Session 4 Repair 1 PDF

Regeneration and Fibrous Repair  Aim I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechan...

Regeneration and Fibrous Repair  Aim I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation  Definitions: Regeneration vs. Repair REGENERATION: Proliferation of REPAIR: Response to injury involving cells and tissues to replace lost or BOTH regeneration and scar formation damaged cells and tissues. Normal (fibrosis). Normal structure is structure is restored. permanently altered.  Repair (Regeneration Chronic with Injury Fibrosis) After years of chronic injury: fibrosis & loss of tissue with inadequate regeneration NORMAL Fibrosis: interstitial and  What determines regeneration vs. ?repair with fibrosis 1. What is capacity of injured cells for regeneration? 2. Is extracellular matrix framework damaged or largely intact? Left: hepatocyte damage with intact matrix: complete regeneration of normal (e.g., after acute hepatitis A) Right: hepatocyte AND matrix damage: some regeneration with reparative scarring (e.g., cirrhosis) Mechanisms for regulation of cell populations Proliferation: increase in cell number by replication (hyperplasia) Differentiation: “achievement of adult cell phenotype” Apoptosis: programmed cell death  I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation  Stem Cells: Definitions Stem cells: normal undifferentiated cells with two features: – Self-renewal – Can generate differentiated (mature) cells Critical for regeneration of cells in self-renewing tissues Regenerative medicine: therapeutic applications of stem cells to repair damaged tissues that do not typically regenerate after injury: e.g. Adult stem cell: heart, brain, skeletal muscle fibroblast in tissue culture  Stem Cells: Origins and Types Pluripotent SC: Multipotent SC: more Adult (somatic) SCs: capable of restricted than embryonic restricted capacity to generating all tissue SC; eventually become generate certain cell types; types “lineage committed” thus “lineage-committed” Niches: microenvironments in which somatic stem cells reside Niche cells dialogue with SC Liver adult SCs (“oval cells”): reside in to regulate canals of Hering (thick arrow); canals carry hepatocyte’s bile secretion to portal bile tissue’s demand for differentiated  Niche Cells Niche cells are non-stem cells that “provide a sheltering environment that sequesters stem cells from differentiation stimuli, apoptotic stimuli, and other stimuli that would challenge stem cell reserves.” Niche cells contribute to balance between adult stem cell quiescence and replication. Niche cells dialogue with SCs to regulate tissue’s demand for differentiated cells  Stem Cells: therapy Left: “therapeutic cloning” using embryonic stem cells Transfer diploid nucleus from patient’s skin fibroblast into enucleated oocyte activate oocyte ⎝ zygote becomes blastocyst with donor DNA ⎝ harvest ESCs, induce differentiation in culture Right: therapy using iPS cells Patient’s skin fibroblast cells cultured ⎝ transduction with genes encoding transcription factors ⎝ cells formed ⎝ induce differentiation in culture Both methods: attempt to repopulate damaged tissues with cells that avoid immune-mediated rejection  Stem Cells: Normal Tissue Maintenance Organ Adult (Somatic) Stem Cells Functions Bone Hematopoietic stem cells Generate all blood cell lineages, used marrow (from bone marrow, umbilical cord therapeutically after bone marrow blood, peripheral blood) depletion by disease or treatment Liver Stem cells (“oval cells”) ⇒ differentiate Recruited only when hepatocyte into both hepatocytes and biliary duct proliferation is inadequate: hepatic cells failure, chronic hepatitis or cirrhosis Brain Neural stem cells in subventricular zone Generate neurons (!), astrocytes, and and hippocampus of temporal lobe oligodendrocytes. ?? Unclear if new cells integrated into neural circuits Skeletal Satellite cells replicate and become new myocytes after injury; normal Stem cells = “satellite cells”, located myocytes do not divide after injury under myocyte basal lamina, comprise reserve pool of stem cells  Learning Route I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation Cell cycle: landmarks and controls Phases of cell cycle G1: presynthetic S: DNA synthesis G2: premitotic M: mitosis 2 ways to enter G1: from G0 or after mitosis Checkpoints (G1/S and G2/M): quality control checks that identify DNA damage and allow DNA repair; if damage too severe, cell is eliminated by apoptosis. Progression through checkpoints is tightly regulated by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. Defective checkpoints allow cells with mutations to replicate, possibly Restriction point: rate-limiting causing neoplasia step in cell cycle; after this, normal cells are committed to  Regulation of cell cycle Cyclins – Proteins that develop peak activity during specific phases of cell cycle – Rapidly degraded as cell enters next phase of cycle Cyclin-dependent kinases (CDKs) – Enzymes which complex with cyclins to facilitate important transitions through phases of cell cycle – Cyclin-CDK complexes act by phosphorylation of proteins critical for transitions, Cyclin-dependent kinase inhibitors (CDKIs) – Exert negative control over cell cycle – Mutation or inactivation of CDKIs involved in pathogenesis of malignant neoplasms Cell Type Reprise: Quiescent, Labile, Permanent  Cell types: capacity for regeneration Cell type Examples Regenerative capacity Labile Epithelial surfaces Unlimited; characterized (skin, g.i. tract) and by continuous regeneration hematopoietic cells Quiescent Most internal organs Limited, in response to (liver, kidney, stimuli; requires intact endocrine); basement membranes mesenchymal cells (extracellular matrix) for (fibroblast, smooth organized regeneration muscle, vascular) Permanent CNS neurons; Very Little; repaired by skeletal and cardiac replacement with scar muscle cells  I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation Mechanisms Signaling Cell Growth & Replication Polypeptide growth factors Autocrine Endocri Paracrine ne Effects Effects on cells Effects in on same nearby other cell organs Growth factors bind to specific receptors on target cells Stimulate transcription Activate genes that regulate of genes that were entry of cells into and previously silent: protein through synthesis the cell cycle: proliferation  Growth Factors & Effects Symbol (Factor) Effects EGF Mitogenic for keratinocytes and fibroblasts, stimulates (epidermal growth factor) keratinocyte migration and granulation tissue formation PDGF Chemotaxis and activation of neutrophils, macrophages, (platelet-derived growth fibroblasts and smooth muscle cells; mitogenic for factor) fibroblasts, endothelial, smooth muscle cells. Stimulates angiogenesis, wound contraction, matrix degradation FGF Family of >10 factors with many effects: macrophage, (fibroblast growth factor) fibroblast, and endothelial migration (wound repair), mitogenic for fibroblasts and kertinocytes; stimulates angiogenesis, wound contraction, matrix deposition VEGF (vascular endothelial Family of factors stimulating vasculogenesis (in embryo), growth factor) angiogenesis (in repair); increase vessel permeability TGF-β Pleiotropic (diverse effects according to tissue and injury): (transforming growth chemotactic for WBCs, fibroblasts, myocytes; normally factor-beta) inhibits epithelial proliferation but potent stimulator of fibroplasia and angiogenesis HGF Mitogenic for hepatocytes, epithelial cells, endothelial (hepatocyte growth cells; increases cell motility and promotes cell scattering in factor/scatter factor) embryogenesis  Signal Transduction Pathways Systems which detect extracellular signals through binding of ligands to specific receptors, initiating an intracellular cascade of events that change gene expression, thus generating a cellular response. Pathways usually involve sequential activation of protein kinases Important signal transduction pathways regulating cell growth: – Mitogen Activated Protein-kinase (MAP-kinase) – Phosphatidylinositol 3-kinase (PI3-kinase) – Inositol-triphosphate (IP3) – Cyclic adenosine monophosphate (cAMP) – JAK/STAT (Janus Kinase/Signal Transducers and Activators of Transcription)  Signal Transduction Systems that Require Surface Receptors Chemokines, histamine, serotonin, hormones, many drugs Steroid hormone receptors: in nucleus  Signaling from receptors with intrinsic tyrosine kinase activity Growth factors: EGF, TGF-α, HGF, PDGF, VEGF, FGF, insulin Ligand-receptor binding induces dimerization of receptor, auto-phosphorylation, attachment of bridging proteins to inactive RAS MK phosphorylates cytoplasmic proteins & transcription factors Result: synthesis of growth factors, receptors, and proteins that induce cells in G0 to enter the ©cell cycle 2005 Elsevier  Transcription Factors Proteins regulating transcription of genes after signal transduction system transfers information to the nucleus Phosphorylated by proximal kinases Contain functional domains – DNA-binding domains: recognize short sequences of DNA – regulatory domains: for activation or suppression of transcription Transcription factors that regulate cell proliferation: – Products of growth-promoting genes: c-MYC, c-JUN – Products of cell-cycle-inhibiting genes: p53 – Mutations that alter these growth-regulating TFs may result in a dysregulated, uncontrolled proliferation of cells: neoplasia.  I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation Liver after Partial Hepatectomy: Compensatory Hyperplasia In humans, liver remnant doubles in size by one month after a 60% resection After partial hepatectomy, nearly all hepatocytes recruited from G0 into G1; maximal replication and mitosis occurs 24-36 hours after surgery. Sequential transcription of key genes: Immediate early genes (>70) induce G0 → G1 transition: c-fos, c-jun, c-myc Through G1: anti-apoptosis gene bclx G1/S checkpoint for DNA damage: mdm2, p53 genes  Regeneration of Human Liver (living donor) Upper: CT scan before surgery, outlining portion of right lobe to be donated for transplantation Lower: CT scan 1 week after partial hepatectomy; markedly enlarged left lobe due to compensatory hyperplasia (outlined); no regrowth of right lobe 3 phases of response to partial hepatectomy: PRIMING: mediated by cytokines that bind to surface receptors and activate signal transduction pathways PROLIFERATION: primed hepatocytes enter cell cycle, mediated by growth factors and adjuvants GROWTH INHIBITION: poorly understood, but it works at the right time! Most hepatocytes replicate once or twice, then return to G0  I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation  Extracellular matrix (ECM) Definition: macromolecules secreted and assembled into an extracelluar supportive network between cells Macromolecules synthesized by: fibroblasts, myofibroblasts, endothelial cells, adipocytes, chondrocytes, osteocytes Two anatomic compartments – Interstitial matrix (filling spaces between cells) – Basement membrane (closely applied to cell surfaces) Functions – Support: for cell-cell interactions, adherence, migration, and scaffolding structure for regeneration of cells – Sequester substances: H2O (turgor), minerals (rigidity), growth factors (proliferation) 3 Groups of macromolecules in ECM – 1) Fibrous structural proteins: strength and recoil (collagen, elastin) – 2) Adhesive glycoproteins: connect cells & matrix (fibronectin, laminin) – 3) Gel proteins: resilience and lubrication (proteoglycans, hyaluronan)  Functions of ECM Mechanical support: anchors cells; medium for cell migration Control of cell growth: regulate proliferation by ligands binding to surface integrin receptors Modulation of cell differentiation: ECM proteins affect degree of differentiation via integrins Storage of regulatory proteins: growth factors secreted & stored for response to injury and regeneration Scaffolding for regeneration: organized tissue structure requires intact basement membranes – Injury to tissues capable of regeneration: normal structure restored only if ECM is not disrupted – If ECM disrupted: collagen replaces normal cells (scar)  Histologic Structure of ECM 1: BM 2: IM Major Types of Collagen, Distribution, and Genetic Disorders Collagen Type Tissue Distribution Fibrillar Collagens I Ubiquitous in hard and soft tissues II Cartilage, intervertebral disc, vitreous III Hollow organs, soft tissues V Soft tissues, blood vessels IX Cartilage, vitreous Basement Membrane Collagens IV Basement membranes  Adhesion Proteins (“cell adhesion molecules”, CAMs) Function: cell surface receptors that mediate binding with other cells or ECM 1) Adhesive matrix glycoproteins: fibronectin & laminin Fibronectin: binds to both cells and matrix proteins Laminin: glycoprotein in basement membrane; polymerizes with collagen IV 2) Integrins Transmembrane receptors, connecting cells to ECM proteins Bind adhesive proteins in other cells (cell-cell contacts) Link cell surface to intracellular cytoskeleton. Ligand binding causes clustering of integrin receptors into “focal adhesion complexes”. Focal adhesion complexes bind to cytoskeletal filaments, providing mechanism for transmission of external mechanical forces into cell. Integrin – cytoskeleton complexes activate signal transduction pathways  Cell Adhesion Molecules: cadherins 3) Cadherins = “calcium-dependent adherence proteins” Proteins connecting plasma membranes of cells of same type  Integrins and Cadherins: Function Ligands: fibronectin & laminin Integrins: connection between ECM Cadherins: regulate migration of proteins and cytoskeletal filaments; keratinocytes, formation of mechanism for cell to respond to desmosomes, regeneration of epidermis Mechanisms Used by ECM and Growth Factors to Influence Cells 3 1 2 4  The Extracellular Matrix Collagen – Type I - Bone, tendon, scars. Type III - ‘tissue scaffold’. Type IV - non-fibrous, basement membranes... Elastin Glycoproteins – Fibronectin, Osteonectin, Tenascin,... Proteoglycans – Heparan sulphate proteoglycan,...  I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation  Tissue Repair by Fibrosis Why fibrosis? Severe or chronic tissue damage may alter both cells and ECM of organ, such that repair cannot be accomplished by regeneration of parenchymal cells only. Fibrosis fills the “gaps” in injured tissues that are not replaced by regenerating cells. Fibrosis = repair by deposition of collagen and ECM components = “scar” Damage of the ECM is characteristic of chronic inflammation (and extensive necrotizing acute inflammation) Processes Involved in Tissue Repair by Fibrosis: 1. Induction of inflammation (removes dead or damaged cells) 2. Formation of new blood vessels (angiogenesis) 3. Migration and proliferation of fibroblasts 4. Scar formation 5. Connective tissue remodeling  FIBROUS REPAIR:.The development of a fibrous scar Rabbit ear chamber example. – Blood clot forms. – Acute inflammation around the edges. – Chronic inflammation: Macrophages infiltrate the clot. – Capillaries and lymphatics sprout and infiltrate. – Myofibroblasts infiltrate and differentiate. – Glycoproteins and COLLAGEN are produced – Cell population falls, vessels differentiate and are reduced in number. – Collagen matures AND CONTRACTS.  Rabbit Ear Chamber: Direct observation of fibrous repair. 1) Exudate 2) Neutrophils 3) Macrophages and clots. infiltrate lymphocytes are and digest clot recruited  Rabbit Ear Chamber: Direct observation of fibrous repair. 4) Vessels sprout, 5) Vascular 6) Maturity. Cells myofibroblasts network; much reduced; make collagen collagen glycoproteins synthesised; matures, contracts, macrophages remodels reduced Angiogenesis Angiogenesis: 2 Mechanisms Angiogenesis = formation of new blood vessels after infancy (neovascularization) Angioblast: embryonic precursor of endothelial cells, pericytes, vascular smooth muscle cells Mechanism A: sprouting new vessels from pre-existing vessels (1) vasodilation (NO, VEGF) (2) proteolysis of basement membrane by metalloproteinases (3) migration of ECs (4) proliferation of ECs behind the migrating front of cells (5) maturation of ECs (6) recruitment pericytes & smooth muscle cells to support new vessel Mechanism B: angioblast-like endothelial-precursor cells (EPCs) recruited from bone marrow, homing to site of  Tissue Repair by Fibrosis Why fibrosis? Severe or chronic tissue damage may alter both cells and ECM of organ, such that repair cannot be accomplished by regeneration of parenchymal cells only. Fibrosis fills the “gaps” in injured tissues that are not replaced by regenerating cells. Fibrosis = repair by deposition of collagen and ECM components = “scar” Damage of the ECM is characteristic of chronic inflammation (and extensive necrotizing acute inflammation) Processes Involved in Tissue Repair by Fibrosis: 1. Induction of inflammation (removes dead or damaged cells) 2. Formation of new blood vessels (angiogenesis) 3. Migration and proliferation of fibroblasts 4. Deposition of extracellular matrix 5. Connective tissue remodeling  Fibrosis: 3 sequential phases Phase 1: Migration & Proliferation of Fibroblasts – Fibroblasts migrate into injured tissue and replicate – Proliferation is stimulated by growth factors secreted by macrophages (main source), activated endothelial cells, and platelets: TGF-beta, PDGF, EGF, FGF; cytokines IL-1 and TNF – TGF-beta is the most effective growth factor promoting fibrosis Produced by most cell types in granulation tissue Promotes both migration and proliferation of fibroblasts Increases synthesis of collagen and fibronectin Decreases degradation of ECM by metalloproteinases (stabilizes ECM as it develops into mature fibrosis)  Tissue Repair: 3 sequential phases Phase 2: Deposition of Extracellular Matrix – Fibroblasts become less mitotic and more synthetic – Collagen synthesis begins 3-7 days post-injury and continues for weeks – Growth factors for collagen synthesis similar to fibroblast proliferation – Net collagen deposition depends both on increased synthesis and decreased degradation Phase 3: Maturation and Remodeling – Balance between ECM synthesis and degradation remodeling of tissue – Decreasing vascularity and fibroblast proliferation – Increasing collagen synthesis and cross-linking: fibrosis gradually acquires tensile strength Histology of Early & Late Repair: balance of angiogenesis & fibrosis Trichrome histochemical stain (mature collagen stains blue) Early response (3-7 days): Late response (> 4 weeks): granulation tissue fibrosis Mature collagen proliferating capillaries & fibroblasts dominates the picture, with with minimal mature collagen decreased vessel density  ECM remodeling by matrix metalloproteinases Fibroblasts synthesize inactive precursors of matrix metalloproteinases Activation of precursors by plasmin Matrix Metalloproteinases: family of >20 enzymes that degrade ECM components (interstitial collagenases, gelatinases, stromelysins, membrane-bound MMPs) TIMPs = tissue inhibitors of metalloproteinases (from mesenchymal cells; prevent excessive degradation)  Learning Route I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation Phases of Wound Healing in Skin 3  Wound healing 1- healing by first intention or primary union 2- healing by second intention or secondary union Wound Healing by Primary Union (first intention) First intention: Wound damages few keratinocytes and dermal cells, disrupts short segment of basement membrane. Example: surgical incision Result: thin scar  Healing by Secondary Union (Second Intention) Second intention: wounds that create a large defect Healing requires: --more inflammation --larger volume granulation tissue --more collagen deposition --wound contraction Example: deep traumatic abrasion Result: wide scar, often with skin depression or elevation Application: surgical closure of wounds Goal of suturing wounds: restore normal anatomic relationships to minimize size of the defect that will be filled by granulation tissue and subsequent fibrosis smaller scar LEFT: simple suture closing a superficial clean laceration Right: subcuticular suture approximating edges of dermis in a deep clean laceration Phases of Wound Healing and Wound Strength Beyond 10 days, accumulation of collagen type I and remodeling control wound healing At 10 days, wound strength is 10% of normal, but increases to 70-80% of normal by 3 months. Therefore, limited activity after surgery is required to avoid separation of wound edges  Learning Route I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation  Systemic Factors Influencing Wound Healing Factor Effect Nutrition Profound effect; deficiencies of protein and vitamin C deficiency inhibit collagen synthesis Metabolic Diabetes mellitus delays healing (insulin status necessary for nucleic acid & protein synthesis) Circulatory Inadequate blood supply slows healing; arterial status atherosclerosis (limiting the inflow of arterial blood) or venous stasis (limiting outflow) Steroid Glucocorticoids inhibit beneficial early hormones inflammatory response  Local Factors Influencing Wound Healing Factor Effect Infection Persistent inflammation; single most important cause of delayed healing Mechanical Early tension applied to wound may separate edges, delaying wound healing Foreign bodies Fragments of metal, glass, wood, bone: prolong the inflammatory response and inhibit healing Anatomic location Sites with rich vascularity (e.g., face) heal faster than sites with reduced vascularity (e.g., foot) Type of wound Sharp incisions (e.g., surgical) heal faster than larger wounds (e.g., traumatic deep abrasion)  Learning Route I. Control of Normal Cell Proliferation A. Regeneration and repair B. Stem cells: biology & therapeutic applications C. Cell cycle and regulation of cell replication D. Growth factors and signaling mechanisms II. Mechanisms of Tissue and Organ Regeneration III. Extracellular Matrix and Cell-Matrix Interactions IV. Repair of Tissues After Injury A. Angiogenesis and fibrosis B. Normal wound healing in the skin C. Local and systemic factors influencing wound healing D. Pathologic repair Summary: Responses to Injury and Inflammation  Pathologic Wound Repair: Spectrum Deficient scar formation due to wound dehiscence: separation of wound edges due to (a mechanical forces, e.g., vomiting or coughing after abdominal surgical incision wound ulceration: inadequate blood supply (e.g., (b atherosclerosis) wound necrosis: infection vs. inadequate blood supply (c Excessive repair: hypertrophic scar or keloid Excessive granulation tissue Contracture formation: deformity of tissues due to excessive or exaggerated wound contraction  Deficient Scar Formation: Chronic Ulceration Chronic ulcer associated with venous stasis Chronic ulcer associated with arterial atherosclerosis and compromised inflow  Hypertrophic scar (keloid) Keloid formation has a genetic predisposition; more common in African-Americans Keloid: excess deposition Keloid after ear-piercing of abnormally thick bundles of collagen in  Wound Contracture, post-burn Occur in large surface wounds that heal by secondary union Mechanism: network of myofibroblasts at edges of wound, contracting Before After surgical skin tissues and treatment graft repairs producing excess ECM Summary: fibrosis associated with chronic inflammation Summary: Responses after Injury & Inflammation Special features of healing in specific organs For self-directed study. As a minimum, learn about: Liver ( regeneration in acute versus chronic damage) Kidney (‘acute tubular necrosis’) Heart (see ‘myocardial infarction’) Bone (. ‘Callus’) Cartilage (Can it???) Peripheral nerve (. ‘Wallerian degeneration’; axon sprouting) Central nervous system (. gliosis) Thank you