basement membrane; endothelial cell migration and formation of capillary sprout p proliferation and maturation of endothelial c ells, which includes remodeling into capillary tubes; and recruitment of periendothelial cells including pericytes for small capillaries and vascular smooth muscle cells for large vessels to support endothelial tube. Angiogenesis controlled by; growth factors and receptors, ECM proteins and angiogenesis inhibitors.

Angiogenesis

Fibrosis (Fibroplasia) Fibroblasts migration and proliferation; increase vascularity lead to deposition of plasma protein as fbronectin and fibrinogen, which produce provisional stroma for ingrowth of fibroblasts. ECM depositions; as repair progress, the number of proliferating endothelial cells and fibroblasts decreases, fibroblasts become more synthetic and deposit increase amounts of collagenand other component of ECM.

Tissue remodeling Replacement of granulation tissue with a scar involves transition in the composition of ECM. Some growth factors that stimulate synthesis of collagen and other connective tissue molecules modulate the synthesis and activation of matrixmetallloproteinases (MMP), enzyme that serve to degrade these ECM component. Secretion of MMPs by fibroblasts and leukocytes is induced by growth factors and cytokines and inhibited by TGF-B. Net effect of ECM synthesis versus degradation result in debridement of injured sits and remodeling of CT framework- important feature of both chronic inflammation and wound repair.

Wound healing Wound healing is body replacement of a destroyed tissue by living tissue. Tissue destruction caused by same causes Of cell damage, and inflammation in general: 1-trauma. 2-physical. 3-chemical. 4-microbial. 5-ischaemic. 6-immunological.

Repair in Skin EARLY 1. Thrombosis: Formation of a growth factor-rich barrier having significant tensile strength 2. Inflammation: Necrotic debris and microorganisms must be removed by neutrophils; the appearance of macrophages signals and initiates repair 3. Re-epithelialization: Newly formed epithelium establishes a permanent barrier to microorganisms and fluid

MID 4. Granulation tissue formation and function: This specialized organ of repair is the site of extracellular matrix and collagen secretion; it is vascular, edematous, insensitive, and resistant to infection 5. Contraction: Fibroblasts and possibly other cells also transform to actin-containing myofibroblasts, link to each other and collagen, and contract, stimulated by TGF. LATE 6. Accretion of final tensile strength results primarily from the cross- linking of collagen 7. Remodeling: The wound site devascularizes and conforms to stress lines in the skin

Conditions that Modify Repair Local Factors May Influence Healing: Location of the Wound: In addition to the size and shape of the wound, its location also affects healing. Sites in which skin covers bone with little intervening tissue, such as skin over the anterior tibia, are locations where skin cannot contract. Skin lesions in such areas, particularly burns, often require skin grafts because their edges cannot be apposed. Complications or other treatments, such as infection or ionizing radiation, also slow the repair process

2. Blood Supply: Lower-extremity wounds of diabetics who suffer from disease-related vasculopathies often heal poorly or even require amputation. In such cases, advanced atherosclerosis in the legs compromises blood supply and impedes repair. 3. Infection delay healing. 4. Mechanical factors. 5. Foreign bodies which imped healing. 6. Size and type of wound.

Systemic Factors Nutritional status of the host (protein and Vit. C). Metabolic status (Diabetes mellitus delay healing). Hormones (glucocorticoid therapy). Circulatory status or adequacy of blood supply.

Specific Sites Exhibit Different Repair Patterns Skin Healing in the skin involves both repair (primarily dermal scarring) and regeneration (principally of the epidermis and vasculature). Healing by primary intention occurs when the surgeon closely approximates the edges of a wound. The actions of myofibroblasts are minimized, and regeneration of the epidermis is optimal, because epidermal cells need migrate only a minimal distance. Dermis undergo regeneration. Minimal scarring, good strength Risk of trapping infection under skin - produces abscess

Healing by ‘primary intention’: A clean, sutured wound.

Healing by secondary intention proceeds when a large area of hemorrhage and necrosis cannot be completely corrected surgically. In this situation, myofibroblasts contract the wound, and subsequent scarring repairs the defect. The success and method of healing following a burn wound depends on the depth of the burn injury. If the burn is superficial or does not extend beyond the upper dermis, stem cells from the sweat glands and hair follicles will regenerate the epidermis. If the deep dermis is involved, the regenerative elements are destroyed, and surgery and engraftment are necessary to cover or heal the wound site and reduce scarring and contractures.

Comparison with primary intention: Takes longer Produces a larger scar; not necessarily weaker Produces more late contraction

An open wound: Healing by ‘secondary intention’

Wound Strength Skin incisions and surgical anastomoses in hollow viscera ultimately develop 75% of the strength of the unwounded site. Despite a rapid increase in tensile strength at 7 to 14 days, by the end of 2 weeks, the wound has acquired only about 20% of its ultimate strength. Most of the strength of the healed wound results from intermolecular cross-linking of type I collagen.

A 2-month-old incision, although healed, is still visibly obvious A 2-month-old incision, although healed, is still visibly obvious. The incision line and suture marks are distinct, vascular, and red. 3rd month recovery of tensile strength to 70-80% of normal. By 1 year, the incision is white and avascular but usually still identifiable. As the scar fades further, it is often slowly deformed into an irregular line by stresses in the skin.

Complication in wound healing Deficient scar formation: lead to two type of complication Wound dehiscence. Ulceration. Excessive formation of repair component (hypertrophic scar). Formation of contracture as in hand and face.

Effects of Scarring Although scarring is essential to the repair of most injuries, scarring in parenchymal organs modifies their complex structure and never improves their function. For example, in the heart, the scar of a myocardial infarction serves to prevent rupture of the weakened wall of the heart but reduces the amount of contractile tissue. If extensive enough, it may be associated with congestive heart failure or the formation of a ventricular aneurysm.

Alveolar fibrosis in the lung causes respiratory failure. Infection within the peritoneum or even surgical exploration may lead to adhesions and intestinal obstruction. Scarring in the skin following burns or surgical excision of lesions may produce unsatisfactory cosmetic results or worse, deficits in limb function because of wound contractions.

Excessive Scar Formation Inordinate deposition of extracellular matrix, mostly excessive collagen, at the wound site results in a hypertrophic scar. keloid is an exuberant hypertrophic scar that tends to progress beyond the site of initial injury and recurs after excision. Histologically, both of these types of scars exhibit broad and irregular collagen bundles, with more capillaries and fibroblasts than expected for a scar of the same age.

More clearly defined in keloids than in hypertrophic scars, the rate of collagen synthesis, the ratio of type III to type I collagen, and the number of reducible cross-links, remain high.

Excessive Regeneration and Repair pyogenic granuloma. This lesion is a localized, persistent, exuberant overgrowth of granulation tissue, most commonly seen in gum tissue in pregnant women. pyogenic granuloma is a transitional lesion, resembling granulation tissue but behaving almost as an autonomous benign neoplasm.