Healing & Repair Dr. Srikumar Chakravarthi Repair & Healing: Are they same? Repair :Regeneration of injured cells by cells of same type, as with regeneration of skin/oral mucosa (requires basement membrane) Epidermis, GI, blood, liver. Healing :Replacement by fibrous tissue (fibroplasia, scar formation) Incision, MI, stomach ulcers. Tissue Regeneration Controlled by biochemical factors released in response to cell injury, cell death, or mechanical trauma Most important control: inducing resting cells to enter cell cycle Balance of stimulatory or inhibitory factors Shorten cell cycle Decrease rate of cell loss Varieties of Proliferative Potential Labile (always dividing) cells: Replace dying cells Epithelia: skin, oral cavity, exocrine ducts, GI tract, GYN, hematopoietic. Stable (quiescent) cells: Usually G 0 and low rate of division Driven into G 1 and rapid proliferation Liver, kidney, pancreas, endothelium, fibroblasts Permanent (non-dividing ) cells: Permanently removed from cell cycle Irreversible injury leads only to scar Nerve cells, myocardium, skeletal muscle Stem cells Remarkable potential to develop into many different cell types in the body. Repair system for the body, they can theoretically divide without limit to replenish other cells. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function (muscle cell, RBC, neuron). Embryonic, Adult ( BM, tissue) 1
Intercellular Signaling 3 pathways Autocrine: cells have receptors for their own secreted factors (liver regeneration) Paracrine: cells respond to secretion of nearby cells (healing wounds) Endocrine: cells respond to factors (hormones) produced by distant cells, circulate in blood Growth Factors and Molecular Events Polypeptide growth factors with many (pleiotropic) effects : Proliferation, migration, differentiation, remodeling (all part of wound healing) EGF : Keratinocytes, fibroblasts VEGF : Angiogenesis TGF- α, β : Fibrogenesis PDGF : Migration and proliferation of fibroblasts, smooth muscle, and monocytes FGF, HGF, KGF, IGF, Cytokines. Extracellular Matrix (ECM) ECM provides turgor, rigidity, support, adhesion substrate, reservoir for factors ECM must remain intact for parenchymal healing Three ECM protein components Collagens (fibrous structural proteins): most common; extracellular framework of body; 14 types 2
ECM (Cont d) Adhesive glycoproteins: e.g., Laminin, fibronectin, CAM, cadherins, integrins which bind ECM components to each other, & to other cells Proteoglycans & hyaluronic acid: sugars linked to proteins; influence ECM permeability and structure Connective Tissue Repair (Healing/ Scar Formation) Loss of parenchyma and ECM Formation of new blood vessels (angiogenesis), fibroblast migration and proliferation (lay down collagen) < 24 hr Granulation tissue : pink, soft, granular grossly Maturation and organization (remodeling) of fibrous tissue Granulation tissue Appearance of small, red, granular foci which bleed easily. Demonstrated in the base of skin wounds below the overlying scab. It consists of clusters of fragile newlyformed capillary blood vessels which proliferate and grow into damaged tissue along with fibroblasts. 3
New vessels derived from budding of preexisting vessels BM degradation Endothelial migration Endothelial proliferation Endothelial maturation Angiogenesis Fibrosis (Fibroplasia) Occurs within the granulation tissue framework (new blood vessels and loose ECM) Proliferation of fibroblasts at site of injury Growth factors (TGF-β, PDGF, EGF, FGF) Cytokines (IL-1, TNF-α) Deposition of ECM (collagen) & tissue remodelling Scar Remodeling Remodeling to strengthen repair Metalloproteinases (interstitial collagenases, gelatinases, stromelysins) degrade collagen. Produced by macrophages, neutrophils, fibroblasts as inactive precursors Debris carried away by phagocytes Wound Healing: Primary Union / 1 st intention Successful wound healing is more favourable, when less tissue is damaged. The best prognosis is seen with clean, smooth, closely abutting incision wounds in a well-vascularised area, with no foreign bodies. Line of closure fills with clotted blood Dehydration at surface creates scab 4
Primary union Wound Healing: Primary Union 24 hr: neutrophils, mitoses of basal epithelium 1-2 days: epithelial basal cells grow along cut dermis 3 days: neutrophils gone, macrophages enter, granulation tissue forms 5 days: space filled with granulation tissue and collagen fibrils bridge line of closure, epidermis at pre-incision thickness Primary Union (Cont d) Week 2: accumulation of collagen, fibroblasts, and blanching begins (oedema and inflammation reduced) End of first month: connective tissue devoid of inflammation; epidermis intact Tensile strength increases to 70-80% of unwounded skin in 3 months 5
Wound Healing: Secondary Union When large tissue defects have to be refilled or when purulent infections prevent direct association of the wound edges. Wound surfaces split away from each other. Granulation tissue has to be generated in order to close the dermal defect and may be gradually transformed into stable scar tissue. More inflammation, Wound contraction - myofibroblasts 6
Fibrous scar Factors Influence Repair - Local Persisting infection, foreign material (steel, glass, suture) or other stimulus to inflammation Inadequate blood supply Excessive movement Irradiation Size of wound Locally applied drugs, e.g. corticosteroids Factors Influence Repair - Systemic Age: the healing process becomes slower and less effective with increasing age. Nutritional deficiencies, e.g. vitamin C, zinc, protein inhibit collagen synthesis Metabolic diseases, e.g. renal failure, diabetes mellitus (microangiopathy) Catabolic state associated with malignancies Systemic drugs, e.g. corticosteroids Circulatory disorders retarding blood flow atherosclerosis. Aberrations of Inflammation and Repair Inadequate scar formation Wound dehiscence - abdomen Ulceration diabetic neuropathy Hypertrophic scar/ keloid excess collagen Exuberant granulation tissue - proud flesh Wound contracture - burns 7
Proud flesh Summary Regeneration of injured cells by cells of same type. Replacement by fibrous tissue (fibroplasia, scar formation). Angiogenesis, fibroblasts Granulation tissue Primary & secondary union Thank you References Pathologic Basis of disease Robbins & Cotran, 7 th Ed General & Systematic pathology Underwood, 4 th Ed Principles of Internal Medicine Harrisons, 15 th Ed Textbook of Medical Physiology Guyton, 9 th Ed Aids to Pathology Dixon & Quirke, 4 th Ed 8