INFLAMMATION & CHEMICAL MEDIATORS-2.pptx

DR MA OBIO FMCPath CONTENTS 1. INFLAMMATION: OUTLINE 2. INTRODUCTION 3. ACUTE INFLAMMATION 4. SEQUENCE OF EVENTS IN ACUTE INFLAMMATION 5. MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION 6. OUTCOME OF ACUTE INFLAMMATION 7. CHRONIC INFLAMMATION 8. GRANULOMATOUS INFLAMMATION 9. CHEMICA...

DR MA OBIO FMCPath CONTENTS 1. INFLAMMATION: OUTLINE 2. INTRODUCTION 3. ACUTE INFLAMMATION 4. SEQUENCE OF EVENTS IN ACUTE INFLAMMATION 5. MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION 6. OUTCOME OF ACUTE INFLAMMATION 7. CHRONIC INFLAMMATION 8. GRANULOMATOUS INFLAMMATION 9. CHEMICAL MEDIATORS OF INFLAMMATION LEARNING OBJECTIVES i. Be able to define the term inflammation ii. Understand the cardinal signs, causes and the sequence of events of acute inflammation iii. Be able to differentiate between acute and chronic inflammation iv. Learn the outcome of an acute inflammatory reaction v. Know the morphologic patterns of acute inflammation vi. Understand the term chronic and granulomatous inflammation vii. Know the chemical mediators involved in inflammation INTRODUCTION Inflammation is a complex local response of the living vascularized tissues to injury. Usually a protective beneficial response: Acts by localizing the cause of the injury. A times it may be harmful as in the destruction of the joints in septic arthritis, hypersensitivity reactions & auto-immune diseases. Types: Acute or Chronic Cardinal signs of inflammation This was first described by Aulus Cornelius Celsus as: Rubor.----- -Redness Tumor.----- Swelling Calor.------- Heat Dolor. -------Pain Functio laesa. ---- Loss of function. This fifth clinical sign was added by Rudolf Virchow ACUTE INFLAMMATION Causes Infections & microbial toxins Physical agents Chemical agents Ischaemia with tissue necrosis Immune reactions Foreign bodies Components 1. Blood vessels & plasma 2. Circulating cells: Neutrophils, eosinophil's, monocytes, lymphocytes, basophils, platelets & mast cells 3. Extracellular matrix proteins: Collagen, fibronectin, laminin & others SEQUENCE OF EVENTS IN ACUTE INFLAMMATION There are 2 major components of acute inflammation: 1. Vascular changes (Reaction of blood vessels). 2. Cellular changes (Reaction of Leukocytes) VASCULAR EVENTS Purpose: Reactive changes in the blood vessels deliver the circulating cells, fluid & plasma proteins from the blood circulation to the site of tissue injury e.g. site of infection CHANGES IN THE BLOOD VESSELS 1. Changes in vascular flow & caliber (Hemodynamic changes). 2. Increased vascular permeability. SEQUENCE OF EVENTS IN ACUTE INFLAMMATION 1. Vascular changes (Reaction of blood vessels). 2. Cellular changes (Reaction of Leukocytes). A.VASCULAR EVENTS : CHANGES IN THE BLOOD VESSELS i. Hemodynamic changes ii. Increased vascular permeability. Iii. Changes in vascular flow & caliber B.Cellular changes i. Leukocyte recruitment/Extravasation a. In the vascular lumen b. Across the vessel wall & endothelium c. Outside the vessel wall ii. Leukocyte activation Changes in vascular flow & caliber. 1. Vasodilatation & increased blood flow. The earliest change seen in acute inflammation is the dilatation of the arterioles at the injury site. The vasodilatation results in increased blood flow & is responsible for the local heat (Calor) & redness (Rubor). 2. Increased vascular permeability. Vasodilatation is followed by increased permeability of the microvasculature. (Arterioles, capillaries, Venules). Increased vascular permeability leads to escape of protein-rich fluid from the blood circulation into the extravascular tissues leading to edema. 3. Slowing of blood flow. The loss of fluid along with vasodilatation results in slowing of blood flow & the concentration of RBCs in small vessels. 4. Stasis. In the dilated small vessels with slowed blood flow, the slow moving RBCs get packed known as stasis responsible, for the localized redness (Rubor). 5. Reaction of leukocytes (Leukocyte events). Delivery of leukocytes capable of phagocytosis (Neutrophils & macrophages) to the site of injury, can be divided into leukocyte recruitment & leukocyte activation. Leukocyte recruitment/Extravasation Normally, leukocytes move rapidly in the blood but in inflammation, they slow down & escape to the site of the injury in the extravascular space. Thus leukocyte extravasation is the process of migration of the leukocytes from the lumen of the vessels to the site of injury in the extravascular tissues. Steps in leukocyte recruitment/extravasation A. In the vascular lumen: a. Margination: Is due to stasis of blood, leukocytes (Mainly neutrophils) move towards the peripheral column & accumulate along the endothelial surface of the vessels. b. Rolling & Pavementing: Marginated leukocytes attach weakly (Selectins)to the endothelium, detach & bind again with a mild jumping movement causing a kind of rolling movement of the leukocytes on the endothelial surface of the vessels c. Adhesion of leukocytes to the endothelium: The endothelium gets activated & the leukocytes bind more firmly (Integrins) B. Across the vessel wall & endothelium: 1. Transmigration or diapedesis: Leukocytes migrate through the vessel wall by squeezing through the intercellular junction between the endothelial cells 2. Migration across the basement membrane: Leukocytes penetrate the basement membrane of the vessel. C. Outside the vessel wall 1. Chemotaxis: Process of migration of leukocytes toward the inflammatory stimulus in the direction of the gradient of locally produced chemoattractants. These are chemicals which attract leukocytes to the site of the injury & can be either endogenous or exogenous. 2. Accumulation of leukocytes at the site of infection or injury. LEUKOCYTE ACTIVATION 1. Activation of leukocytes: The recognition of microbes or dead cells by leukocytes initiates several responses in the leukocytes known as leukocyte activation. The most important of these are phagocytosis & intracellular killing. 2. Phagocytosis & clearance of the stimuli (Offending agent). Many leukocytes recognize, internalize & digest foreign material, micro-organisms or cellular debris by the 1. Recognition & attachment 2. Engulfment: Formation of phagocytic vacuole. Cytoplasmic extensions of the leukocyte forms pseudopods that surrounds the particle to be ingested to form a vesicle or vacuole called the phagosome. The membrane of the phagosome fuses with the membrane of lysosomes to form a phagolysosome. The granules in the lysosomes of the leukocytes are discharged into the phagolysosome. 3. Killing & degradation of the ingested material: Takes place within neutrophils & macrophages, & the microbicidal agents are the reactive oxygen species. (Microbial killing is mainly performed by free radicals generated by the reactive oxygen species (ROS) The ROS generated by H202-MPO-Halide system is the most efficient bactericidal system of neutrophils. The enzyme myeloperoxidase (MPO) present in the neutrophils converts weak ROS into powerful ROS. Examples of ROS are: 1. Superoxide ion (One electron)---Weak 2. Hydrogen peroxide(Two electrons)----Weak 3. Hydrogen peroxide(Three electrons)----Highly reactive 4. Others are the ROS derived from nitric oxide (NO) & lysosomal enzymes. DEFECTS IN THE FUNCTIONIG OF LEUKOCYTES 1. Reduced number of leukocytes-Radiation, chemotherapy, bone marrow aplasia 2. Defective adhesion----Deficiency of adhesion molecules, diabetes, chronic alcoholism, corticosteroids, long term hemodialysis 3. Defective migration----Microtubular dysfunction, Chediak-Higashi syndrome 4. Defective chemotaxis & locomotion----Deficiency of chemoattractants, microtubular dysfunction, drugs like colchicine 5. Defective opsonization---- Deficiency of opsonin's 6. Defective killing----Deficiency of myeloperoxidase, lactoferrin, lysozyme, G6PD, chronic granulomatous disease of childhood(X-linked disease with deficiency of oxidase) 7. Mixed defects----Malnutrition, DM, anaemia, neonates, elderly, sepsis, chediak-Higashi syndrome MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION 1. Serous inflammation: Characterized by marked outpouring of thin serous fluid. Accumulation of serous fluid in serous cavities (Peritoneal, pleural, pericardial) is called an effusion. A serous effusion has a yellow, straw-like colour Microscopically shows no or few cells. Example is pleural effusion as a complication of lobar pneumonia. 2. Fibrinous inflammation. The exudate is rich in fibrin called Fibrinous exudate. It develops when the vascular leakage allows exudation of fibrinogen from the blood which is then converted to fibrin. Example: Fibrinous pericarditis seen in rheumatic fever. (Classically called “Bread & Butter” pericarditis).  MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION Morphologic Features Examples pattern Serous Outpouring of thin watery fluid Blisters in burns, ascites, pleural effusions Fibrinous Deposition of fibrin Pericarditis, pleuritis, pneumococcal & staphylococcal infections Serofibrinous Serous exudation with fibrin debri Rheumatic pericarditis (Bread & Butter type) Catarrhal Outpouring of mucinous material Common cold Suppurative Accummulation of purulent material (Pus) Abscesses, Carbuncles Haemorrhagic Vascular damage Influenza, Klebsiella infections Membranous Deposition of a true membranous Membranous bronchitis or structure colitis Pseudomembranou Deposition of a fibrinous membrane-like Pseudomembranous colitis )C. material difficile) s Gangrenous Necrosis with putrefaction Sepsis, C. perfringens Ulcer Local defect in mucosa Acute peptic ulcers, stress ulcers  Suppurative (Purulent) Inflammation: Characterized by the production of large amounts of pus or purulent exudate. An example is Suppurative appendicitis. Another example is an Abscess defined as the localized collection of pus. It consist of a cavity containing pus formed by liquefactive necrosis & inflammatory cells in a solid tissue. Pus consist of liquefied necrotic cell debris, dead leukocytes & macrophages (Called scavenger cells) Abscess shows a cavity containing pus & surrounding wall with granulation tissue & inflammatory cells. Note that an ulcer is a local defect or excavation of the surface of an organ or tissue, commonly seen in the mucosa of the mouth, stomach, intestines or the genitourinary tract. A typical example is peptic ulcer of the stomach or duodenum OUTCOMES OF ACUTE INFLAMMATION 1. Complete resolution: To normal tissue structure & function following inflammation. 2. Organization of exudates(Healing by scarring): The process of replacement of the dead tissue by living connective tissue which matures to form a scar tissue known as organization 3. Progression to chronic inflammation One of the complications is Abscess formation. CHRONIC INFLAMMATION Defined as inflammation of a prolonged duration in which inflammation, tissue damage & healing occurs at the same time. It may develop when acute inflammation does not resolve or begin insidiously (Gradual) as a low grade inflammatory reaction. It can result in disabling tissue damage like in tuberculosis, Atherosclerosis, Rheumatoid arthritis. Causes of chronic inflammation. 1. Persistent infection by microbes that are difficult to eradicate e.g. mycobacteria 2. Immune mediated inflammatory disease. Caused by abnormal activation of the immune system such as autoimmune diseases & allergic reactions. 3. Prolonged exposure to potentially toxic agents. When a toxic agent (Endogenous or Exogenous) cannot be degraded, it may result to chronic inflammation such as silicosis caused by the inhalation of silica particles that are not degradable. Morphologic features of chronic inflammation Chronic inflammation is characterized by the following: 1. Mononuclear cellular infiltrate: Macrophages, lymphocytes, plasma cells. 2. Tissue destruction: Results from the persistence of the injurious agent or the inflammatory cells. 3. Healing by fibrosis: Tissue destruction is accompanied by an attempt to heal thus the damaged tissue is replaced by granulation tissue which later leads to fibrosis. GRANULOMATOUS INFLAMMATION This is a distinctive type of chronic inflammation & the microscopic feature is the presence of a granuloma. Granuloma: Defined as a distinctive type of chronic inflammation characterized by microscopic aggregation of macrophages that are transformed into epithelium-like (Epithelioid cells), surrounded by lymphocytes & occasional plasma cells. Older granulomas have additional rim of fibroblasts & connective tissue at the outermost layer. Components of a granuloma 1. Epitheliod cells: These are modified macrophages resembling epithelial cells. They have pink granular cytoplasm with indistinct borders, often appearing to merge into one another. The nucleus is oval or elongated & may show folding of the nuclear membrane. 2. Giant cells: Epitheliod cells fuse to form giant cells found in the periphery or at the center of granulomas. They usually have more than one nucleus which may reach up to 20 or more arranged either peripherally (Langhans-type giant cell) or haphazardly (Foreign body-type giant cell) Types of granuloma (According to pathogenesis) 1. Foreign body granulomas: Caused by inert foreign bodies like suture materials & talc. 2. Immune granulomas: Caused by poorly degradable or particulate agents which can induce cell-mediated immune response as with Mycobacterium tuberculosis infection. CHEMICAL MEDIATORS OF INFLAMMATION These are a group of substances released endogenously & act at various levels of vascular & cellular events of inflammation The general features are: Synthesized by cells & plasma Short duration of action Acts through the specific receptors on the cells Can act on the same cell which has produced it (Autocrine) May have harmful effects Classification: Generally into cell derived & plasma derived mediators Cell derived: Categorized into preformed & newly synthesized mediators Preformed cell derived Histamine Serotonin Lysosomal enzymes( Myeloperoxidase, acid hydrolases, elastase, neutral proteases, lactoferrin, defensin, collagenases) Newly synthesized cell derived i. Prostaglandins ii. Leukotrienes iii. Platelet activating factor iv. Cytokines (Interleukin-1, 8, Tumour necrosis factor TNF, Interleukin gamma v. Free oxygen radicals (Superoxide, hydrogen peroxide, singlet oxygen, hydroxyl ion, hypochlorite ion) vi. Nitric oxide Plasma derived mediators Complement system(C3a,C4a,C5a, C3b, C5b-9 Coagulation cascade (Fibrinopeptides) Fibrinolytic system (Fibrin split products) Kinnins (kallikrein, Bradykinin) Arachidonic Acid (Cyclo-oxygenase pathway) ----Prostacyclin, thromboxane, prostaglandins D2, E2 & F2 alpha Arachidonic Acid (lipo-oxygenase pathway) ----Leukotriene A4, B4, C4, D4 & E4