Acute Inflammation Lecture One & Two PDF

Dr. hanan abdulqader 1- To define inflammation, its types and causes 2- To have an idea about the cellular and tissue changes during and after inflammation 3- To correlate these changes to the clinical settings and the advantages and disadvantages of inflammation. 4- To predict the fate of inflamm...

Dr. hanan abdulqader 1- To define inflammation, its types and causes 2- To have an idea about the cellular and tissue changes during and after inflammation 3- To correlate these changes to the clinical settings and the advantages and disadvantages of inflammation. 4- To predict the fate of inflammation.  OBJ 1 Definition: Inflammation is a response of vascularized connective tissues to injury that brings cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents and limit the spread of injurious agents as well as to remove the consequent necrotic cells and tissues. Inflammation may be of two types, acute and chronic.  OBJ 1 So inflammation is a protective response 3 aims to 1- Get rid of the injurious agent, wall it off or dilute it to minimize its effect. 2- Remove the necrotic tissue. 3- Reconstruction of the damaged tissue either by the native parenchymal cells - the same cell type - (regeneration) or by filling the defect with a fibrous connective tissue (Scarring).  OBJ 1 Inflammation involves 2 basic processes : 1- inflammatory response. 2- healing process.  OBJ 1 1 The offending agent, which is located in extravascular tissues, is recognized by host cells and molecules. 2 Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located. 3 The leukocytes and proteins are activated and work together to destroy and eliminate the offending substance. 4 The reaction is controlled and terminated. 5 The damaged tissue is repaired.  OBJ 1 Infections & infestations (Bacteria, viruses, parasites). 2 Chemical & physical agents (Heat, cold, radiation, strong alkali or acids). Tissue necrosis from any cause. 4 Hypersensitivity Reactions anaphylaxis Ex  OBJ 1 + itis: Gastritis, appendicitis, tonsillitis With exceptions: Pneumonia, pleurisy OBJ 3  OBJ 1 Acute, sub-acute & chronic. 1-The acute inflammation is the immediate or early response to injury and is short lasting. The acute inflammation is characterized by exudation and neutrophils emigration. 2-The chronic inflammation is usually insidious and last for longer period. There is more tissue damage. The most abundant cells in the inflamed area are the lymphocytes and the macrophages and usually there is accompanying new blood vessels and connective tissue proliferation. 3- Subacute: Between the two  OBJ 3 1- Redness(rubor) 2- Swelling (tumor) 3- Heat (calor) 4- Pain(dolor) And last thing the fifth sign 5 - Loss of function  OBJ 1 1-Rapid onset 2- Short lasting ( minutes, hours, few days) 3- Represent the early body reaction. 4- The body response is mainly exudative 5- Usually followed by repair.  OBJ 2 Tissue changes in acute inflammation involve the following: 1- Vascular changes 2- Vascular leakage 3- Cellular events  OBJ 2 1- Vascular changes: BP A- Initial & transient vasoconstriction for few seconds. B- This is followed by vasodilitation and increased blood flow to the inflamed area, so it will look red BP and felt hot. C- Due to vascular dilatation there will be a leak of fluid and proteins from the vessels to the interstitial tissue and this will result in a local hemo- concentration that causes stasis of blood flow. Leakage and Slowdown: As the blood vessels get bigger, some of the uid (along with proteins) leaks out into the surrounding tissues. This can cause swelling. At the same time, the blood gets thicker because of the uid loss, and it ows more slowly in that area, causing a slowdown (or stasis) in blood ow. Ease's  OBJ 2 2- Vascular leakage or exudation Protein rich local edema is the hallmark of acute inflammation. Exudation results in swelling of the inflamed area. Exudate has some beneficial effects and involve the following: viii A- Dilution of toxins. B- Nutrition of the inflamed tissue. C- Fibrinogen also escapes outside the vessel and will form a mesh of fibrin that prevents the spread of bacteria away. D- Immuno-globulins in the exudates contribute to microbial killing or neutralization of their toxins. E- Lastly, this edema fluid will be drained to the regional lymph nodes carrying with it microbes or their toxins and there a proper immune response will be initiated.  1-Transient vasoconstriction of arterioles (few secs). 2-Vasodilatation of arterioles and then capillaries ,so lead to increase in blood flow (heat and redness). 3-Increased permeability of blood vessels---> exudation of protein –rich fluid into tissues ---> slowing of circulation 4-Concn of RBCs in small vessels and increased viscosity of blood = STASIS. they  Fluid flow across vessel walls is determined by 1 raise pressie the balance of hydrostatic pressure within the vessel and the difference in 2colloid osmotic pressure (proteincontent) between the plasma and interstitial fluid:- 1-Increase hydrostatic pressure ---> increase fluid flow out of vessel 2-Increase colloid osmotic pressure of interstitium ---> increase fluid flow out of vessel.  a Yes Acute inflammation more -arteriolar dilatation leads to increase in hydrostatic pressure. -increased permeability of vessel walls leads to loss of protein into interstitium. me t.EE Net flow of fluid out of vessel. E intissifEiry  hydrostyssure 1-Exudate: reeds A-Fluid loss in inflammation. B-high protein content. C-specific gravity above 1.02 2-Transudate: A-Fluid loss due to hydrostatic pressure the not mmention imbalance only (eg. venous outflow Obstruction) B-low protein content. C-specific gravity less than 1.012.  5ᵗʰ Oedema = excess of fluid in interstitium, can be transudate or exudate. Oedema leads to increased lymphatic drainage. Pus = a purulent exudate, rich in neutrophils and cell debris.  OBJ 2 3 - Cellular events: Leukocytes extravasation and phagocytosis. The fundamental function of inflammation is to deliver leukocytes to the site of injury. Leukocytes kill microbes, digest and remove the necrotic tissue but unfortunately they can promote inflammation and damage the tissue by their enzymes, chemical mediators and the toxic oxygen species. Leukocytes extravasation passes in stages:  OBJ 2 Leukocytes A- Margination, rolling and adhesion to the endothelial cells until the endothelium is lined by leukocytes. Such appearance is called pavementation. Stiffires the B- Transmigration: In this process the leukocytes squeeze themselves between the endothelial cells and traverse the basement membrane. C- Migration in the interstitial fluid and chemotaxis. Chemotaxis means a directional locomotion oriented 515 toward a chemical gradient of chemotaxins. towards of area highercongot The chemotaxins may be exogenous like bacterial products or endogenous like C5a, Leukotriene B4 and certain cytokines. D- Phagocytosis: Phagocytosis and enzyme released are the main benefits gained from leukocytes accumulation in the focus of inflammation. Phagocytosis is achieved in three stages: recognation exigent  OBJ 2 Recognition and attachment of the phagocyte (Neutrophil and macrophage) to the bacteria or other agents. This process is greatly facilitated by certain opsinins like the Fc fragment of IgG and C3b. When the IgG or C3b binds to the bacteria they also bind to the phagocytic cell through special receptors on the cell membrane of the phagocytes. However, phagocytic cells also have receptors to bacterial LPS (Lipopolysaccharides) and can engulf bacteria without the intervention of complement or Ig. The second stage is engulfment in which cytoplasmic pseudopods extend from the leukocyte to encircle the antigen until it is put in a phagocytic vacuole completely. antigen until it is  OBJ 2 ◦ The third stage is killing and degradation. Bacterial killing is greatly mediated by the toxic oxygen species after union of the phagocytic vacuole with the lysozome. Bacterial degradation takes place by the lysozomal enzymes. At this stage the phagocytes may release their enzymes outside the cell for example when there is failure of phagocytosis. This is called frustrated phagocytosis which occurs when the agent is present on a flat surface like the glomerular basement membrane. Another mechanism is the regurgitation during feeding before the complete closure of the phagocytic vacuole. Another possibility is that the phagocytes release their enzymes by exocytosis. All these three mechanisms can lead to tissue damage.  smile EEE 1-Stasis causes neutrophils to line up at the edge of blood vessels along the endothelium = MARGINATION. 2-Neutrophils then roll along endothelium, sticking to it intermittently = ROLLING. 3-Then stick more avidly = ADHESION. 4-Followed by EMIGRATION of neutrophils through blood vessel wall. OBJ 2 OBJ 2  1-Neutrophils migrate to site of injury under influence of chemotactic agents. ( chemotaxis = migration along a chemical gradient). lethocytes 2-Neutrophils phagocytose microorganisms. 3-Activated neutrophils may release toxic metabolites and enzymes causing damage to the host tissue.  A- EXUDATE (of FLUID) B- INFILTRATE (of CELLS) 1-Exudation of fluid Delivers plasma proteins to area of injury immunoglobulins inflammatory mediators fibrinogen Dilutes toxins Increases lymphatic drainage Delivers micro-organisms to phagocytes and antigens to immune system  94mm ftp.tEys at site 2.Infiltration of Cells: Removes pathogenic organisms, necrotic debris. 3.Vasodilatation: Increases delivery, increases temperature. 4.Pain and loss of function: Enforces rest, reduces chance of further traumatic damage.  1-Proteases (plasma proteins, produced in liver). A-Kinins (Bradykinin and Kallikrein). B-Complement system C3a, C5a. C-Coagulation / fibrinolytic system. 2-Prostaglandins / Leukotrienes. Metabolites of arachidonic acid. Synthesis blocked by NSAIDs, e.g. aspirin  3-Cytokines / chemokines (produced by wbc’s). Many and varied! Interleukins, PAF, TNF alpha, PDGF, TGF beta....WE the mate wants  1-From platelets: 5-HT, Histamine, ADP 2-From neutrophils: Lysosomal constituents. (Products released on neutrophil death) 3-From endothelium: Prostacyclin,Nitric oxide. 4-Plasminogen activators / inhibitors 5-Oxygen derived free radicals : a-Endothelial damage b-inactivation of antiproteases c-injury to other cells  Three phases: Phase I:Immediate early response (1/2 hr) A-HISTAMINE: -Released from mast cells, basophils and platelets. -In response to many stimuli: physical damage, immunologic reactions, C3a, C5a, IL1, factors from neutrophils and platelets. -----vascular dilatation. -----transient increase in vascular permeability. -----pain. -----Not chemotactic.  Not always seen. Due to direct damage to endothelial cells  1-Many and varied chemical mediators, interlinked and of varying importance. 2-Incompletely understood e.g. leukotrienes, bradykinin IMPORTANT because of possibility of therapeutic intervention.  1-Vascular dilatation: Histamine, prostaglandins, nitric oxide. 2-Increase in vascular permeability: Transient –Histamine. Bradykinin, leukotrienes C4, D4, E4. 3-Emigration of neutrophils: (chemotactant factors) C5a, leukotriene B4, Bacterial products particularly peptides with N-formylmethionine termini, Cytokines, especially those of the chemokine family.  1-Neutrophil adhesion and emigration due to binding of complementary adhesion molecules on endothelial and neutrophil surfaces. 2-Chemical mediators change surface expression or avidity of adhesion molecules: a-Selectins. b-Immunoglobulins. c-Integrins.  1-Recognition is facilitated by opsonins e.g. Fc and C3b receptors on phagocyte will recognise organisms coated with immuno- globulin or complement. 2-Phagosomes fuse with lysosomes to produce secondary lysosomes.  reactive oxygen species reactive oxygen intermediate lysosomal enzymes The killing of microbes and the destruction of ingested materials are accomplished by: 1-reactive oxygen species ROS, also called reactive oxygen intermediates. (O2dependent) 2-reactive nitrogen species, mainly derived from nitric oxide (NO). (O2dependent) 3-lysosomal enzymes. (O2 independent)  1-Swelling: Blockage of tubes, e.g. bile duct, intestine 2-Exudate: Compression e.g. cardiac tamponade Serositis. 3-Loss of fluid e.g. burns 4-Pain & loss of function especially if prolonged.  1-Fever -Endogenous pyrogens’ produced: IL1 and TNF. -Prostaglandins, aspirin etc reduce fever. 2-Leukocytosis –IL1 and TNF produce an accelerated release from marrow. –Macrophages, T lymphocytes produce colony- stimulating factors. –Bacterial infections -neutrophils, viral -lymphocytes. –Clinically useful. OBJ 2 OBJ 2  OBJ 3 1- Vasoactive amines: Like histamin (From mast cells) & Serotonin 2- Plasma proteins: Clotting system, kinin system, complement system 3- Arachidonic acid derivatives: Prostaglands & leukotrines 4- Platelet-activating factor 5- Cytokines 6- NO (EDRF) & Oxygen derived free radicals 7- Lysosomal constitutes  OBJ 3 nitrifide 1- Vasodilation: PGs & NO 2- Increased vascular permeability: Vasoactive amines, C3a & C5a, leukotrines, PAF WEEN 3- Chemotaxis & leukocytes adhesion: C5a, Chemokines 4- Fever: IL-1. IL-6 & TNF-α, PG 5- Pain: PGs & Bradykinin 6- Tissue damage: lysosomal enzymes, Oxygen metabolites & NO  OBJ 3 Now we understand the usefulness of inflammation, but inflammation also has some disadvantages: 1- There is partial or complete loss of function and this can be serious if a vital organ is inflamed like in myocarditis and encephalitis. 2- Exudation and swelling of the inflamed hallow organ can be serious because it leads to obstruction of the lumen for example laryngitis in children. It may lead to suffocation. 3- Increased tissue pressure especially in compact organs can press the vessels and lead to distal ischemia, further necrosis and more inflammation like in inflammation of the bones (osteomyelitis). 4- The inflammation may be inappropriate for example the hypersensitivity reactions to harmless or even useful agents or drugs.  1-Swelling: – Blockage of tubes, e.g. bile duct, intestine 2-Exudate: Compression e.g. cardiac tamponade Serositis. 3-Loss of fluid e.g. burns 4-Pain & loss of function especially if prolonged.  1-Fever -Endogenous pyrogens’ produced: IL1 and TNF. -Prostaglandins, aspirin etc reduce fever. 2-Leukocytosis –IL1 and TNF produce an accelerated release from marrow. –Macrophages, T lymphocytes produce colony- stimulating factors. –Bacterial infections -neutrophils, viral - lymphocytes. –Clinically useful.  Acute phase response Spread of micro-organisms and toxins SHOCK a clinical syndrome What may happen after the development of acute inflammation? 1-Complete resolution. 2-Continued acute inflammation with chronic inflammation; chronic suppuration. 3-Chronic inflammation and fibrous repair, probably with tissue regeneration. 4-Death.  OBJ 4 1- Complete resolution: If the injury is short lived and limited with minimal tissue destruction, the exudates will be drained by lymphatics and the dead tissue and cellular debris will be removed by the leukocytes. The dead cells are replaced through division of the adjacent surviving cells. The best examples are the complete resolutions in lobar pneumonia and the acute viral hepatitis.  OBJ 4 2- Suppuration: It means pus formation. Pus is a thick yellow creamy fluid composes of dead cells, dead & living bacteria, dead and living leukocytes all suspended in a protein rich exudates. The localized collection of pus is called abscess. The bacteria which cause pus formation are called pyogenic bacteria like Staphylococcus aureus and streptococcus pyogens.  OBJ 4 3- Healing by fibrosis: This occurs in (3) situations: A- When there is destruction of a substantial amount of tissue with low regenerative power. B- When there is excess exudation of fibirin, which cannot be removed by the leukocytes completely. The best example is pleurisy and peritonitis. Fibrin stimulates connective tissue formation (Fibrosis) and this will cause pleural adhesions or peritoneal adhesions. C- When the acute inflammation progresses into chronic inflammation 4- Failure of resolution and progression into chronic inflammation  1_ serous inflammation _ outpouring of fluid. 2_ fibrinous inflammation _ sever destructiin either resolution or organization. 3_ suppurative purulent inflammation abd abscess formation. 4_ ulceration LOBAR PNEUMONIA: Causative organism: Streptococcus pneumoniae (‘Pneumococcus’) Population at risk: Young adults in confined conditions, alcoholics. Clinical course: Worsening fever, prostration, hypoxaemia over few days. Dry cough. Fairly sudden. improvement (‘resolution by crisis’) when antibodies appear. Causes: heat, sunlight, chemical Predominant features: 1- PAIN 2- EXUDATE –Collection of fluid strips off overlying epithelium –more pain, more tissue damage. –Inflammatory cells relatively few: therefore exudate clear UNLESS bacterial infection develops. Solid tissues -Inflammatory exudate forces tissue apart -Liquefactive necrosis in centre - May cause high pressure therefore PAIN - May cause tissue damage - May squash adjacent structures Exudate pours into cavity - ascites, pleural or pericardial effusion - respiratory or cardiac impairment - Localized fibrin deposition ‘- bread and butter’ pericarditis