5..inflammation

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5..inflammation

  1. 1. Inflammation
  2. 2. Inflammation Response of the vascularized living tissue to injury. Purpose:  To defend against and to eliminate the injurious agent responsible for injury  Rid the tissue of the consequences of injury (necrotic cells ) and  To start healing and repair of injured tissue. 
  3. 3.  The suffix which indicates inflammation is "-itis"  Examples:       Appendix  appendicitis Pancreas  pancreatitis Meninges  meningitis Pericardium  pericarditis Stomach Brain -
  4. 4.  Inflammation and repair both can cause harm to the body.  Harmful effects of inflammation seen in: Severe infection Chronic infection Inadequate response Harmful effects of repair Formation of scars e.g Intestinal obstruction     
  5. 5. Do not get confused inflammation with infection !!!!
  6. 6. Stimuli for Acute Inflammation       Infections (bacterial, viral, fungal, parasitic) Trauma (blunt and penetrating) Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation) Tissue necrosis (from any cause), Foreign bodies (splinters, dirt, sutures) Immune reactions (also called hypersensitivity reactions) Each of these stimuli may induce reactions with some distinctive characteristics, but all inflammatory reactions have the same basic features.
  7. 7. Types of inflammation 1.    Acute: Short duration (minutes – days) Fluid and plasma protein (edema) Neutrophilic accumulation 2. Chronic:   Longer duration (days – years) Influx of lymphocytes & macrophages.
  8. 8. Acute Inflammation
  9. 9.      Acute inflammation is an immediate and early response to injury. Short duration: Minutes, hours, days. Purpose : To get the neutrophils to the site of injury. To clear the invading organism/agents and begin the process of healing.
  10. 10. Signs of acute inflammation
  11. 11. Five signs of acute inflammation 1. Rubor (redness) 2. Calor (heat) 3. Tumor (swelling) 4. Dolor (pain) 5. Functio lasea (loss of function)
  12. 12. Important components of acute inflammation 1. Vascular changes: 1. 2. 2. Cellular events: 1. 2. 3. Change in vessel caliber (vasodilatation) Structural changes: permit flow of plasma proteins = increased vascular permeability. Emigration of leucocytes Accumulation at the site of injury Chemical mediators
  13. 13. Vascular changes 1. 2. 3. 4. Initial transient vasoconstriction Massive vasodilatation mediated by histamine, bradykinin and prostaglandins. (heat and redness). Increased vascular permeability Blood flow slows (stasis) due to increased viscosity, allows neutrophils to marginate.
  14. 14. Increased vascular permeability  Arteriolar vasodilation and increased blood flow - rise in intravascular hydrostatic pressure, resulting in movement of fluid from capillaries into the tissues.  This fluid, called a Transudate, is essentially an ultrafiltrate of blood plasma and contains little protein.
  15. 15. Mechanism of increased vascular permeability. 1. 2. 3. 4. 5. Endothelial cell contraction and retraction Direct endothelial injury Leukocyte dependent endothelial injury Increased transcytosis Leakage from new blood vessels
  16. 16. Gaps due to endothelial contraction •the most common cause of increased vascular permeability. •elicited by histamine, bradykinin, •Endothelial cell contraction occurs rapidly after binding of mediators to specific receptors •usually short-lived (15-30 minutes)
  17. 17. Direct endothelial injury •usually seen after severe injuries (e.g., burns and some infections). •begins immediately after the injury and persists for several hours (or days •this reaction is known as the immediate sustained response. •Venules, capillaries, and arterioles can all be affected
  18. 18. Leukocyte dependent injury activated leukocytes release many toxic mediators that may cause endothelial injury or detachment.
  19. 19. Increased transcytosis
  20. 20. Cellular events 1. 2. 3. Leukocyte extravasation Chemotaxis and Phagocytosis
  21. 21. Sequence of events in the extravasation of leukocytes 1. Margination 2. Rolling 3. Adhesion 4. Transmigration (also called diapedesis)
  22. 22. Margination  Accumulation of leukocytes along the endothelial surface.
  23. 23. Rolling, adhesion and transmigration Mediated by binding of complementary adhesion molecules on leukocytes and endothelial surfaces
  24. 24. Adhesion molecules: 3 families  Selectins     Integrins     (E-Selectin) (L-Selectin) (P-Selectin). VLA-4 LFA-1 Mac-1 Immunoglobulins    ICAM-1 : intercellular adhesion molecule-1 VCAM-1: vascular cell adhesion molecule-1. PECAM-1: platelet endothelial cell adhesion molecule-1
  25. 25. Endothelial and leukocyte adhesion molecule pairs Endothelial Leukocyte molecule molecule P-selectin Sialyl-Lewis X Role Rolling E-selectin Sialyl-Lewis X Rolling GlyCam1/CD34 VCAM-1 L-Selectin Rolling VLA-4 integrin Adhesion ICAM-1 LFA-1 & MAC-1 Adhesion integrins PECAM-1 PECAM-1 transmigration
  26. 26. Rolling, adhesion and transmigration : The Steps involved 1. 2. 3. 4. 5. Endothelial activation Rolling Leukocyte activation Adhesion Transmigration
  27. 27. Step -1:Endothelial activation At the sites of inflammation, the endothelial cells have increased expression of:  E-selectin and  P-selectin. 
  28. 28. Normal endothelium Endothelial Activation E-Selectin P-Selectin
  29. 29. Step-2: Rolling  Neutrophils weakly bind to the endothelial selectins and roll along the surface.
  30. 30. Integrins (non-activated) Sialyl-Lewis X L-selectin
  31. 31. Rolling Sialyl-Lewis X L-Selectin L-Selectin ligand P-Selectin E-Selectin
  32. 32. Step 3: Leukocyte activation  Neutrophils are stimulated by chemotactic agents (chemokines and C5a ) to express their integrins.
  33. 33. Integrins (nonactivated) Activation of leukocytes (chemokines and C5a)
  34. 34. Step 4: Adhesion    Firm attachment of leukocytes to the endothelial surface. Is mediated by complementary adhesion molecules on the surface of neutrophils and endothelium. binding of the integrins firmly adheres the neutrophil to the endothelial cell.
  35. 35. Adhesion Activated integrins PECAM-1 L-selectin L-selectin ligand ICAM-1
  36. 36. Step-5: Transmigrations   Leukocytes emigrate from the vasculature by extending pseudopods between the endothelial cells Interaction of platelet endothelial cell adhesion molecule 1 (PECAM-1) on leukocytes and endothelial cells mediates transmigration between cells.
  37. 37. Transmigration
  38. 38. Chemotaxis   1. 2. 3. 4. Chemotaxis is the movement of cells toward a chemical mediator that is released in the area of inflammation. Important chemotactic factors for neutrophils Bacterial products Leukotrine B4 (LTB4) Complement system products (C5a) Chemokines (IL-8)
  39. 39. Phagocytosis  1. Three steps: Recognition and attachment 2. Engulfment with subsequent formation of a phagocytic vacuole. 3. Killing and degradation of the ingested material
  40. 40. Recognition and attachment    Facilitated by OPSONINS. Opsonins enhance recognition and phagocytosis of bacteria Important opsonins 1. 2. 3. IgG C3b Plasma protein – Collectins (bind to bacterial cell wall)
  41. 41. Engulfment  Binding of opsonised particle triggers engulfment.  Neutrophil sends out cytoplasmic processes that surround the bacteria.  The bacteria are internalized within a phagosome  The phagosome fuses with lysosome (phagolysosome).  Release of lysosomal contents (degranulation).
  42. 42. The final step in Phagocytosis of microbes is killing and degradation.
  43. 43. Intracellular killing 1. Oxygen dependent killing 2. Oxygen independent killing
  44. 44. Oxygen dependent killing    When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in oxygen consumption, called a respiratory burst, produces reactive oxygencontaining molecules that are anti-microbial. The oxygen compounds are toxic to both the invader and the cell itself, so they are kept in compartments inside the cell. This method of killing invading microbes by using the reactive oxygen-containing molecules is referred to as oxygen-dependent intracellular killing.
  45. 45. Oxygen dependent killing  Respiratory burst     Requires oxygen and NADPH oxidase Produce superoxide, hydroxyl radicals, and hydrogen peroxide. Myeloperoxidase The enzyme from neutrophil granules.   Requires hydrogen peroxide and Halide (CL-) Produces HOCL (hypochlorous acid)
  46. 46. Oxygen independent killing 1. Lysozyme 2. Lactoferrin 3. Hydrolytic enzymes. 4. Defensins
  47. 47.  Lysozymes, these enzymes break down the bacterial cell wall.  Lactoferrins, are present in neutrophil granules and remove essential iron from bacteria.  Hydrolytic enzymes these enzymes are used to digest the proteins of destroyed bacteria.  Defensin are host defense peptides which assists in killing phagocytosed bectaria.
  48. 48. frustrated phagocytosis  If cells encounter materials that cannot be easily ingested, such as immune complexes deposited on immovable flat surfaces (e.g., glomerular basement membrane), the attempt to phagocytose these substances is not successful.
  49. 49. Defects in leukocyte function
  50. 50. Defects in adhesion  Leukocyte adhesion deficiency      LAD-1 and LAD-2 Recurrent bacterial infections Diabetes mellitus Corticosteroid use Acute alcohol intoxication
  51. 51. Defects in phagocytosis  Chediak-Higashi syndrome     Autosomal recessive condition Neutropenia Neutrophils have giant lysosomes Defects in degranulation.
  52. 52.  Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein, which leads to a decrease in phagocytosis.  The decrease in phagocytosis results in recurrent pyogenic infections, peripheral neuropathy etc.
  53. 53. Outcome of acute inflammaton  Four outcomes: 1. Complete resolution with regeneration. 2. Complete resolution with scarring. 3. Abscess (localised collection of pus) 4. Transition to chronic inflammation.
  54. 54. Chemical Mediators
  55. 55. Chemical Mediators in Acute inflammation    Chemical mediators are responsible for these events. Mediators may be produced locally by cells at the site of inflammation or they may be circulating in the plasma (synthesized by the liver) as inactive precursors and activated at the site of inflammation
  56. 56. Chemical Mediators  Cell-derived mediators are stored in intracellular granules and are rapidly secreted on cellular activation (e.g., histamine in mast cells)  or are synthesized de novo in response to a stimulus (e.g., PGs and cytokines).
  57. 57. Chemical Mediators
  58. 58. Vasoactive amines  Histamine  Produced by basophils, platelets and mast cells  Effect: vasodilation and increased vascular permeability  Triggers for release:      IgE mediated mast cell reactions Physical injury Anaphylatoxins (C3a and C5a) Cytokines (IL-1) serotonin:  Produced by platelets  Effect : vasodilation and increased vascular permeability.
  59. 59. MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION
  60. 60. Serous inflammation  Is characterized by the outpouring of a watery, relatively protein-poor fluid that, derives either from the serum or from the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities.  The skin blister resulting from a burn or viral infection is a good example of a serous effusion accumulated either within or immediately beneath the epidermis of the skin. Fluid in a serous cavity is called an effusion. 
  61. 61. Fibrinous inflammation    Occurs in more severe injuries, resulting in greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial barrier. The reaction is most common in serosal surfaces, mucous membrane, and in the Lungs. Such as Rheumatic pericarditis, Dysentry, Pneumonia.
  62. 62. Fibrinous pericarditis: Gross and Microscopic views
  63. 63. Suppurative (purulent) inflammation    Is manifested by the presence of large amounts of purulent exudate (pus) consisting of neutrophils, necrotic cells, and edema fluid. Certain organisms (e.g., staphylococci) are more likely to induce such suppuration and are therefore referred to as pyogenic. Example : Abscess.
  64. 64. Hemorrhagic inflammation  Some infection e.g meningococcemia induced vascular damage followed by hemorrhage.
  65. 65. CHRONIC INFLAMMATION
  66. 66. CHRONIC INFLAMMATION  Of prolonged duration (weeks to months to years) in which active inflammation, tissue injury, and healing proceed simultaneously.  Is characterized by:    Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells. Tissue destruction, largely induced by the products of the inflammatory cells. Repair, involving new vessel proliferation (angiogenesis) and fibrosis.
  67. 67.  May progress to chronic inflammation when the acute response cannot be resolved, either because of the persistence of the injurious agent or because of interference with the normal process of healing.  For example, a peptic ulcer of the duodenum initially shows acute inflammation followed by the beginning stages of resolution. However, recurrent bouts of duodenal epithelial injury interrupt this process and result in a lesion characterized by both acute and chronic inflammation.  Alternatively, some forms of injury (e.g., viral infections) produce a response that involves chronic inflammation from the onset
  68. 68. Chronic inflammation arises in the following settings:  Persistent and difficult to eradicate infections : Mycobacteria, Treponema pallidum , and certain viruses and fungi, which initiate T lymphocyte-mediated immune response called delayed-type hypersensitivity  Immune-mediated inflammatory diseases (hypersensitivity diseases) due to excessive and inappropriate activation of the immune system  Autoimmune diseases  Allergic diseases, such as bronchial asthma  Prolonged exposure to potentially toxic agents (silicosis) and endogenous agents such as chronically elevated plasma lipid components (atherosclerosis )
  69. 69. Chronic Inflammatory Cells and Mediators  A fundamental feature of chronic inflammation is its persistence, and this results from complex interactions between the cells that are recruited to the site of inflammation and are activated at this site.  Understanding the pathogenesis of chronic inflammatory reactions requires an appreciation of these cells and their biologic responses and functions.
  70. 70. Macrophages  Dominant cells of chronic inflammation, circulating blood monocytes after their emigration from the bloodstream.  Macrophages are normally scattered in most connective tissues, and are also found in organs such as the liver (k/a Kupffer cells), spleen and lymph nodes (sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages).  In all tissues, macrophages act as filters for particulate matter, microbes, and senescent cells, as well as acting as guard to alert the specific components of the adaptive immune system (T and B lymphocytes) to injurious stimuli
  71. 71. Macrophages  When monocytes reach the extravascular tissue, they undergo transformation into larger macrophages, which have longer half-lives and a greater capacity for phagocytosis than do blood monocytes.  Macrophages may also become activated, resulting in increased cell size, increased content of lysosomal enzymes, more active metabolism, and greater ability to kill ingested organisms.
  72. 72. The roles of activated macrophages in chronic inflammation  When monocytes reach the extravascular tissue, they undergo transformation into larger macrophages, which have longer half-lives and a greater capacity for phagocytosis than do blood monocytes.  Macrophages are activated by bacterial endotoxin, ECM protein (Fibronectin) and Cytokines (IFN-γ) which is secreted by sensitized T lymphocyte.  After activation Macrophages secrets host of biologically active products which itself can result in tissue injury and Fibrosis, which is characteristic feature of Chronic inflammation.
  73. 73. Lymphocytes  Lymphocyte travels to the site of inflammation due to any specific immune stimulus (infections) as well as non-immune-mediated inflammation (e.g., due to tissue trauma).  Both T and B lymphocytes migrate into inflammatory sites.  Lymphocytes and macrophages interact in a bidirectional way, and these interactions play an important role in chronic inflammation.
  74. 74. Macrophage-lymphocyte interactions in chronic inflammation
  75. 75. Secretions of Macrophages  After activation, macrophages secrete:     Acid and neutral proteases. Other enzymes, such as plasminogen activator ROS and NO Cytokines such as IL-1 and TNF, as well as a variety of growth factors that influence the proliferation of smooth muscle cells and fibroblasts and the production of ECM.
  76. 76. Fate of Macrophages    After the initiating stimulus is eliminated and the inflammatory reaction completes, macrophages eventually die or wander off into lymphatics. In chronic inflammatory sites, however, macrophage accumulation persists, and macrophages can proliferate IFN-γ can also induce macrophages to fuse into large, multinucleated cells called giant cells.
  77. 77. Eosinophils  Characteristically found in inflammatory sites around parasitic infections or as part of immune reactions mediated by IgE, typically associated with allergies.  Eosinophil granules contain major basic protein, a highly charged cationic protein that is toxic to parasites but also causes epithelial cell necrosis.
  78. 78. Mast cells  Widely distributed in connective tissues and they participate in both acute and chronic inflammation.  Mast cells can also elaborate cytokines such as TNF and chemokines and may play a beneficial role in some infections.
  79. 79. Types of chronic inflammation  General chronic inflammation :   Active cellular proliferation occurs during healing process. Cells involved in this process are Macrophages, endothelium, epithelium and fibroblast.  In chronic condition lymphocyte and plasma cell are predominant .  Granulomatous Inflammation : Characterized by:     Aggregates of activated macrophages that assume an epithelioid appearance, Rimmed by lymphocytes, plasma cells and fibroblsts With or without central caseuos necrosis With or without presence of multinucleated cell.
  80. 80. Granulomatous Inflammation Infective granuloma :  Common in TB, Fungal infections, Syphillis, Leprosy.  TB granuloma consists of central caseous necrosis surrounded by epitheloid Macrophages, Giant cells, Lypmocytes and Fibroblast. Foreign body granuloma :  It is due to foreign bodies e.g Sutures, Splinters etc.
  81. 81. Inflammatory polyps :  They form in reaction to Ulceration or Irritation e.g Ulcerative collitis, Crohn’s disease. Inflammatory pseudo tumor :  They are pseudo tumor which consists of Lymphocytes , plasma cell, Histiocytes, Macrophages and Foam cell.
  82. 82. Granulomatous Inflammation
  83. 83. SUMMARY Of Chronic Inflammation  Features of Chronic Inflammation:  Prolonged host response to persistent stimulus.  Caused by microbes that resist elimination.  Characterized by coexisting inflammation, tissue injury, attempted repair by scar formation. Cellular infiltrate consists of macrophages, lymphocytes, plasma cells; fibrosis is often prominent   Mediated by cytokines (IL12) produced by macrophages and lymphocytes (notably T lymphocytes);  Bidirectional interactions between these cells tend to amplify and prolong the inflammatory reaction.
  84. 84. SYSTEMIC EFFECTS OF INFLAMMATION  Systemic effects of inflammation, collectively called the acute-phase reaction, or the systemic inflammatory response syndrome (SIRS)  Cytokines TNF, IL-1, and IL-6 are the most important mediators of the acute-phase reaction.
  85. 85. The acute-phase response consists of several clinical and pathologic changes  Fever, with elevation of body t°, usually by 1°to 4°C, is one of the most prominent manifestations of the acutephase response, especially when caused by infection.  Fever is produced in response to pyrogens that stimulates PG synthesis, in the vascular and perivascular cells of the hypothalamus.  Bacterial products, such as lipopolysaccharide (LPS; exogenous pyrogens), stimulate leukocytes to release IL-1 and TNF (endogenous pyrogens) that increase the levels of cyclooxygenases that convert AA into prostaglandins.
  86. 86. The acute-phase response consists of several clinical and pathologic changes  In the hypothalamus the PGs, especially PGE2, stimulate the production of neurotransmitters, which resets the temperature set point at a higher level.  NSAIDs, including aspirin , reduce fever by inhibiting cyclooxygenase and thus blocking PG synthesis  Concentrations of plasma levels of acute-phase proteins, mostly synthesized in the liver, may increase several 100-fold in response to inflammatory stimuli  Three acute phase proteins are: C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein.
  87. 87.  CRP and SAA, bind to microbial cell walls, and act as opsonins and fix complement, thus promoting the elimination of the microbes  Fibrinogen binds to RBCs and causes them to form stacks (rouleaux) that sediment more rapidly than individual erythrocytes  This is the basis for measuring the erythrocyte sedimentation rate (ESR) as a simple test for the systemic inflammatory response, caused by any number of stimuli, including LPS.
  88. 88.  Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infection.  Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia.  Viral infections, such as infectious mononucleosis, mumps, and German measles, are associated with increased numbers of lymphocytes (lymphocytosis).
  89. 89.  Bronchial asthma, hay fever, and parasite infestations all involve an increase in the absolute number of eosinophils, creating an eosinophilia  Certain infections (typhoid fever & infections caused by some viruses, rickettsiae, and certain protozoa) are paradoxically associated with a relatively decreased number of circulating white cells (relative leukopenia )
  90. 90.  Other manifestations of the acute-phase response include increased heart rate and blood pressure; decreased sweating, anorexia, and malaise  Chronic inflammation is associated with a wasting syndrome called cachexia, which is mainly the result of TNF-mediated appetite suppression and mobilization of fat stores  High levels of TNF cause disseminated intravascular coagulation (DIC), hypoglycemia.

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