Inflammation_ILA_2023_James Lyons.pptx

Inflammation ILA 2023 Dr. Lyons (2-hour ILA) Please see slide notes! Special Thanks To Dr. Alston For Major Contributions To This ILA Objectives • • • • • • • • • • • • Define and understand specific gravity Describe hydrostatic pressure and plasma oncotic pressure Describe the two main component...

Inflammation ILA 2023 Dr. Lyons (2-hour ILA) Please see slide notes! Special Thanks To Dr. Alston For Major Contributions To This ILA Objectives • • • • • • • • • • • • Define and understand specific gravity Describe hydrostatic pressure and plasma oncotic pressure Describe the two main components of inflammation Describe the cardinal features of inflammation Describe possible triggers of inflammation Compare and contrast acute and chronic inflammation Describe and recognize the different types of leukocytes involved in inflammation Describe the vascular changes in acute inflammation Describe edema Describe the effects of capillary hydrostatic pressure and plasma oncotic pressure on edema Describe the features of a transudate Describe the features of an exudate Objectives • Describe the steps of leukocyte recruitment to sites of inflammation • Describe leukocyte activation and phagocytosis • Describe the roles of the principal mediators of inflammation, particularly those mediators that cause pain, fever, and bronchospasm • Discuss possible outcomes of inflammation. • Discuss the roles of components of the inflammatory process including blood cells, vessels, mediators of inflammation • Give examples of diseases caused by acute and chronic inflammatory reactions • Describe possible systemic effects of inflammation • Describe morphologic patterns of inflammation Notes • Reference reading for ILA and IS, Robbins and Cotran Pathologic Basis of Disease, 10th ed., Chapter 3 • See slides in normal slide view to see notes. These will help with navigation of the slides. • Key Concepts slides from Robbins have been added to help studies and mastery. Use for both previews and reviews! • IS will emphasize clinical examples that will reinforce concepts and mechanisms. • Use these slides as guide for depth. • Note the organization of this discussion into topics and sections. This will be helpful in seeing the ”big picture”, organizing features and concepts, and helping with discussion and review. Specific Gravity • Specific gravity (SG) is the ratio of the weight (mass) of a solution compared to the weight (mass) of an equal volume of water • Specific gravity of pure water is 1.000 • More dense  higher specific gravity • Example: Maple syrup will have higher specific gravity than water SG > 1.000 SG = 1.000 Hydrostatic pressure • The pressure that a fluid exerts on the walls of its container • This pressure drives fluid out of the circulatory system • Remember that normal capillaries are semipermeable (there are junctions between endothelial lining cells) Plasma Oncotic Pressure • Also referred to as colloid osmotic pressure • Large plasma proteins like albumin cannot easily cross capillary walls • Albumin generates about 70-80% of the oncotic pressure in capillaries • Oncotic pressure pulls fluid into the circulatory system INFLAMMATION – BACKGROUND AND INTRODUCTION A Inflammation • The reaction of vascularized living tissue to local injury or invasion • Closely intertwined with the process of repair • Fundamentally a protective response but may sometimes harm host – without inflammation infections would go unchecked – wounds would not heal • Inflammatory response consists of 2 main components – A vascular reaction – A cellular reaction Inflammation Cardinal Features Signs - Latin Signs - English Associated “Cause” Rubor Redness Vasodilation, Stasis Tumor Swelling Edema, Cellular Infiltration Calor Warmth Vasodilation, Fever Dolor Pain Bradykinin, Prostaglandins (PGE2) Functio Laesa Loss of Function (may be permanent) Inflammation • May harm host – anaphylaxis – rheumatoid arthritis/autoimmunity – lupus • Triggers of inflammation include – infections – trauma – physical and chemical agents – foreign bodies – ischemia/necrosis from any cause – hypersensitivity reactions Inflammation • Acute – Rapid onset: minutes to hours – Short duration: minutes to days – Characteristics • Edema – excessive fluid within tissues or a body cavity • Emigration of leukocytes: mainly neutrophils • Chronic – Slower onset: days – Longer duration: days to years – Leukocytes typically include lymphocytes and macrophages – Often see proliferation of blood vessels, fibrosis, tissue necrosis – may see granulomas • • • • • Types of Leukocytes (White Blood Cells) Neutrophils Lymphocytes Eosinophils Monocytes Basophils Types of White Blood Cells –Junquiera’s Basic Histology 15th ed Table 12-2 Remember that monocytes are the circulating precursors of macrophages Types of White Blood Cells –Junquiera’s Basic Histology 15th ed Table 12-2 Diseases Caused By Inflammatory Reactions Acute Inflammation Components • Vascular changes • Cellular events/Leukocyte recruitment • Chemical mediators ACUTE INFLAMMATION – VASCULAR CHANGES Key Concepts Vascular Reactions in Acute Inflammation Vascular Changes Changes in Blood Vessels with inflammation include – Vasodilation (may occur after a transient vasoconstriction) – Increased permeability/Vascular Leakage – Stasis due to loss of fluid from vessels • Vessels become packed with cells • Flow within vessels slows Acute Inflammation Increased Vascular Permeability • Leads to escape of exudate (fluid with cells) into injured tissue • Blood remaining within vessels is concentrated (with increased viscosity) causing blood to flow slow (stasis) • Multiple mechanisms (See the following slide) –Formation of endothelial gaps in venules –Direct endothelial injury, resulting in endothelial cell necrosis and detachment –Leukocyte-mediated endothelial injury –Increased transcytosis –Leakage from new blood vessels See Figure Legend in notes Acute Inflammation – Mechanisms of Increased Vascular Permeability Endothelial cell contraction •Occurs only in venules •Endothelial cells “shorten”, leading to widening of interendothelial junctions. Exudate escapes through resultant gaps between endothelial cells. •Rapid, reversible, and short-lived (lasts 15-30 minutes). Thus known as “immediate, transient response” •Mediated by histamine, bradykinin, leukotrienes and other chemical mediators. Direct endothelial cell injury •Can involve arterioles, capillaries, venules •Direct damage to endothelial cells by certain injurious agents leads to necrosis and detachment from blood vessel wall. Huge gaps created. •Begins immediately and lasts until tissue is healed (can be long time). Thus known as “immediate, sustained” response. •Caused by burns, severe bacterial infections, chemicals/toxins. Leukocyte mediated endothelial injury •Occurs in venules, as well as pulmonary and glomerular capillaries. •During acute inflammation, leukocytes adhere to endothelial cells and, by doing so, become activated (see pages 4 and 6). Adherent, activated leukocytes release toxic substances (proteolytic enzymes and oxygen-derived free radicals) that cause endothelial injury and detachment of endothelial cells from inner wall of blood vessel. Gaps created. •Delayed onset, lasts for hours. Acute Inflammation – Mechanisms of Increased Vascular Permeability (continued) Increased transcytosis •Occurs in venules •Caused by increase in number and size of endothelial cytoplasmic channels. Allows more substances to travel from within blood stream to tissue space •Mediated by vascular endothelial growth factor (VEGF). Leakage from new blood vessels •As acutely inflamed tissue heals, new blood vessels form within the tissue (a process known as angiogenesis). The new, immature endothelial cells that line these new vessels are small, and thus do not come in contact with one another. This leads to many endothelial gaps, allowing exudate to escape. •This process stops once the endothelial cells mature and “grow up”. •Task – Add these concepts and aspects related to vascular permeability to consideration of transudate vs. exudate. Task – Add these concepts and aspects related to vascular permeability to consideration of transudate vs. exudate. Edema • A component of inflammation as a result of the above vascular processes. • Excessive fluid within tissues or a body cavity – Cells can also leak out of the vessels • Consistent feature of inflammation • Two types – Exudate – Transudate Transudate • It is a filtrate of plasma resulting from an abnormal increase in hydrostatic pressure or decrease in plasma oncotic pressure (or colloid osmotic pressure) • Not associated with increase in vascular permeability • Low protein content (< 3 gm/dL) • Specific gravity < 1.012 • Hypocellular Exudate • Also called inflammatory edema • Results from the increase in blood vessel permeability that is characteristic of inflammation • Contains the cellular and chemical mediators critical to inflammation • High protein content (> 3 gm/dL) • Specific gravity > 1.020 • Contains cellular debris • Pus is an exudate rich in neutrophils, the debris of dead cells, and often microbes Formation of exudates and transudates. A, Normal hydrostatic pressure (blue arrow) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrow) , which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. B, An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces. C, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. Inflammation and Repair Kumar, Vinay, MBBS, MD, FRCPath, Robbins and Cotran Pathologic Basis of Disease, Chapter 3, 69-111 Copyright © 2015 Copyright © 2015, 2010, 2004, 1999, 1994, 1989, 1984, 1979, 1974 by Saunders, an imprint of Elsevier Inc. ACUTE INFLAMMATION CELLULAR EVENTS/LEUKOCYTE RECRUITMENT Acute Inflammation Cellular Events Leukocytes • Expected – Adhesion and Transmigration – Go from lumen to and through vessel wall – Chemotaxis – Attracted to injury/offending agent – Leukocyte Recognition and Activation – Change to killing state – Phagocytosis/Killing - Results in elimination of offending agent – Termination – End of response • Undesired Aspects – Release of Leukocyte Products/Tissue Injury – Normal tissues can be injured Key Concepts Leukocyte Recruitment • ACUTE INFLAMMATION – NEUTROPHIL ARRIVAL AND FUNCTION Key Steps • • • • • • • Margination Rolling Activation Firm Adhesion Transmigration Chemotaxis Phagocytosis Leukocyte Adhesion • Attachment of leukocytes to endothelium is mediated by complementary adhesion molecules on leukocyte membranes and endothelial cells – Selectins (initial interactions) – Integrins (firm adherence) • When stasis occurs, leukocytes within the bloodstream move toward the inner (endothelial) wall of the blood vessel (called margination) • Rolling of leukocytes along the endothelial surface occurs due to loose binding of glycosylated ligands on the leukocytes, such as Sialyl-Lewis-X and PSGL1 (P-selectin glycoprotein ligand 1), to P-selectin and E-selectin on endothelial cells and L-selectin on other leukocytes • Chemokines from the inflamed tissue cause activation of leukocytes and their integrins • Firm adhesion of leukocytes, mediated by integrins, subsequently occurs Transmigration (AKA Diapedesis) • Occurs after leukocyte / endothelium adhesion • Leukocytes “squeeze” through endothelial gaps in venules, and into the tissues • Involves homophilic adhesion molecule CD31/PECAM-1 • The neutrophil is the predominant cell that transmigrates during acute inflammation Chemotaxis • Occurs after transmigration • Leukocytes emigrate, or move, within the tissue along an increasing chemoattractant gradient toward the site of injury. • Chemoattractant - the chemical mediators of chemotaxis – Exogenous - Originating from the source of inflammation, e.g. bacterial products – Endogenous - Produced by the injured host, e.g. complement components, leukotrienes, cytokines, PAF (platelet activating factor) The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process: selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, Intercellular adhesion molecule 1; PECAM-1 (CD31), platelet endothelial cell adhesion molecule-1; TNF, tumor necrosis factor. Inflammation and Repair Kumar, Vinay, MBBS, MD, FRCPath, Robbins and Cotran Pathologic Basis of Disease, Chapter 3, 69-111 Copyright © 2015 Copyright © 2015, 2010, 2004, 1999, 1994, 1989, 1984, 1979, 1974 by Saunders, an imprint of Elsevier Inc. ACUTE INFLAMMATION – LEUKOCYTE ACTIVATION AND REMOVAL OF OFFENDING AGENTS Key Concepts Leukocyte Activation and Removal of Offending Agents Leukocyte Activation • Stimulation of the leukocyte by chemoattractants to produce a variety of responses, of which 5 are essential – Production of arachidonic acid metabolites by the leukocyte – Degranulation and release of lysosomal enzymes – Activation of oxidative burst within the leukocyte – Secretion of cytokines by the leukocyte – Increase in binding affinity of adhesion molecules Phagocytosis • • • Recognition and attachment – Binding of microbe to phagocyte receptors • Mannose receptor • Scavenger receptors– bind modified LDL, variety of microbes • Opsonin receptors – for microbes coated w/opsonins Engulfment – Lysosomal digestion Killing and degradation – Oxygen-dependent • NADPH oxidase (and other oxidases) • Myeloperoxidase (H202-MPO-Halide system) – Oxygen-independent • Bactericidal permeability increasing protein • Lysozymes • Lactoferrin • Major basic protein Kumar, Vinay, MBBS, MD, FRCPath, Robbins and Cotran Pathologic Basis of Disease, Chapter 3 Copyright © 2015 ACUTE INFLAMMATION CHEMICAL MEDIATORS Chemical Mediators of Inflammation • General Principles – 1. Mediators originate from plasma or from cells – 2. Plasma mediators circulate in precursor form and must be activated enzymatically. – 3. Cellular mediators can be preformed and thus immediately available, or may be synthesized de novo from within the cell (takes time) – 4. Most mediators act by binding to specific receptors on target cells Chemical Mediators of Inflammation • General Principles – 5. Released mediators can bind to other mediatorcontaining cells causing a secondary wave of mediator release (Amplification) – 6. Mediators can act on one type of target cell, or a variety of different types – 7. Mediators are short-lived (usually seconds to minutes) – 8. Most mediators can have harmful effects (When inappropriate, not balanced, or deficient, injury can result) Key Concepts Actions of the Principal Mediators of Inflammation Types of Mediators One way to organize mediators • Cellular – Preformed – Histamine, Serotonin, Lysosomal enzymes – Newly synthesized – Arachidonic acid metabolites, platelet activating factor, free radicals, nitric oxide, cytokines • Plasma proteins/systems – Factor XII activation (clotting) • Kinin • Coagulation/fibrinolysis system – Complement • C3 and C5 cleavage • See Robbins Table 3-5 – Principal Mediators of Inflammation • See Robbins Table 3-8 – Principal Roles of Mediators In Inflammation IL-1 = interleukin-1; TNF= tumor necrosis factor. Mediator Example - Preformed • Vasoactive Amines – Histamine • Preformed, and thus immediately available • Primarily found within mast cells, which are inflammatory cells that reside within tissues, adjacent to blood vessels • Actions include dilatation of arterioles (increasing blood flow to injured area), increasing vascular permeability of the venules via endothelial cell contraction (“immediate transient response”), redistribution of P-selectin • Notorious for causing tissue damage – Serotonin - Within Platelet granules • Lysosomal Enzymes Newly Synthesized Mediators • Arachidonic Acid Metabolites (AA) – AKA eicosanoids – Produced by many cell types including leukocytes, platelets, endothelial cells – AA is normally bound to cell membrane phospholipids – Phospholipases that have been activated by inflammatory stimuli will release AA into cell cytoplasm (Steroids are antiinflammatory due to their ability to inhibit these phospholipases) – AA is then metabolized by 1 of 2 enzymatic pathways • Cyclooxygenase pathway • Lipoxygenase pathway • See Table 3-5 Arachidonic Acid Metabolism Cyclooxygenase pathway • Produces prostaglandins • Prostaglandins cause pain and fever (particularly PGE2 ) – PGI2 (prostacyclin) • Vasodilatation • Inhibits platelet aggregation. – Thromboxane A2 • Vasoconstriction • Promotes platelet aggregation – PGD2, PGE2, and PGE1 • Vasodilatation • Potentiate edema by enhancing vascular permeability effects of other mediators Lipoxygenase pathway • Generates leukotrienes and lipoxins – Leukotriene B4 • Chemoattractant (cell movement & leukocyte activation) – Leukotriene C4, D4 and E4 • Increase vascular permeability by endothelial cell contraction • Vasoconstriction • Bronchospasm (can be fatal) – Lipoxins A4 and B4 • Inhibit neutrophil chemotaxis and inhibit ability of neutrophil to adhere to endothelium Production of arachidonic acid metabolites and their roles in inflammation. Note the enzymatic activities whose inhibition through pharmacologic intervention blocks major pathways (denoted with a red X). COX-1, COX-2, Cyclooxygenase 1 and 2; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid. Inflammation and Repair Kumar, Vinay, MBBS, MD, FRCPath, Robbins and Cotran Pathologic Basis of Disease, Chapter 3, 69-111 Copyright © 2015 Copyright © 2015, 2010, 2004, 1999, 1994, 1989, 1984, 1979, 1974 by Saunders, an imprint of Elsevier Inc. Cytokines and Chemokines • Cytokines are proteins produced by cells that mediate/regulate immune/inflammatory reactions – e.g. TNF, IL-1 • Chemokines – are a type of cytokine which are small proteins that primarily act as chemoattractants for leukocytes – e.g. – C-X-C chemokines (neutrophils), C-C chemokines (monocytes, eosinophils, basophils, lymphocytes); also organize cell types in different anatomic regions Major roles of cytokines in acute inflammation. PDGF, Platelet-derived growth factor; PGE, prostaglandin E; PGI, prostaglandin I. Inflammation and Repair Kumar, Vinay, MBBS, MD, FRCPath, Robbins and Cotran Pathologic Basis of Disease, Chapter 3, 69-111 Copyright © 2015 Copyright © 2015, 2010, 2004, 1999, 1994, 1989, 1984, 1979, 1974 by Saunders, an imprint of Elsevier Inc. Plasma Proteins – Clotting • • • • • • Factor XII of the clotting system (Hageman Factor) - activated by contact with injured tissue, Kinin cascade • Produces Bradykinin – Increases vascular permeability (potent) – Major contributor to the pain that often accompanies inflammation • Produces Kallikrein – Activates Hageman Factor – Produces more bradykinin Clotting Cascade – Produces Thrombin – Binding induces several responses resulting in inflammation Complement – Produces Complement Cleavage Products • C3a, C5a and C4a (lesser extent) - vasodilatation/increased vascular permeability (mast cells) • C5a - potent chemoattractant – stimulates chemotactic movement of leukocytes and activation • C3b - opsonin, thereby enhancing phagocytosis by leukocytes Fibrinolytic Pathways – Produces Plasmin • Cleaves C3 • Fibrin Split Products – Increases vascular permeability • Activation of Hageman Factor See Figure 3-12 Termination • Mediators are often short-lived • Active mechanisms which stop processes • Other mechanisms CHRONIC INFLAMMATION Key Concepts Chronic Inflammation Chronic Inflammation • Prolonged Duration (weeks or months) • Inflammation by mononuclear cells (macrophages, lymphocytes, plasma cells), tissue injury, attempts at repair (fibrosis) • Tissue destruction by cells and offending agents occur • Healing is by fibrosis/scar formation • Important in many varied diseases – rheumatoid arthritis, atherosclerosis, cancer, Alzheimer disease • Can result in granulomatous inflammation Chronic Inflammation - Stimuli • Persistent infections – mycobacteria, viruses, fungi • Immune-mediated diseases – Autoimmune diseases (Lupus, Multiple Sclerosis, Rheumatoid arthritis, Sarcoidosis) • Prolonged Exposure to potentially toxic agents – endogenous or exogenous - Silicosis Chronic Inflammation • Cells – MACROPHAGES! – LYMPHOCYTES (B and T) – Plasma Cells – Eosinophils – Often seen in immune reactions mediated by IgE and in parasitic infections – Mast Cells – Have receptors that bind IgE • Often organized into granulomas • Necrosis is sometimes present – Present in TB – Not present in Sarcoidosis Typical tuberculous granuloma showing an area of central necrosis surrounded by multiple Langhans-type giant cells, epithelioid cells, and lymphocytes. Inflammation and Repair Kumar, Vinay, MBBS, MD, FRCPath, Robbins and Cotran Pathologic Basis of Disease, Chapter 3, 69-111 Copyright © 2015 Copyright © 2015, 2010, 2004, 1999, 1994, 1989, 1984, 1979, 1974 by Saunders, an imprint of Elsevier Inc. Outcomes of Inflammation SYSTEMIC EFFECTS OF INFLAMMATION Key Concepts Systemic Effects of Inflammation Systemic Effects Cytokines (e.g. TNF, IL-6, and IL-1) can induce systemic effects, acute phase reactions. – Fever – Production of acute-phase proteins (usually by liver) • C-reactive protein • Fibrinogen • Serum Amyloid A – Leukocytosis (Increase in a WBC population) • Neutrophilia (e.g. with acute bacterial infections) • Lymphocytosis (e.g. with viral infections) • Eosinophilia (e.g. with allergic reactions, parasites) – Leukopenia (decrease in WBC) – Other • Heart rate and BP increases • Decreased sweating • Shivering/rigors • Anorexia, somnolence, malaise – Sepsis • Shock • Disseminated Intravascular Coagulation (DIC) • Metabolic disturbances (hyperglycemia, insulin resistance) IS – CLINICAL EXAMPLES/PATTERNS Morphologic Patterns Key Concepts - Add Summaries • Cells (Fig 3-6) – Neutrophils early – Monocytes/macrophages later • Patterns – Serous Inflammation – Fibrinous inflammation – Suppurative or Purulent Inflammation – Ulcers Use your textbook and a medical dictionary. Serous Inflammation • Inflammation characterized by exudation of cell poor fluid into spaces created by a body injury (e.g. skin blister) or into body cavities lined by the peritoneum, pleura, or pericardium Fibrinous Pericarditis Inflammation that is typically characterized by significantly increased vascular permeability, which allows large molecules such as fibrinogen pass out of the blood. Fibrin is then formed from fibrinogen and deposited in the extracellular space. May be seen in the lining of body cavities, such as the meninges, pericardium, and pleura. Purulent Inflammation Inflammation that is characterized by the formation of pus (an exudate consisting of neutrophils, liquefied cells, and edema fluid). Usually caused by bacterial infections. An abscess is a localized collection of pus Ulcer An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue. Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. It is most common in the mucosa of the mouth, stomach, intestines, or genitourinary tract, and in the skin and subcutaneous tissue Leukocytosis • Definition – white blood cell count is elevated above the normal range in the blood • Examples – Neutrophilia – elevated number of neutrophils – Lymphocytosis – elevated number of lymphocytes – Eosinophilia – elevated number of eosinophils Defects in Leukocyte Functioning • Adhesion – Genetic deficiencies in leukocyte adhesion molecules • Phagolysosome – Chediak-Higashi – Reduced transfer of lysosomal enzymes to phagocytic vesicles • Microbiocidal activity – Chronic granulomatous disease – Deficient NADPH oxidase mutations (superoxide production) • Bone marrow suppression – Chemotherapy, metastatic cancer