Inflammation and repair darpan

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Inflammation and repair darpan

  1. 1. INFLAMMATION AND REPAIR Darpan Nenava PG Ist year 1
  2. 2. CONTENTS History Introduction Definition Types of inflammation Acute inflammation Chemical mediators Chronic inflammation Healing and repair 2
  3. 3. HISTORICAL PERSPECTIVES Earliest reference to inflammation in medical literature (1650 BC, Egypt) in the Smith Papyrus associated inflammation with heat via symbol of flame Ancient Greeks used a term which meant inflammation also indicating a hot thing – The greek term persists in our word "phlegmon" used to describe internal inflammatory lesions Cornelius Celsus(1st century AD Rome):cardinal signs of inflammation redness, swelling, heat, pain 3
  4. 4. CARDINAL SIGNS OF (ACUTE) INFLAMMATION  Rubor  Tumor  Calor  Dolor = redness = swelling = heat = pain (described by Celsus 1st. Century AD)  Functio laesa = loss of function (added by R. Virchow 19th Century)
  5. 5. INTRODUCTION  The inflammatory response is closely intertwined with the process of repair.  During repair the injurious tissue is replaced by regeneration, filling of the defect by fibrous tissue(scaring). 5
  6. 6. INTRODUCTION The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix “-itis” e.g pancreatitis meningitis pericarditis arthritis 6
  7. 7. DEFINITION Inflammation“It is a complex reaction to injurious agents such as microbes and damaged necrotic cells that consist of vascular response, migration and activation of leucocytes and systemic reactions.” OR “Inflammation is a complex reaction in tissue that consist mainly of responses of blood vessels and leukocyte” 7
  8. 8. TYPES OF INFLAMMATION Acute “The immediate and early response to an injurious agents” Min to Days 1. Characterized by fluid and protein 2. PMN’s 3. Exudates 4. SG >1.020 8
  9. 9. TYPES OF INFLAMMATION Chronic “Inflammation of prolonged duration, week or months and there is active inflammation tissue destruction, with attempts at repair are proceeding simultaneously” Week to Year 1. Lymphocytes 2. Macrophages 9
  10. 10. Exudates1. Increase vascular permeability 2. High protein and cell debris 3. SG > 1.020 Transudate1. Normal vascular permeability 2. Low protein(mostly albumin) 3. SG < 1.020 10
  11. 11. 11
  12. 12. Edema1. Exudates and transudate 2. In interstitial or in cavity 12
  13. 13. Acute inflammation major components Transient vasoconstriction Vasodilatation Increase epithelial permeability Extravasations of PMN’s With five cardinal signs of inflammation 13
  14. 14. Acute inflammation major components 14
  15. 15. Inflammatory response consist of Vascular reaction Cellular reaction 15
  16. 16. Vascular and cellular changes Transient vasoconstriction Vasodilatation Exudation of protein rich fluid Blood stasis Margination Emigration/ Transmigration 16
  17. 17. Vascular changes Increase intravascular hydrostatic pressure Endothelial gaps in intercellular junction Fluid exits vessels Protein exits vessels Decrease intravascular osmotic pressure Immediate transient response Histamine, bradykinin, leucotrienes and substance P 17
  18. 18. Vascular changes 18
  19. 19. Lewis experiment of triple response 19
  20. 20. Red line appears within seconds resulting from vasodilatation of capillaries and venules Flare is a bright reddish appearance or flush surrounding the red line results from vasodilatation of the adjacent arterioles Wheal is the swelling or edema of the skin occurring from transudation of fluid in extra vascular space 20
  21. 21. Vascular permeability Vasodilatation- increase blood flow Increased intravascular hydrostatic pressure Transudate - ultra filtration of blood plasma (contain little protein, very transient just get the process started) Exudates- Protein rich with PMNs Exudates is characteristic of acute inflammation 21
  22. 22. Vascular permeability Intravascular osmotic pressure decreases Osmotic pressure of interstitial fluid Outflow of water and ions – edema 22
  23. 23. How do endothelial cells become permeable? Gap due to Endothelial cell contraction Direct endothelial cell injury (Immediate system response) Leukocyte- dependent endothelial injury Increase transcytosis of fluid Leakage from new vessels 23
  24. 24. Gap due to Endothelial cell contraction 24
  25. 25. Direct endothelial cell injury (Immediate system response) 25
  26. 26. Leukocyte- dependent endothelial injury 26
  27. 27. Increase transcytosis of fluid 27
  28. 28. Leakage from new vessels 28
  29. 29. Cellular events Margination and rolling Adhesion and transmigration Migration into interstitial tissue 29
  30. 30. Selectin  Weak and transient binding Results in rolling Integrins  Unregulated and activated for increase affinity to CAMS Results in firm adhesion 30
  31. 31. Margination Normal flow- RBCs and WBCs flow in the center of the vessels. A cell poor plasma is flowing adjacent to endothelium As blood flows slow WBCs collect along the endothelium Margination 31
  32. 32. Endothelium activation The underlying stimuli causes release of mediators Activate the endothelium causing selectin and other mediators to be moved quickly to the surface 32
  33. 33. Four families of adhesion molecules are involved in leukocyte migration Selectins E-selectin (on endothelium) P-selectin (on endothelium & platelets; is preformed and stored in Weible Palade bodies) L-selectin (leukocytes) Ligands for E-and P-Selectins are sialylated glycoproteins (e.g Sialylated Lewis X) Ligands for L-Selectin are Glycanbearing molecules such as GlyCam-1, CD34, MadCam-1 Integrins (a + b chain) Heterodimeric molecules VLA-4 (b1 integrin) binds to VCAM-1 LFA1 and MAC1 (CD11/CD18) = b2 integrin bind to ICAM Expressed on leukocytes Immunoglobulin family ICAM-1 (intercellular adhesion molecule 1) Mucin-like glycoproteins Heparan sulfate (endothelium) VCAM-1 (vascular adhesion molecule 1) Ligands for CD44 on leukocytes Are expressed on activated endothelium Bind chemokines Ligands are integrins on leukocytes 33
  34. 34. Rolling and Adhesion Selectin transiently binds to the receptors PMNs bounces or roll along the endothelium Mediated by integrins ICAM-1 and VCAM-1 34
  35. 35. TRANSMIGRATION CHEMOTAXIS • Mediated/assisted by VCAM 1 • Movements towards the site of injury along a chemical and ICAM 1(integrins) gradient • Chemotactic factor include • Diapedesis (cell crawling) 1. Components (20 serum protien) • Primary in venules 2. Arachadonic acid metabolites • Collagenase degrade 3. Soluble bacterial products basement membrane 4. Chemokines 5. Cytokines • Increase permeability 35
  36. 36. Selectin s Integrins 36
  37. 37. Inflammatory Cells The circulating cells includes Neutrophils  Monocytes  Eosinophils  Lymphocytes  Basophils  Platelets The connective tissue cells are Mast cells  Fibroblast  Macrophages  Lymphocytes 37
  38. 38. Inflammatory Cells 38
  39. 39. Phagocytosis and degranulation Involves three sequential steps 1. Recognition and attachment of the particle to be ingested by leucocytes 2. Phagocytosis (engulf and destroys ) 3. Killing/degranulation –oxygen dependent :reactive O2 species in Lysosomes Oxygen independent- bacterial permeability agents , Lysosomes , lactoferin 39
  40. 40. Leukocyte express several receptors that recognize external stimuli and deliver activating signals • Mannose Receptor • Receptors for microbial products-toll like receptors(TLRs) • G protein-coupled receptors • Receptors for opsonins • Receptors for cytokines 40
  41. 41. 41
  42. 42. Engulfment After particle is bound to phagocyte receptors, extension of cytoplasm(pseudopods flows around it) Plasma membrane pinches off Forms a vesicle enclosing particle Phagosome fuses to lysosomal granules Killing of microbes by lysosomal enzymes in phago Lysosomes 42
  43. 43. 43
  44. 44. KILLING AND DEGRANULATION • Final step • Microbial killing is accomplished largely by reactive oxygen species(ROS)also called as reactive oxygen intermediates • And reactive nitrogen species mainly derived from NO 44
  45. 45. Chemical mediators in inflammation Plasma derived-circulating precursors have to be activated Cell derived-sequestered intracellularly synthesized de novo Most mediators bind to receptors on cell surface but some have direct enzymatic or toxic activity. Mediators are tightly regulated 45
  46. 46. 46
  47. 47. Mediators in acute inflammation 47
  48. 48. Plasma derived mediators Complement Kinin Clotting Fibrinolytic 48
  49. 49. 49
  50. 50. Cell derived mediators-Vasoactive amines Histamine – 1. Found in mast cells , basophils and platelets 2. Release in response to stimuli 3. Promotes arterioles dilation and venules endothelial contraction 4. Results in widening of inter-endothelial cell junction with increase in vascular permeability 50
  51. 51. Serotonin/5 hydroxytryptamine- 1. Vaso-active effects similar to histamine but less potent 2. Found in chromaffin cells of GIT, spleen, nervous system, mast cells and platelets 3. Release when platelet aggregation 51
  52. 52. BradykininPotent bio-molecule 1. Vasodilatation 2. Increase vascular permeability 3. Contraction of smooth muscle 4. Short life 52
  53. 53. Arachodonic acid/eicosanoids AA is component of cell membrane phospholipids AA is activated by some stimuli or mediators like C5a so as to form AA metabolites Metabolites of AA –short range hormone Acts locally at the site of generation Rapidly decay or destroys 53
  54. 54. AA metabolites occurs by two major pathways named for the enzymes that initiates the reaction, lypoxygenase and cycloxygenase Cycloxygense synthesize-prostaglandin, thromboxane Lypoxygenase synthesize- leucotrines and lipoxins 54
  55. 55. Cycloxygense pathway Cycloxygense is a fatty acid enzyme act on activated AA to form prostaglandin which further activated by enzyme to form3 metabolitesProstaglandin-Increase vascular permeability, vasodilatation, inhibit inflammatory cell function Prostacyclin- Vasodilatation and inhibits platelet aggregation Thromboxane A2-Vasoconstriction,broncoconstriction, enhances inflammatory cell function Promotes platelet aggregation 55
  56. 56. Lipoxygenase pathway Enzyme lypoxygenase acts an activator to AA to form 5-HETE (hydroperoxy eico-astetraeonic acid) which on further per oxidation forms 2 metabolites Leucotrines Lipoxins Causes Vasoconstriction Bronchospasm Increase vascular permeability 56
  57. 57. 57
  58. 58. AA metabolites Participate in every aspect of acute inflammation Affective anti-inflammatory agent E.g.. Aspirin, NSAIDS-cycloxygenase pathway Steroids acts by inhibiting phospolipase A2 58
  59. 59. Lysosomal components Inflammatory cells contains lysosomal granules which release mediators of inflamation Granules of neutrophils-2 types azurophil or primary (myeloperoxidase, acid hydrogenasecollagenase, elastase, collagenase) Specific or secondary (lectoferrin, lysozyme, alkaline phosphatase, collagense) Granules of monocyte-protease, collagenase, elastase, plasminogen activator 59
  60. 60. Platelet activating factor Another phospholipids derived mediator release by phospholipase Induces Aggregation of platelets Vasoconstriction Broncho-constriction 100-1000 times more potent then histamine in inducing vasodilatation and vascular permeability Enhances leukocyte adhesion, chemo taxis, degranulation and oxydative burst 60
  61. 61. Cytokines Polypeptides that are secreted by cells Act to regulate cell behavior Autocrine, paracrine, endocrine effects 61
  62. 62. IL-1 /TNF Acute phase reactionIncreases sleep Acute phase protein hemodynamic effects Decreases appetite Endothelial effectsIncreases Leukocyte adhesion, PG synthesis, procoagulants Decreases anticoagulants Increases IL-1,IL-8, IL-6 62
  63. 63. Neuropeptides Secreted by sensory nerves and various leucocytes Role in initiation and propagation of inflammatory response Substance P and neurokinnin A are neuropeptides Has many biological function like transmission of pain signals, regulation of B.P., increasing vascular permeability 63
  64. 64. Different morphological patterns of acute inflammation can be found depending on the cause and extend of injury and site of inflammation Serous inflammation Fibrinous inflammation Purulent inflammation Ulcer 64
  65. 65. Outcomes of acute inflammation Resolution Fibrosis Abscess formation Progression to chronic inflammation 65
  66. 66. 66
  67. 67. MONONUCLEAR PHAGOCYTES They are important in acute inflammation, as well as being a key element in chronic inflammation Like neutrophils, monocytes bear C3b receptors on their surfaces famous role as scavengers 67
  68. 68. CHRONIC INFLAMMATION Chronic inflammation is an inflammation of prolonged duration(weeks or months) in which inflammation, tissue injury, and attempts at repair co exits, in varying combination. It may follow acute inflammation or begin as a low grade, smoldering response like on rheumatoid arthritis, atherosclerosis, tuberculosis, pulmonary inflammation 68
  69. 69. Causes of chronic inflammation  Persistent infection-that are difficult to eradicate  Immune mediated inflammatory disease  Prolonged exposure to potentially toxic agents, either exogenous or endogenous 69
  70. 70. Persistent infection-that are difficult to eradicate  Evoke an immune reaction called delayed –type hypersensitivity  Sometimes occurs as granulomatous reaction 70
  71. 71. Immune mediated inflammatory disease Caused by excessive and inappropriate activation of immune system Immune reaction develops in individual own tissue Results in autoimmune disease Ex. Rheumatoid arthritis, multiple sclerosis 71
  72. 72. Prolonged exposure to potentially toxic agents, either exogenous or endogenous Exogenous agent: silica results in inflammatory lung disease called silicosis Endogenous agent: toxic plasma lipid component causes atherosclerosis 72
  73. 73. Morphological features of chronic inflammation 1. Infiltration with mononuclear cell-macrophages, lymphocytes, plasma cell 2. Tissue destruction-induced by persistent offending agents or by inflammatory cells 3. Attempts at healing, replacement of damaged tissue 4. (angiogenesis, fibrosis) 73
  74. 74. Role of Macrophages Dominant cell Component of mononuclear phagocyte system Scattered in connective tissue or in liver(kuffer cell), spleen and lymph nodes(sinus histeocytes), lungs (alveolar macrophages), CNS(microglea) Journey from bone marrow to tissue macrophages is regulated by growth and differentiation factors, cytokines, adhesion molecule and cellular interaction 74
  75. 75. Begins to appear in acute inflammation and predominant after 48 hrs Extravasations is same like neutrophils When monocyte reaches to extra vascular tissue undergo transformation into large phagocytic cell called macrophage Macrophages are activated by stimuli including microbial product that engage TLRs and other cellular receptors, cytokines(IFN-Y) 75
  76. 76. Activated macrophagesServes to eliminate injurious agents Initiate the process of repair Responsible for much of the tissue injury Increases level of lysosomal enzyme ROS and NOS system Production of cytokines, growth factors, other mediators 76
  77. 77. 77
  78. 78. Other cells in chronic inflammation LymphocytesMobilized in cell mediated and antibody mediated immune reaction Antigen stimulated lymphocytes are – T and B cells Uses same adherent molecule (selectin, integrin, ligands) and chemokines to migrate into inflammatory sites 78
  79. 79. 79
  80. 80. Plasma cellsDevelops from activated B lymphocytes Produce antibodies against foreign bodies Present in germinal center of lymph nodes EosinophilsAre abundant in immune reaction mediated by IgE and in parasitic infection Chemokine toxin is important for eosinophilic recruitment They also contribute to tissue damage in immune reactions such as allergies 80
  81. 81. Mast cellsWidely distributed in connective tissue Contribute in acute and chronic inflammation Releases mediators such as histamine and prostaglandin Responses occurs in allergic reaction to food, insect venom, or drugs, anaphylaxis Mast cells also take part in chronic inflammation As they secrete a plethora of cytokine they have the ability to promote and limit inflammatory reaction 81
  82. 82. Systemic effects of inflammation Fever Acute phase response increases 1 to 4 degree temp Produce in response to substance pyrogens that stimulates the prostaglandin synthesis. Bacterial products stimulate leukocyte to release IL-1, TNF which causes increase in the enzyme cycloxygenase causing conversion of AA into prostaglandin Stimulate the production of neurotransmitter (cyclic adenosine monophosphate) which in turn regulates the temp 82
  83. 83. Acute phase protein – Are Plasma proteins whose concentration increases thousand times in inflammation C reactive protein, amyloid protein, fibrinogen by hepatocytes Causes amylodoisis of organ, increases risk of myocardial infarction, atherosclerosis, thrombosis, infarction. 83
  84. 84. Leukocyte count Usually climbs to 15,000 to 20,000 Bone marrow output is increased Other systemic effects are – Increase pulse Increase blood pressure Decrease sweating Shivering, chills Anorexia Malaise sometimes in severe bacterial infection =sepsis 84
  85. 85. Repair of the damaged tissue is separated into two processes: REGENERATION HEALING 85
  86. 86. Definitions: Regeneration: growth of cells and tissue to replace lost structures. Healing: is a tissue response – to a wound to inflammatory processes to cell necrosis in an organ incapable of regeneration. It consists of variable proportion of two distinct processes – regeneration and laying down of fibrous tissue, or scar formation. 86
  87. 87. Regeneration V/s Healing Regeneration requires an intact tissue scaffold. By contrast healing with scar formation occurs if the extracellular matrix (ECM) framework is damaged causing alteration in tissue architecture. 87
  88. 88. Growth factors and cytokines involved in regeneration and wound healing Epidermal growth factor (EGF) Mitogenic; stimulate keratinocytes migration and granulation tissue formation. Transforming growth factor alpha (TGF-α) Similar to EGF; replication of hepatocytes. Hepatocytes growth factor / Scatter factor (HGF) Proliferation of hepatocytes & epithelial / endothelial cells Vascular endothelial cell growth factor (A,B,C,D) Increased vascular permeability; mitogenic for endothelial cells Platelet deived growth factor (PDGF-A,B,C,D) Chemotaxis and activation of PMNs, macrophages & fibroblast; Mitogenic for fibroblast endothelial cells; stimulates angiogenesis and wound contracture. Fibroblast growth factor 1,2 and family (FGF-1,2..) Chemotactic and mitogenic for fibroblast. Angiogenesis, wound contraction & matrix deposition Transforming growth factor-beta (TGF-β) Keratinocyte migration; Angiogenesis & fibroplasia; regulates integrin expression. Keratinocyte growth factor (KGF) also called FGF-7 Keratinocyte migration, proliferation & differentiation. Insulin like growth factor (IGF-1) Synthesis of sulfated protioglycan, collagen. Tumour necrosis factor (TNF) Activates macrophages, regulate other cytokines. Interleukins (IL-1 etc.) Synthesis of IL-1 ; Angiogenesis ( IL-8). Interferon (IFN-α etc.) Inhibit fibroblast proliferation & synthesis of MMPs. 88
  89. 89. There are three general modes of signalingAutocrine Paracrine Endocrine Autocrine: Cells respond to the molecule that they themselves secrete Paracrine: One cell type that contains an appropriate receptor responds to the legand produced by the adjacent cell. Juxtacrine: the signaling molecule is anchored in a cell and bind a receptor in the plasma membrane of another cell. Endocrine: The signaling molecule, hormone, is synthesized by cells of endocrine organs and acts on target cells distant from there site of synthesis. 89
  90. 90. 90
  91. 91. Extracellular Matrix & Cell Matrix Interactions Synthesis & degradation of ECM is involved in morphogenesis, wound healing, chronic fibrotic processes & also in tumors invasion and metastasis Constituent of ECMFibrous structural proteins e.g. collagen & elastin. Adhesive glycoproteins. Proteoglycans and hyaluronic acid. These macromolecules assemble into two forms Interstitial matrix and Basement membrane 91
  92. 92. Interstitial matrix & Basement membrane IM consists of:- BM consists of:- Fibrillar & nonfibrillar collagen Amorphous nonfibrillar collagen (type-4) Elastin Laminin Fibronectin Heparin sulphate Proteoglycan Proteoglycan Hyaluronate Other glycoproteins Other components 92
  93. 93. Repair by Healing, Scar Formation, and Fibrosis Fibro-proliferative response that “patches” rather than restores a tissue. Involving a number of processes: Induction of an inflammatory process with removal of damaged and dead tissue. Proliferation and migration of parenchymal deposition. Formation of new blood vessels (angiogenesis) and granulation tissue. 93
  94. 94. Repair by Healing, Scar Formation, and Fibrosis Synthesis of ECM proteins and collagen deposition. Tissue remodeling Wound contraction Acquisition of wound strength 94
  95. 95. Inflammatory reaction contain the damage, eliminates the damaging stimulus, removes injured tissue, initiates the deposition of ECM components For tissue that are incapable of regeneration repair is accomplished by connective tissue deposition , producing a scar. If damages persists, inflammation becomes chronic, tissue damages and repair may occur concurrently. Connective tissue deposition in these condition is usually referred to as FIBROSIS. 95
  96. 96. GRANULATION TISSUE As early as 24 hours fibroblasts and vascular endothelial cell begin proliferating to form a specialized type of tissue that is the hallmarks of healing, called granulation tissue. Characteristic: the formation of new small blood vessels (angiogenesis) and the proliferation of fibroblasts . 96
  97. 97. Angiogenesis Blood vessels are assembled during embryonic development by vasculogenesis. Process of blood vessel formation in adults is known as angiogenesis or neo- vascularization, branching and extension of adjacent blood vessels also occur by recruitment of endothelial progenitor cells (EPCs) from bone marrow. 97
  98. 98. Angiogenesis from Endothelial Precursor Cells Angio-blasts proliferate, migrate to peripheral sites, differentiate into endothelial cells that form arteries, veins, lymphatics . Also can generate pericytes and smooth muscle cells of vessel wall (periendothelial cells) 98
  99. 99. Angiogenesis from Pre-Existing Vessels Major steps: Vasodilatation increased permeability Proteolytic degradation of the BM of the parent vessel ( by metalopoteinase) and disruption of cell-tocell contact between endothelial cell of vessel (by plasminogen activator). Migration of endothelial cells Proliferation of endothelial cells Maturation of endothelial cells & remodeling into capillary tube. Recruitment of periendothelial cells & formation of mature vessel. 99
  100. 100. ANGIOGENESIS FROM PREEXISTING VESSELS 100
  101. 101. Scar formation Scar formation can be divided in three processesEmigration and proliferation of fibroblasts Deposition of ECM Tissue remodeling Fibroblast migration & proliferation Migration of fibroblast to the site of injury & their subsequent proliferation are triggered by multiple growth factors (TGF , PDGF, EGF, FGF)) and the cytokines (IL-1 & TNF) Source of these factors are platelets, inflammatory cells (notably macrophages) & activated endothelium. 101
  102. 102. ECM deposition & Scar formation As repair continues proliferating endothelial cells and fibroblasts decreases. Fibrillar collagen provides the strength in healing wounds. Ultimately the granulation tissue scaffolding is converted into a scar composed of spindle shaped fibroblasts , dense collagen, fragment of elastic tissue and other ECM components. As the scar matures the richly vascularized granulation tissue is converted into pale avascular scar. 102
  103. 103. Tissue Remodeling Balance between ECM synthesis and degradation results in remodeling of the connective tissue. Degradation is achieved by matrix metaloproteinases (MMPs). MMPs includes :Interstitial collagenases(MMP-1,2 &3) Gelatinases (MMP-2 & 9) stromelysins (MMP- 3,10 & 11) Membrane bound MMP Activated collagenases are rapidly inhibited by tissue inhibitors of metalloproteinases (TIMPs) 103
  104. 104. CUTANEOUS WOUND HEALING It is divided into three phases- Inflammation Granulation tissue formation and re-epithelization Wound contraction, ECM deposition and remodeling Wound healing is by primary or secondary intention which is based on the nature of the wound rather than the healing process itself. 104
  105. 105. HEALING BY PRIMARY INTENTION Healing of clean, uninfected surgical incision approximated by surgical suture is reffered as primary union or healing by first intension . Five phases of healing are – 1.Immediately- capillaries of either side of wound are thrombosed Gap is filled with blood Coagulation and sealing of defect If clot reaches the surface, it dries to form a crust or scab 105
  106. 106. 106
  107. 107. Inflammatory phase 2nd dayNeutrophils appear at margins of incision Acute inflammatory response on either side of narrow incision space Swelling, redness, pain at the wound site Epithelial cells at edge of wound undergo mitosis and begin to migrate across the wound 107
  108. 108. 108
  109. 109. Proliferative phase Cellular proliferation involves three processes Angiogenesis-the wound surface or edge is relatively ischemic and healing cannot effectively proceed until sufficient flow is restored Also called as neo-vascularisation Involves formation of new blood vessels by proliferation and migration of endothelial cells from preexisting blood vessels 109
  110. 110. Epithelial cell proliferation The epidermis at the cut ends thickens (mitotic division of basal cells) Within 48 to 72 hrs epithelial cells from both the margins grows towards the cut end depositing the basement membrane as they moves They fuses in the midline, beneath the scab, thus producing a continuous but thin epithelial layer 110
  111. 111. By day 3:The neutrophils are largely replaced by macrophages. Granulation tissue progressively invades the incision space. Collagen at first are vertically oriented, not bridging the incision site Epithelial cells proliferation thickens The thickening of epidermal covering layer yields mature epidermal architecture with surface keratinisation 111
  112. 112. By day 5:Incisional space is filled with granulation tissue. Neo-vascularization is maximal. Collagen begin to bridge the incision. Epidermis recovers its normal thickness. Surface keratinization starts Day 7- interstitial matrix production 112
  113. 113. 113
  114. 114. Day 10th Fibrous Union phase begins on about 10th day 114
  115. 115. Remodeling Day 30 Scar is largely devoid of inflammatory cells and covered by an essentially normal epidermis 3 Months Devascularisation of tissue, remodeling of collagen by enzyme action , scar is now minimum and merges with surrounding tissues 115
  116. 116. Healing by second intention Edges are separated. More extensive loss of cells and tissue. Prone for infection Regeneration of parenchymal cells can not completely restore the original architecture, and Hence, abundant granulation tissue grows is referred to as secondary union. Cannot be brought together by sutures 116
  117. 117. Early phase Edges cannot be brought together and defect remains Base of wound may covered with plasma Plasma oozes out from the base of the wound Wound are filled with the blood from the cut ends of capillaries, fibrin threads and platelets 117
  118. 118. 118
  119. 119. One week approximatelyFibrovascular granulation tissue gradually fills the wound space and epithelium grows over its surface The exudative inflammatory changes and migration of neutrophills subsides Formation of loose connective tissue by fibroblast Macrophages come to clear the debris Granulation tissue grows into the wound from the base 119
  120. 120. 120
  121. 121. Second weekDuring the second week continuous accumulation of collagen and proliferation of fibroblast Leukocyte infiltration, edema, increased vascularity is greatly reduced Increased collagen deposition within the incision scar and disappearance of vascular channels Months Contraction of wound by myofibroblast present in granulation tissue Wound contraction occur in case of shrinkage of granulation tissue that pulls the edges together 121
  122. 122. 122
  123. 123. Wound strength First week:- 10 % of unwounded Next 4 weeks:- rapid increase 3rd month:- rate slows down & reaches a plateau at about 70 % to 80 % of tensile strength. 123
  124. 124. Local & Systemic factors that influence Wound Healing • Systemic factors:– Nutrition: Vit-c def. retards healing – Metabolic state: Diabetes retards healing. – Circulatory status: atherosclerosis and venous diseases retards healing – Hormones: glucocorticoids have anti-inflammatory effects & inhibits collagen synthesis. • Local factors:– Infection (most imp.) retards healing – Mechanical factors:early motion retards healing – Foreign bodies: inhibits healing – Size location & type of wound: richly vascularised sites heal quickly 124
  125. 125. Complications In Cutaneous Wound Healing Deficient scar formation Excessive formation of the repair components The accumulation of excessive amounts of collagen may give to a raised scar known as a hypertrophic scar If scar tissue grows beyond the boundaries of the original wound and does not regress, it is called a keloid Exuberant proliferation – Desmoids, or aggressive fibromatoses (interface between benign proliferations and malignant tumors) Formation of contractures: Serious burns. 125
  126. 126. 126
  127. 127. Healing of extraction socket The removal of tooth initiates the same sequence of inflammation, epithelialization, fibroplasia and remodeling seen in skin wound Socket heals by secondary intension After extraction the empty socket consist of cortical bone(radiographic lamina dura )covered by torn periodontal ligament with a rim of oral epithelium 127
  128. 128. The socket fills with blood clot which seals the socket from oral environment During first week inflammatory stage takes place WBCs enter the socket and clear the microorganism, begins to break down any debris, bony fragments left in the socket Fibro-plasia begins with ingrowths of fibroblast and capillaries 128
  129. 129. The epithelium migrates down the socket wall Reaches a level at which it contacts the epithelium Other side of socket Encounters the bed of granulation tissue under the clot Osteoclast accumulates over the crestal bone 129
  130. 130. During second week Large amount of granulation tissue fills the socket Osteoid deposition along the lining of the socket The process begin during second week continue Third and forth week of healing The cortical bone continues to resorb from the crestal bone and walls of the socket 130
  131. 131. New trabecular bone is laid down across the socket As bone fills the socket epithelium moves towards the crest and eventually becomes level with the adjacent crestal gingiva 131
  132. 132. FIBRINOLYTIC ALVEOLITIS (DRY SOCKET) Postoperative complication appears 2–3 days after the extraction. The blood clot disintegrates and is dislodged, resulting in delayed healing and necrosis of the bone surface of the socket. This disturbance is termed fibrinolytic alveolitis and is characterized by an empty socket, fetid breath odor, a bad taste in the mouth, denuded bonewalls, and severe pain that radiates to other areas of the head 132
  133. 133. Clinical photograph of fibrinolytic alveolitis (dry socket) in the region of the maxillary second molar
  134. 134. 134
  135. 135. HEALING OF FRACTURED BONE Phases of fracture healing There are three major phases of fracture healing, two of which can be further sub-divided to make a total of five phases; 1. Reactive Phase i. Fracture and inflammatory phase(immediately) ii. Granulation tissue formation(24-48 hrs) 2. Reparative Phase iii. Cartilage Callus formation(2 -3 weeks) iv. Lamellar bone deposition(external callus removed, intermediate callus is converted into compact bone, internal callus into cancellous bone) 3. Remodeling Phase v. Remodeling to original bone contour(months to year) 135
  136. 136. 136
  137. 137. REFERENCES • Robbins and Cotrans.Pathologic basis of diseases,9th edition; 43-108 • Mohan Harsh.Essentials of pathology,4th edition;90-109 • Sant Mrinali. A textbook of pathology,1st edition; 86-90 • Peterson.contemporary oral and maxillofacial surgery,4th edition;54-55 • Fragiskos D. Fragiskos. Oral Surgery; 199 137
  138. 138. THANK YOU 138

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