Wound Healing and Regeneration (Tissue Repair) PDF

WOUND HEALING AND REGENERATION (TISSUE Dr Norsyahida Mohd Fauzi Lecturer in Biopharmacy and REPAIR) Pharmacology Discipline, Member of Drug and Herbal Research Centre LECTURE OBJECTIVES At the end of this lecture, s...

WOUND HEALING AND REGENERATION (TISSUE Dr Norsyahida Mohd Fauzi Lecturer in Biopharmacy and REPAIR) Pharmacology Discipline, Member of Drug and Herbal Research Centre LECTURE OBJECTIVES At the end of this lecture, student should be able to: 1. describe cell and tissue regeneration. 2. discuss the process of repair by connective tissue, angiogenesis and scar formation 2. explain the mechanism of cutaneous wound healing  TISSUE REPAIR It occurs by two types of reactions: - regeneration of the injured tissue - scar formation by the deposition of connective tissue VIDEO: https://www.youtube.com/watch?v=G3B0ApUsYag  CELL AND TISSUE REGENERATION The regeneration of injured cells and tissues involves cell proliferation, which is driven by growth factors and is critically dependent on the integrity of the extracellular matrix. Mechanisms regulating cell  PROLIFERATIVE CAPACITIES OF TISSUES The ability of tissues to repair themselves is critically influenced by their intrinsic proliferative capacity. Induced Pluripotent Stem Cells (iPS) - Derived by introducing into mature cells genes that are characteristic of ES cells - iPS cells acquire many characteristic of stem cells., Growth Factors - Mostly proteins. - Stimulate survival, proliferation, migration, differentiation, angiogenesis and fibrogenesis. - Major activity is to stimulate the function of growth control genes (called proto- oncogenes; mutation of these genes can lead to cancer). - Many GFs involved in repair are produced by macrophages and lymphocytes. - Some GFs are produced by parenchymal/stromal cells in response to injury.  Growth factor signaling can be classified into different classes based on the types of receptors involved and their signaling mechanisms. Three common classes include: Receptor with Intrinsic Kinase Activity: Receptor Tyrosine Kinases (RTKs): These receptors have intrinsic kinase activity, meaning they possess a kinase domain that can phosphorylate tyrosine residues on the receptor itself and downstream signaling proteins. When growth factors bind to RTKs, the receptor undergoes autophosphorylation, creating docking sites for downstream signaling molecules. Examples of RTKs include the epidermal growth factor receptor (EGFR) and the insulin receptor. G Protein-Coupled Receptors (GPCRs): GPCRs are a diverse family of cell surface receptors that use G proteins to transmit signals. While not typically associated with intrinsic kinase activity, GPCRs can activate a variety of intracellular signaling pathways through the activation of G proteins. GPCR signaling can indirectly influence growth factor-related pathways by modulating cyclic AMP (cAMP), inositol trisphosphate (IP3), and other second messengers. Examples of GPCRs involved in growth factor signaling include the receptors for epinephrine and various chemokines. Receptor Kinases without Intrinsic Kinase Activity: Some growth factor receptors lack intrinsic kinase activity but are associated with other kinases that mediate signaling. These receptors rely on non-receptor kinases to transmit signals downstream. An example of this class is the Transforming Growth Factor-beta (TGF-β) receptor, which recruits and activates downstream kinases, such as the TGF-β receptor-activated Smads (R-Smads), to initiate intracellular signaling..  ROLE OF THE EXTRACELLULAR MATRIX IN TISSUE REPAIR Tissue repair depends not only on growth factor activity but also on interactions between cells and ECM components. The ECM is a complex of several proteins that assembles into a network that surrounds cells and constitutes a significant proportion of any tissue. ECM sequesters water, providing turgor to soft tissues, and minerals, giving rigidity to bone. It also regulates the proliferation, movement, and differentiation of the cells living within it, by supplying a substrate for cell adhesion and migration and serving as a reservoir for growth factors. The ECM is constantly being remodeled; its synthesis and degradation accompany morphogenesis, wound healing, chronic fibrosis, and tumor invasion and metastasis. ECM occurs in two basic forms: interstitial matrix and basement membrane Important functions of ECM - Mechanical support to tissues (collagen and elastin) - Substrate for cell growths and the formation of tissue microenvironments - Regulate cell proliferation and differentiation: - Proteoglycans bind GFs and display them at high concenttaion - Fibronectin and laminin stimulate cells through cellular integrin receptors. - An intact ECM is required for tissue regeneration. If ECM is damaged, repair can be accomplished by scar formation. Scar formation - Tissues can be repaired by: - regeneration with complete restoration of form/function. - replacement with connective tissue and scar formation. - Scar formation occurs when - tissue injury is severe/chronic and result in damage in parenchymal cells, epithelia and connective tissue. - Nondividing cells are injured FACTORS THAT INFLUENCE WOUND HEALING Infection (delay the healing and prolong inflammation) Nutrition ( protein and Vit C deficiency, inhibit collagen synthesis & retard healing) Glucocorticoid (results in weakness of the scar because it inhibit growth factor; but in corneal infection, glucocorticoid reduce the likelihood of opacity Mechanical variables Poor perfusion (impair healing) Type and extent of tissue injury (e.g., labile tissues: complete restoration) The location of injury and character of tissues Abberation of cell growth (can cause formation of keloid) CLINICAL EXAMPLES OF TISSUE REPAIR AND FIBROSIS Cutaneous wound healing is a process that involves both epithelial regeneration and the formation of connective tissue scar and is thus illustrative of the general principles that apply to healing in all tissues. Depending on the nature and size of the wound, the healing of skin wounds is said to occur by first or second intention.  HEALING BY FIRST INTENTION 24 hours: neutrophils are seen at the incision margin, migrating toward the fibrin clot. 24 to 48 hours: epithelial cells from both edges have begun to migrate and proliferate along the dermis. Day 3: neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space. Day 5: Neovascularization reaches its peak as granulation tissue fills the incisional space. Collagen fibrils become more abundant and begin to bridge the incision. 2nd week: there is continued collagen accumulation and fibroblast proliferation. The long process of “blanching” begins, accomplished by increasing collagen deposition within the incisional scar and the regression of vascular channels. End of the first month: the scar consists of a cellular connective tissue, largely devoid of inflammatory cells, covered by an essentially normal epidermis. However, the dermal appendages destroyed in the line of the incision are permanently lost. The tensile strength of the wound increases with time.  HEALING BY SECOND INTENTION When cell or tissue loss is more extensive, such as in large wounds, at sites of abscess formation, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process is more complex and involves a combination of regeneration and scarring. The inflammatory reaction is more intense, and there is development of abundant granulation tissue, with accumulation of ECM and formation of a large scar, followed by wound contraction mediated by the action of myofibroblasts. Secondary healing differs from primary healing in several respects: A larger clot or scab rich in fibrin and fibronectin forms at the surface of the wound. Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed. Consequently, large defects have a greater potential for secondary, inflammation-mediated, injury. Larger defects require a greater volume of granulation tissue to fill in the gaps and provide the underlying framework for the regrowth of tissue epithelium. A greater volume of granulation tissue generally results in a greater mass of scar tissue. Secondary healing involves wound contraction. Within 6 weeks, for example, large skin defects may be reduced to 5% to 10% of their original size, largely by contraction. This process has been ascribed to the presence of myofibroblasts, which are modified fibroblasts exhibiting many of the ultrastructural and functional features of contractile smooth muscle cells.