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  1. 1. Overview
  2. 2. Introduction  Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as necrotic cells and tissues resulting from the original insult.  It sets into motion the events that eventually heal and reconstitute the sites of injury.
  3. 3. Inflammation  Definition Inflammation (Latin, inflamatio, to set on fire) is a localized protective response elicited by injury or destruction of tissues, which serves to destroy, dilute or wall off (sequester) both the injurious agent and the injured tissue. (Dorland’s medical dictionary; 30th ed)
  4. 4. Inflammation  Definition Inflammation is a complex reaction to injurious agents such as microbes and damaged, usually necrotic, cells that consists of vascular responses, migration and activation of leukocytes and systemic reactions. (Robins and Cotran; 7th ed.)
  5. 5. History  Egyptian papyrus (3000 BC)  Celsus (1st century AD) – 4 cardinal signs of inflammation  Virchow – fifth clinical sign i.e. functio laesa  John Hunter (1973)– inflammation is not a disease but a non-specific response that has a salutary effect on its host.
  6. 6. History  Julius Cohnheim (1839-1884) – described the process of inflammation  Ellie Metchnikoff – Phagocytosis  Sir Thomas Lewis – chemical substances, such as histamine locally induced by injury, mediate the vascular changes of inflammation
  7. 7. Inflammation  Inflammation is divided into two basic patterns: Acute Inflammation : It is the immediate and early response to injury, designed to deliver leukocytes to the site of injury. (Robbins 7th ed.) Also defined as inflammation usually of sudden onset characterized by classical signs, with predominance of vascular and exudative processes. (Dorlands Dic.)
  8. 8. Inflammation  Chronic Inflammation : It is considered to be inflammation of prolonged duration (weeks to months to years) in which active inflammation, tissue injury and healing proceed simultaneously. (Robbins 7th ed.)  Inflammation of slow progress and marked chiefly by the formation of new connective tissue. (Dorlands Dic.)
  9. 9. Inflammation  The inflammatory response has many players  These include:  Circulating cells  Neutrophils  Eosinophils and Basophils  Lymphocytes and Monocytes  Platelets
  10. 10. Inflammation  Circulating Proteins :  Clotting Factors  Kininogens  Complement components  Vascular wall cells :  Endothelial cells in direct contact with blood  Smooth muscle cells that impart tone to vessels
  11. 11. Inflammation  Connective tissue cells  Mast cells  Macrophages  Lymphocytes  Fibroblast  Extra cellular Matrix :  Fibrous Structural Proteins (e.g. Collagen & Elastin)  Gel forming proteoglycans  Adhesive glycoprotein (e.g. Fibronectin)
  12. 12. Acute Inflammation STIMULI FOR ACUTE INFLAMMATION Infections (bacterial, viral, parasitic) and microbial toxins  Trauma (blunt and penetrating)  Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation; some environmental chemicals) Tissue necrosis (from any cause) Foreign bodies (splinters, dirt, sutures) Immune reactions (also called hypersensitivity reactions)
  13. 13. Acute Inflammation  Lewis experiment. Lewis induced the changes in the skin of inner aspect of forearm by firm stroking with the blunt point eliciting the triple response Red line appears in a few seconds due to local vasodilation. Flare is the bright reddish appearance also due to vasodilation of the adjacent arterioles. Wheal is the swelling or edema due to transudation of fluid into extravascular space.
  14. 14. Acute Inflammation Red line – direct vasodilating effect of histamine Flare – indirect vasodilating effect of histamine by stimulating axon reflex Wheal – Histamine induced increased permeability
  15. 15. Acute Inflammation  Classical signs of inflammation (Celsus) 1. Heat (Calor) 2. Redness (Rubor) 3. Swelling (Tumor) 4. Pain (Dolor) 5. Loss of function (Functio laesa) (Virchow)
  16. 16. Acute Inflammation  Acute inflammation has two main components: Vascular Changes : Alteration in the vessel caliber resulting in increased blood flow (vasodilation) and structural changes that permits plasma proteins to leave circulation (increased vascular permeability). Cellular Events : Emigration of leukocytes from the microcirculation and accumulation in the focus of injury (cell recruitment and activation).
  17. 17. Vascular Changes
  18. 18. Vascular Changes Starling’s Law: Movement of fluid in and out of arterioles, capillaries and venules is regulated by the balance between 1.Intravascular hydrostatic pressure – tends to force fluid out of vessels 2.Osmotic pressure of the plasma proteins – tends to retain fluid within the vessels
  19. 19. Vascular Changes
  20. 20. Transudate Vs Exudate Transudate Exudate Filtrate of blood plasma without changes in endothelial permeability Oedema of inflamed tissue with increased vascular permeability Non-Inflammatory Oedema Inflammatory Oedema Protein < 1g/dl Protein -- High 2.5-3.5 g/dl Glucose – same as plasma Glucose – Low (<60 mg/dl) Specific Gravity < 1.015 Specific Gravity > 1.018 pH > 7.3 pH < 7.3 Few Cells, mainly mesothelial cells and cellular debris Inflammatory as well as parenchymal cells eg. Oedema in congestive cardiac failure Purulent exudate such as pus
  21. 21. Increased vascular permeability Endothelial cell contraction leads to intercellular gaps in venules.
  22. 22. Increased vascular permeability Endothelial cell retraction :  Reversible mechanism  Induced by cytokine mediators (TNF & IL-1)  Cause structural reorganization  Cells retract  Takes 4 to 6 hrs to develop and persists for 24hrs or more
  23. 23. Increased vascular permeability  Direct endothelial injury :  Seen in severe injuries (burns, infections etc.)  Leakage begins immediately after surgery and persists for several hours. (immediate sustained response)
  24. 24. Increased vascular permeability  Leukocyte dependent endothelial injury :  Leukocytes may accumulate during inflammatory response.  These leukocytes may release toxic oxygen species and proteolytic enzymes causing injury.
  25. 25. Increased vascular permeability  Leakage from new blood vessels :
  26. 26. Cellular Events
  27. 27. Cellular Events
  28. 28. Transendothelial Migration  E-selectins are expressed at low levels or are not present at all on normal cells. They are upregulated after stimulation by specific mediators. eg.IL-1 and TNF.  P-selectins are found intracellularly in Weibel-Palade bodies, which once stimulated by mediators such as histamine are distributed over the cell surface.  L-selectins interact with carbohydrate molecules known as vascular addresins (eg.sialomucin) on the luminal surface of endothelial cells. This brief interaction manifests itself as rolling of the leukocyte along the luminal surface of endothelium.
  29. 29. Transendothelial Migration
  30. 30. Chemotaxis and Activation  After extravasating from the blood, leukocytes migrate toward sites of injury along a chemical gradient in a process called chemotaxis.  Both exogenous and endogenous substances can be chemotactic for leukocytes.  Soluble bacterial products : N-formylmethionine termini.  Components of complement system : C5a  Products of lipoxygenase pathway : leukotriene B4  Cytokines : IL-1, IL-8
  31. 31. Chemotaxis and Activation
  32. 32. Biochemical Events In Leukocyte Activation
  33. 33. Phagocytosis and Degranulation  Phagocytosis and the elaboration of degradative enzyme are two major benefits of having recruited leukocytes at the site of inflammation.  Phagocytosis consists of three distinct but interrelated steps:  Recognition and attachment of the particle to the ingesting leukocyte.  Engulfment with subsequent formation of a phagocytic vacuole  Killing and degradation of the ingested material.
  34. 34. Phagocytosis and Degranulation
  35. 35. Phagocytosis and Degranulation
  36. 36. Phagocytosis and Degranulation  2O2 +NADPH NADPH oxidase 2O2 - + NADP+ + H+  Superoxide is then converted by spontaneous dismutation to hydrogen peroxide.  O2 - + 2H+ H2O2 Cl-  H2O2 Myeloperoxidase HOCl + H2O
  37. 37. Chemical Mediators Of Inflammation
  38. 38. Vasoactive Amines  Histamine – widely distributed in mast cells; also present in circulating basophils and platelets.  Preformed histamine is stored in mast cell granules and released in response to a variety of stimuli :  Physical injury  Immune reactions involving binding of IgE antibodies to Fc receptors on mast cells.  Anaphylatoxins; C3a and C5a  Leukocyte derived histamine releasing proteins.  Neuropeptides  Certain cytokines (IL-1; IL-8)
  39. 39. Vasoactive Amines  Histamine causes arteriolar dilatation and is the principal mediator of immediate phase of increased vascular permeability.  Soon after its release it is inactivated by histaminase.  Serotonin is also a preformed vasoactive mediator with effects similar to those of histamine.  Found in platelets and released during platelet aggregation.
  40. 40. Neuropeptides  Like vasoactive amines neuropeptides can initiate inflammatory responses  Nerve fibers that secrete neuropeptides are prominent in lungs and GIT  They are small proteins, such as substance P, that transmit pain signals, regulate vascular tone and modulate vascular permeability.
  41. 41. Plasma Proteases  Many effects of inflammation are mediated by three interrelated plasma derived factors :  The Kinins all linked by initial activation of  The clotting system Hageman Factor( factor XII)  The complement system  Hageman factor is a protein synthesized by liver that circulates in an inactive form until it encounters collagen, basement membrane or activated platelets.
  42. 42. Plasma Proteases
  43. 43. Complement system
  44. 44. Arachidonic acid metabolites
  45. 45. Platelet-Activating Factor (PAF)  Platelets, basophils, mast cells, neutrophils, monocytes/macrophages and endothelial cells  Vasoconstriction and bronchoconstriction  Increased leucocyte adhesion to endothelium  Chemotaxis, degranulation and oxidative burst
  46. 46. Cytokines
  47. 47. Nitric Oxide
  48. 48. Summary
  49. 49. References  Robbins & Cotran. Pathologic basis of disease; 7th ed.  Dorland’s medical dictionary; 30th ed  Harsh Mohan. Essential Pathology for Dental Students.; 3rd ed.  Henry Trowbridge. Inflammation A review of the process; 4th ed.
  50. 50. Contents  Fate of Acute Inflammation  Morphologic patterns of Acute Inflammation  Chronic Inflammation  SIRS & Sepsis  Anti-Inflammatory agents
  51. 51. Fate of Acute Inflammation
  52. 52. Fate of Acute Inflammation Abscess A localized collection of pus (suppurative inflammation) appearing in an acute or chronic infection, and associated with tissue destruction, and swelling. Pathogenesis: the necrotic tissue is surrounded by pyogenic membrane, which is formed by fibrin and help in localize the infection.
  53. 53. Abscess
  54. 54. Fate of Acute Inflammation Abscess Pathogenesis: the necrotic tissue is surrounded by pyogenic membrane, which is formed by fibrin and help in localize the infection.
  55. 55. Morphologic Patterns Serous Inflammation Inflammation of serous membrane characterized by clear fluid in serous cavity (pleural, peritoneal pericardial & synovial cavities) E.g. skin Blisters caused by Burns OR viral infection
  56. 56. Morphologic Patterns
  57. 57. Morphologic Patterns Fibrinous Inflammation Severe injury with excessive deposition of Fibrin in serous cavity Exudate and Fluid is removed by lymphatic Fibrinous exudate may be degraded by Fibrinolysis and removed by macrophage resulting in Resolution. Incomplete Removal of fibrin resulting in organization and scarring with Fibrous Adhesion of pleura OR pericardium.
  58. 58. Morphologic Patterns
  59. 59. Morphologic Patterns Suppuration (purulent ) Inflammation Large amount of Purulent exudates (pus) caused by pyogenic Bacteria staph aureus and Streptococcus pyogenes E.g Boil = Furuncle = Abscess of Hair follicles .
  60. 60. Morphologic Patterns Pseudomembraneous Inflammation Very severe ulcerative inflammation of mucous membranes Extensive Necrosis of surface epithelium Severe acute Inflammation of underlying tissue Pseudo membrane, consisting of exudate, fibrin, neutrophils RBC, Bacteria and tissue debris e.g. Diphtheria – Larynx . pseudomembraneous Colitis – clostridium difficile
  61. 61. Morphologic Patterns Pseudomembraneous Inflammation
  62. 62. Morphologic Patterns Ulceration An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing of inflammatory necrotic tissue Tissue necrosis and resultant inflammation exist on or near a surface e.g Gastric (peptic) ulcer
  63. 63. Chronic Inflammation  Inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously (Robbins 7th ed.)
  64. 64. Chronic Inflammation  Characterized by the following: Chronic inflammatory cell infiltration lymphocytes, plasma cells and macrophage Tissue destruction by Inflammatory cells Healing and Repair – involving New Blood Vesel proliferation (Angiogenesis) and Fibrosis
  65. 65. Chronic Inflammation Causes: Persistent infections Prolonged exposure to potentially toxic agents  Silica  silicosis  Toxic plasma lipid components  atherosclerosis Autoimmunity  Rheumatoid arthritis & LE
  66. 66. SIRS & Sepsis  Systemic inflammatory response syndrome (SIRS) is the clinical expression of the action of complex intrinsic mediators of the acute phase reaction.  SIRS can be precipitated by events such as infection, trauma, pancreatitis, and surgery.
  67. 67. SIRS & Sepsis
  68. 68. SIRS & Sepsis
  69. 69. SIRS & Sepsis  SIRS can compromise the function of various organ systems resulting in Multiple Organ Dysfunction Syndrome (MODS).  Clinicians should learn to identify SIRS in their patients at an early stage to determine the underlying cause and treatment before the SIRS progresses to a more severe form.
  70. 70. H1 Anti-histaminics  Blocks histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle  Blocks triple response  Suppresses manifestations of type I hypersensitivity reactions
  71. 71. Corticosteroids  Corticosteroids have an anti-inflammatory action – Hench et al (1949)  Average rate of cortisol secretion–15-20 mg/day  Increase in response to stress
  72. 72. Corticosteroids
  73. 73. Corticosteroids  Blocking the cleavage of arachidonic acid  inhibit PG synthesis  Stabilizes intracellular lysosome membranes  decreased release of mediators
  74. 74. Corticosteroids  Decreases permeability of capillary membranes & reduces amount of plasma lost  reduced amount of edema  Decreased migration of WBC in inflamed tissues  diminished phagocytosis
  75. 75. Corticosteroids  Primary effect – marked reduction in post- operative edema Therapeutic uses in OMFS:  Removal of impacted teeth (Beirne & Hollander)  Multiple extractions with alveoloplasty  Removal of tori  Apicoectomy
  76. 76. Corticosteroids  Orthognathic surgeries (Schaberg et al)  Rhinoplasty (Koopmann)  Management of TMJ disorders – intraarticular injection of corticosteroid provides relief of symptoms in acute osteoarthritis of TMJ  No more than 3 injections at a minimal interval of 1-3 months are recommended
  77. 77. NSAIDs  Peripheral acting analgesics  Anti-inflammatory, antipyretic and anti-thrombotic activity  Most effective when administered preoperatively or immediately postoperatively, before the effects of anesthesia have been reversed completely
  78. 78. NSAIDs  COX1 – present in platelets, stomach, kidney (cytoprotective to GIT)  COX 2– induced by cytokines & endotoxins at the site of inflammation  Newer NSAIDs safer because they are selective for COX-2
  79. 79. NSAIDs  NSAIDs – control postoperative pain  Corticosteroids – control postoperative edema  Combination provides best results, since NSAIDs potentiate the anti-inflammatory action of steroids Steroids add to the analgesic effect of NSAID
  80. 80. Leukotriene antagonists  Montelukast & Zafirlukast  Antagonize cysLT1 mediated bronchoconstriction, increased vascular permeability and recruitment of eosinophils  Indicated for prophylactic therapy of mild to moderate asthma
  81. 81. Omalizumab
  82. 82. Omalizumab  Does not bind to cell-bound IgE  Therefore, does not trigger cell activation by crosslinking of the IgE molecules on cell membranes.
  83. 83. Omalizumab
  84. 84. Omalizumab  Omalizumab reduces the allergen induced late asthmatic response, airway hyperresponsiveness and sputum eosinophilia  Reduces both asthma exacerbations and corticosteroid requirement  Agent may have a long-term anti- inflammatory effect
  85. 85. Enzymes as anti- inflammatory agents  Cleave the antigenic surface protein of organisms and digest their outer coat  Reduce number and activity of receptors for pathogen on host cells  Detoxify blood and remove viruses from circulation  Cause enhancement of immune cells to kill bacteria, viruses, molds and fungi
  86. 86. Enzymes as anti- inflammatory agents  Break down immune complexes which block the immune cells  Accelerate the volume and fluidity of blood flow  Bromelain modulate arachidonate pathway in such a way that thromboxane production is decreased with no effect on cyclooxygenase
  87. 87. Enzymes as anti- inflammatory agents  Powerful anti-oxidants and effectively combat the harmful free radicals such as nitric oxide  Block pro-inflammatory metabolites that propagate the inflammation  Possess anti-secretory and mucolytic qualities and decrease acute phase reactions
  88. 88. Serratiopeptidase  Proteolytic enzyme isolated from the non-pathogenic enterobacteria Serratia E15 found in silkworms  Acts upon inflammation by thinning the fluids in the body that collect around injured areas and increases fluid drainage
  89. 89. Serratiopeptidase  Enhances tissue repair and reduces pain  Ability to block the release of pain-inducing amines from inflamed tissues  Ability to dissolve dead and damaged tissue  Modifies cell-surface adhesion molecules
  90. 90. References  Robbins & Cotran. Pathologic basis of disease; 7th ed.  Harsh Mohan. Essential Pathology for Dental Students.; 3rd ed.  Henry Trowbridge. Inflammation A review of the process; 4th ed.  Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)  Laskin DM, Giglio JA. The use of steroids and NSAID in Oral and Maxillofacial Surgery. Oral and Maxillofacial Surgery Clinics of North America. 2001 Feb; 13(1): 31-41.
  91. 91. References  M. Soler et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics Eur Respir J 2001; 18: 254–261  G. Hanf et al. Omalizumab inhibits allergen challenge-induced nasal response. Eur Respir J 2004; 23: 414–418.  Shahid S . Role of Systemic Enzymes in Infections . WebmedCentral COMPLEMENTARY MEDICINE 2012;3(1):WMC002504  Chopra et al. A randomized, double-blind, placebo-controlled study comparing the efficacy and safety of paracetamol, serratiopeptidase, ibuprofen and betamethasone using the dental impaction pain model. Int. J. Oral Maxillofac. Surg. 2009; 38: 350–355