Robbins Pathology Chapter 3 PDF

CHAPTER 3: INFLAMMATION AND REPAIR Acute and chronic - Acute inflammation – initial, rapid response to inflammat...

CHAPTER 3: INFLAMMATION AND REPAIR Acute and chronic - Acute inflammation – initial, rapid response to inflammation infection and tissue damage; develops w/in minutes or hours OVERVIEW OF INFLAMMATION: DEFINITION & GENERAL FEATURES o Short duration; last for hours to days o Main characteristic: exudation of fluid  Inflammation is a response of vascularized tissues to infections and and plasma proteins (edema) and damaged tissues that brings cells and molecules of host defense from the emigration of leukocytes (mostly circulation to the sites where they are needed, in order to eliminate the neutrophils) offending agents o May progress to chronic inflammation if  Inflammation is a protective response essential for survival stimulus is not cleared - Chronic inflammation – longer duration; asso. w/ o Rid the host of both the initial cause of cell injury and the consequences of more tissue destruction, presence of lymphocytes and such injury macrophage, proliferation of blood vessels, and o Meidators includes: WBC, antibodies, complement proteins deposition of connective tissue  Innate immunity – serve as the first responders to infection - Innate immunity – acute inflammation o NK cells, dendritic cells, epithelial cells, soluble factors (complement system) - Adaptive immunity – chronic inflammation o Also eliminate damaged cells and foreign bodies Termination of - Inflammation is terminated when agent is eliminated  Steps of inflammatory reaction: inflammation and - Reaction resolves because mediators are broken down initiation of tissue repair and dissipated and WBC have short life span in tissues  Offending agent in extravascular tissue is recognized by host cells - Anti-inflammatory mechanisms are activated  control andmolecules the response and prevent it from causing excessive  WBCs and plasma proteins are recruited from the circulation to the site damage to the host where the agent is located - After agents have eliminated  proceed to tissue  WBC and proteins are activated and work together to destroy and eliminate repair the offending substance - Regeneration – replacement of injured tissue  Reaction is controlled and terminated - Scarring – filling of residual defects  Damaged tissue is repaired  Fundamental properties of inflammatory response: Disorders Cells and Molecules Involved in Injury ACUTE Components of the - Major participants in the inflammatory reaction: blood Acute respiratory Neutrophils inflammatory response vessels and leukocytes distress syndrome - Blood vessels dilate to ↓ blood flow; and ↑ permeability Asthma Eosinophils; IgE antibodies to enable selected protein to enter the site of infection Glomerulonephritis Antibodies and complement; neutrophils, monocytes - Activated WBC ingest and destroy microbes and dead cells, foreign bodies and unwanted materials in the Septic shock Cytokines tissues CHRONIC Harmful consequences - Inflammation may contribute to diseases thought to Arthritis Lymphocytes, macrophages, antibodies of inflammation be primarily metabolic, degenerative, or genetic Asthma Eosinophils, IgE antibodies disorders (DM2, Alzheimer dx, cancer) Atherosclerosis Macrophages; lymphocytes - Wide-ranging harmful consequences of inflammation Pulmonary fibrosis Macrophages; fibroblasts  “the silent killer” Local and systemic - Reaction is largely confined to the site of infection or inflammation damage Feature Acute Chronic - Some disseminated bacterial infections, inflammatory Onset Fast: minutes or hours Slow: days reaction is systemic and cause wide pathologic Cellular filtrate Mainly neutrophils Monocytes/Macrophages & abnormalities  “sepsis” (one form of “systemic lymphocytes inflammatory response syndrome”) Tissue Injury; fibrosis Usually mild and self-limited Often severe and progressive Mediators of - Vascular and cellular reactions of inflammation are Local and systemic signs Prominent Less inflammation triggered by soluble factors produced by various cells or from plasma proteins - Microbes, necrotic cells, hypoxia  also trigger inflammatory mediators and cause inflammation - Mediators initiate and amplify the pattern, severity, and clinical and pathologic manifestations abmrmtmd Causes of Inflammation o Uric acid (product of DNA breakdown) o ATP (released from damaged mitochondria)  Inflammatory reactions may be triggered by a variety of stimuli: o Reduced intracellular K+ concentrations (reflecting loss of ions because of plasma Infections - Bacterial, viral, fungal, parasitic membrane injury) - Most common and medically important causes of inflammation o DNA released in cytoplasm - May be acute or chronic - These receptors activate inflammasome (multiprotein - Outcomes are determined largely by the type of pathogen and cytosolic complex)  produces IL-1  recruits WBC  cx of the host induce inflammation - Autoinflammatory syndrome – caused by gain-of- Tissue necrosis - Elicits inflammation regardless of the cause of cell death: function mutations in the sensor; characterized by ischemia, trauma, physical and chemical injury spontaneous inflammation - Some molecules released from necrotic cells are known to o Treatment: IL-1 antagonist trigger inflammation - Inflammasome has also been implicated in inflammatory Foreign bodies - Splinters, dirt, sutures reactions to: - Elicit inflammation by themselves because they cause traumatic o Urate crystals (gout) tissue injury or carry microbes o Lipids (metabolic syndrome) - Also endogenous substance if large amounts are deposited in o Cholesterol crystals (atherosclerosis) tissues: urate crystals, cholesterol crystals, lipids o Amyloid deposits in brain (Alzheimer disease) Immune - Also called hypersensitivity Other cellular - Many leukocytes express receptors for the Fc tails of reactions - Reactions where normal protective immune system damages the receptors involved in antibodies and for complement proteins individual’s own tissues inflammation - Recognize microbes coated with antibodies and - Autoimmune disease or allergies  stimuli cannot be complement and promote ingestion and destruction of eliminated  persistent and difficult to cure (often asso. w/ the microbes and inflammation chronic inflammation)  important cause of morbidity and - Opsonisation – coating process mortality Circulating proteins - Complement system – reacts against microbes and - Inflammation is a major cause of tissue injury in these produces mediators of inflammation diseases - Mannose-binding lectin – circulating protein that - Inflammation is induced by cytokines and produced by T recognizes microbial sugars and promotes ingestion of lymphocytes and other cells of immune system the microbes and activation of the complement system - Collectins – also bind to and combat microbes Recognition of Microbes and Damaged Cells  Recognition of offending agents is the first step in all inflammatory reactions KEY CONCEPTS: General Features and Causes of Inflammation o Adaptation of multicellular organisms  Inflammation is a beneficial hot response to foreign invaders and necrotic tissue, but  Cellular receptors and circulating proteins  recognize microbes, products of cell it may also cause tissue damage damage, and triggering inflammation  The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators that are derived from plasma proteins and various Cellular receptors for - Receptors in plasma membrane  extracellular cells microbes microbes  The steps of the inflammatory response can be remembered as the five Rs: - Receptors in endosomes  ingested microbes 1. Recognition of the injurious agent - Receptors in cytosol  intracellular microbes 2. Recruitment of leukocytes - Enables cells to sense the presence of foreign invaders 3. Removal of the agent - Toll-like receptors (TLR) – family of receptors 4. Regulation (control) of the response - Receptors are expressed in many cell types: 5. Resolution (repair) o Epithelial cells (where microbes enter from the 6. The cause of inflammation include infections, tissue necrosis, foreign external environment) bodies, trauma, and immune responses o Dendritic cells, macrophage, leukocytes (w/c  Epithelial cells, tissue macrophages and dendritic cells, leukocytes and other cell types may encounter microbes in various tissues express receptors that sense the presence of microbes and damage. Circulating - Engagement triggers production of inflammatory proteins recognize microbes that have entered the blood molecules: adhesion molecules, cytokines, other  The outcome of acute inflammation is either elimination of the noxious stimulus mediators followed by decline of the reaction and repair of damaged tissue, or persistent injury Sensors of cell damage - All cells have cytosolic receptors that recognize resulting in chronic inflammation molecules that liberated or altered as a consequence of cell damage; includes: abmrmtmd ACUTE INFLAMMATION Increased Vascular Permeabilty (Vascular Leakage)  Acute inflammation has three major components: Several mechanisms are responsible for the increased permeability of postcapillary venules, a 1. Dilation of small vessels leading to an increase in blood flow hallmark of acute inflammation: 2. Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation  Contraction of endothelial cells resulting in increased interendothelial spaces is the 3. Emigration of the leukocytes from the microcirculation, their accumulation in most common mechanism of vascular leakage the focus of injury, and their activation to eliminate the offending agent o Elicited by histamine, bradykinin, leukotrienes, and other mediators o Called immediate transient response because it occurs rapidly after Reactions of Blood Vessels in the Acute Inflammation exposure to the mediator ; short-lived (15-30 mins) o Mild injury (burns, irradiation, UV radiation, bacterial toxin)  vascular  Vascular reactions of acute inflammation consists of changes in the blood flow and the leakage begins after delay 2-12 hrs and lasts for several hours or even days permeability of vessels  maximize the movement of plasma proteins and leukocytes  delayed prolonged leakage  Exudation – escape of fluid, proteins, and blood cells from the vascular system in to o Delayed prolonged leakage – caused by contraction of endothelial cells the interstitial tissue or body cavities or mild endothelial damage (e.g., sunburn)  Exudates – extravascular fluid that has high protein concentration and contains  Endothelial injury, resulting in endothelial cell necrosis and detachment cellular debris o Neutrophils that adhere to endothelium may also injure endothelial cells o Implies an increase in permeability of small blood vessels o Leakage starts immediately after injury and is sustained for several hours  Transudate – fluid with low protein content (mostly albumin), little or no cellular until the damage vessels are thrombosed or repaired material, and low SG  Trancytosis (increased transport of fluids and proteins) through the endothelial cell o Essentially an ultrafiltrate of blood plasma o Involve intracellular channels stimulated by certain factors (e.g., VEGF – o Result of osmotic or hydrostatic imbalance w/o an increase in vascular promotes vascular leakage) permeability  Edema – denotes an excess of fluid in the interstitial tissue or serous cavities Response of Lymphatic Vessels and Lymph Nodes o Can be exudate or a transudate  Pus – a purulent exudate; an inflammatory exudate rich in leukocyte (mostly  The lymphatic system and lymph nodes filters extravascular fluids neutrophils), the debris of dead cells and microbes  In inflammation, lymph flow is increased and helps drain edema fluid that accumulates because of increased vascular permeability Changes in Vascular Flow and Caliber  Lymphatic vessel (like blood vessels), proliferate during inflammatory reactions to handle the increase load Consist of the following:  Lymphatics may be secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis)  Vasodilation is induced by the action of several mediators, notably histamine, on  Enlargement of lymph nodes  hyperplasia of lymphoid follicles and increased vascular smooth muscle number of lymphocytes and macrophages o One of the earliest manifestations of acute inflammation  This constellation of pathologic changes is termed reactive, or inflammatory, o Vasodialtion first involves arterioles then capillaries lymphadenitis o Result is increased blood flow  cause of heat and redness (erythema) at  Presence of red streaks near a skin wound is a telltale sign of an infection in the the site of inflammation wound  follows the course of the lymphatic channels; diagnostic of lymphangitis  Increased permeability of microvasculature o Accompanied by enlargement of lymph nodes, indicative of lymphadenitis  Engorgement of small vessels with slowly moving red cells, a condition termed stasis o Loss of fluid and increased vessel diameter  slower blood flow, KEY CONCEPTS: Vascular Reactions in Acute Inflammation concentration of red cells in small vessels and increased viscosity of blood  Vasodilation is induced by chemical mediators such as histamine, and is the cause of o Stasis is seen as vascular congestion and localized redness of the involved erythema and stasis of blood flow tissue  ↑ vascular permeability is induced by histamine and kinins that produce gaps between  As stasis develops, blood leukocytes (esp neutrophils) accumulate along the vascular endothelial cells, by direct or leukocyte-induced endothelial injury, and by increased passage of fluids through the endothelium endothelium  Increased vascular permeability allows plasma proteins and leukocytes, the mediators of host defense, to enter sites of infection or tissue damage. Fluid leak from blood vessels results in edema  Lymph vessels and nodes are involved in inflammation  redness and swelling abmrmtmd Leukocyte Recruitment to Sites of Inflammation - Within 1-2 hrs the endothelial cells begin to express E-selectin and ligand for L-selectin  The changes in blood flow and vascular permeability are quickly followed by an influx - Histamine and thrombin – stimulate the redistribution of P-selectin of leukocytes into the tissue from intracellular stores of endothelial cell granules  called Weibel- Palade bodies o These leukocytes perform the key function of eliminating the offending - Leukocytes express L-selectin at the tips of their microvilli and also agents express ligands for E- and P- selectin  bind to complementary  The most important leukocytes in typical inflammatory reactions are the ones capable molecules on endothelial cells of phagocytosis  neutrophils and macrophages - These are low-affinity interactions with a fast off-rate, and they o Ingest and destroy bacteria, microbes, necrotic tissue and foreign are easily disrupted by the flowing blood substances - As a result, the bound leukocytes bind, detach, and bind again, and  Leukocytes also produced growth factors that aid in repair thus begin to roll along the endothelial surface Integrins - Family of heterodimeric leukocyte surface proteins that mediates firm o Defensive potency of leukocytes  induce tissue damage and prolong adhesion inflammation - TNF & IL-1 – induce endothelial expression of ligands for integrins mainly VCAM-1 and ICAM-1 The journey of leukocytes from the vessel lumen to the tissue is a multistep process - Leukocytes normally express integrins in a low-affinity state that is mediated and controlled by adhesion molecules and cytokines called - Chemokines bind to endothelial cell proteoglycans, and are displayed chemokines. This process can be divided into sequential phases: at high concentrations on the endothelial surface o Bind to and activate the rolling leukocytes 1. In the lumen: margination, rolling, and adhesion to endothelium. o Conversion of VLA-4 and LFA-1 integrins on the leukocyte to a high-affinity state 2. Migration across the endothelium and vessel wall - The combination of cytokine-induced expression of integrin ligands on 3. Migration in the tissue toward a chemotactic stimulus the endothelium and increased integrin affinity on the leukocytes results in firm intergin-mediated binding of the leukocytes Leukocyte Adhesion to Endothelium - Leukocytes stop rolling, their cytoskeleton is reorganized, and they spread out on the endothelial surface  Margination – process of leukocyte redistribution during inflammation; includes: o Stasis (slow blood flow) o Wall shear stress decrease (changes in hemodynamic condition) o More white cells assume a peripheral position along endothelial surface  Leukocytes adhere transiently to the endothelium, detach and bind  rolling  Cells come to rest where they adhere firmly  resembles pebbles  The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules whose expression is enhanced by cytokines  Cytokines – secreted by sentinel cells in tissues in response to microbes and other injurious agents o Ensures that leukocytes are recruited to tissues where stimuli are present  Two major families of molecules involved in leukocyte and migration: selectins and integrins, and their ligands expressed on leukocytes and endothelial cells Selectins - Family of proteins that mediates initial rolling interactions Leukocyte Migration Through Endothelium - Three types: o L-selectin (expressed on leukocytes)  The next step in the process of leukocyte recruitment is migration of the leukocytes o E-selectin (endothelium) o P-selectin (platelets and endothelium) through the endothelium, called transmigration or diapedesis - Ligands for selectins are sialylated oligosaccharides bound to mucin-  Transmigration of leukocytes occurs mainly in postcapillary venules like glycoprotein backbones  Chemokines act on the adherent leukocytes and stimulate migration through - Tissue macrophage, mast cells, & endothelial cells that encounter interendothelial spaces toward the chemical concentration gradient toward the site of microbes and dead tissues respond by secreting several cytokines, injury where chemokines are produced including TNF, IL-1 and chemokines (chemoattractant cytokines)  Adhesion molecules are present in the intercellular junctions between endothelial - TNF & IL-1 – act on endothelial cells of post capillary venules and cells: induce the expression of adhesion molecules o CD31 or PECAM-1 abmrmtmd   After transversing, leukocytes pierce the basement membrane (by secreting KEY CONCEPTS: Leukocyte Recruitment to Sites of Inflammation collagenase), and enter the extravascular tissue  Leukocytes are recruited fromblood into the extravascular tissue where infectious  Cells then migrate toward chemotactic gradient and accumulate in extravascular site pathogens or tissues may be located and are activated to perform their functions  Recurrent bacterial infection  consequence of impaired leukocyte adhesion and  Leukocyte recruitment is a multistep process consisting of loose attachment and rolling on endothelium (mediated by selectins); firm attachment to endothelium defective inflammation (mediated by integrins); and migration through interendothelial spaces  Various cytokines promote expression of selectins and integrin ligands on endothelium Chemotaxis of Leukocytes (TNF, IL-1), increase the avidity of integrins for their ligands (chemokines), and promote directional migration of leukocytes (chemokines); many of these cytokines  After exiting the circulation, leukocytes move in the tissues toward the site of injury by are produced by tissue macrophage a process called chemotaxis  Neutrophils predominate in the early inflammatory infiltrate and are later replaced by  Chemotaxis – locomotion along a chemical gradient monocytes and macrophages o Both exogenous and endogenous substances can act as chemoattractants Once leukocytes (neutrophils and monoyctes) have been recruited, they must be activated to  Exogenous agents perform their functions; response of leukocytes consists of: o Bacterial products (most common) - peptides that posses an N- formylmethionine terminal amino acid and some lipids o Recognition by TLRs and other receptors which deliver signals  Endogenous chemoattractants include several chemical mediators: o Activate the leukocytes to phagocytose and destroy offending agents o Cytokines (chemokine family; IL-8) Phagocytosis and Clearance of the Offending Agent o Components of the complement system (C5a) o Arachidonic acid metabolites (leukotriene B4 or LTB4)  Recognition of microbes or dead cells induces several responses in leukocytes that are  Chemotactic agents bind to seven transmembrane GPCR on the leukocytes collectively called leukocyte activation o Signals result in activation of second messenger that ↑ cytosolic Ca2+   Activation results from signalling pathways triggered in leukocytes  ↑ cytosolic Ca2+ activate GTPs of Rac/Rho/cdc42 family  induce polymerization of actin  and activation of enzyme (PKC, PLA2) localization of myosin filaments at the back  The functional responses that are most important for destruction of microbes and o Leuokocyte moves by extending filopodia that pull the back of the cell in the other offenders are phagocytosis and intracellular killing direction of extension  Phagocytosis involves integration of many receptor-mediated signals that lead to o Net result: leukocytes migrate toward the inflammatory stimulus in the membrane remodelling and cytoskeletal changes direction of the locally produced chemoattarctants  Phagocytosis involves three sequential steps: 1. Recognition and attachment of the particle to be ingested by the leukocyte The nature of the leukocyte infiltrate varies with the age of the inflammatory 2. Engulfment, with subsequent formation of phagocytic vacuole response and the type of stimulus 3. Killing or degradation of the ingested material  In most forms of acute inflammation neutrophils predominate in the inflammatory Phagocytic - Mannose receptors, scavenger receptors, and receptors for various infiltrate during the first 6-24 hrs and are replaced by monocytes in 24-48 hrs Receptors opsonins bind and ingest microbes  Reasons for early preponderance of neutrophils: - Macrophage mannose receptor – lectin that binds terminal o More numerous in the blood than other WBC mannose and fucose residues of glycoproteins and glycolipids o Respond more rapidly to chemokines o Sugars found on microbial cell walls o Attach more firmly to the adhesion molecules that are rapidly induced on o Mammalian glycoproteins and glycolipids contain terminal endothelial cells (such as P- and E- selectins) sialic acid or N-acetylgalactosamine  Neutrophils are short-lived  undergo apoptosis and disappear within 24-48 hrs o Mannose receptor recognizes microbes and not host cells - Scavenger receptors – molecules that bind and mediate  Monocyte survive longer and may also proliferate in tisssues  become the dominant endocytosis of oxidized or acetylated LDL particles that can no population in prolonged inflammatory reactions longer interact with the LDL receptor o Exceptions: Infections by Pseudomonas bacteria  cellular infiltrate is - Mac-1 (CD11b/CD18) – may also bind microbes for phagocytosis domibated by continuously recruited neutrophils for several days - Efficiency of phagocytosis is enhanced when microbes are opsonised o Viral infections  lymphocytes arrive first by opsonins (high affinity receptors) o Hypersensitivity reactions  activated lymphocytes, macrophages and - Major opsonins: plasma cells o IgG antibodies o C3b breakdown product of complement o Allergic reactions  eosinophils are the main cell type o Certain plasma lectins (MBL)  Agents that block TNF  therapy for chronic inflammatory disease abmrmtmd Engulfment - After a particle is bound to phagocyte receptors, pseudopods flow Lysosomal - Neutrophils and monocytes – contain lysosomal granules around it, and the plasma membrane pinches off to form a Enzymes & - Neutrophils have two types of granules: phagosome that encloses the particle Other o Smaller specific/secondary granules – lysozome, - Phagosome + lysosomal granule = discharge of the granule’s Lysosomal collegenase, gelatinase, lactoferrin, plasminogen contents into the phagolysosome Proteins activator, histaminases, ALP - Phagocyte may also release granule contents into the extracellular o Larger azurophil/primary granules – MPO, bacterial space factors (lysozyme, defensin), acid hydrolase, neutral proteases (elastase, cathepsin G, non specific collagenase, proteinase 3)  Phagocytosis is dependent on polymerization of actin filaments  signals that - Both granules can fuse with phagocytic vacuoles containing trigger phagocytosis are also involved in chemotaxis engulfed material - Acid protease – degrade bacteria and debris w/in the phagolysosome  acidified by membrane bound proton pumps Intracellular Destruction of Microbes and Debris - Neutral protease – degrade extracellular components (collagen, basement membrane, fibrin, elastin, cartilage);  Killing of microbes is accomplished by ROS and reactive nitrogen species (derived o also cleave C3 and C5  yield anaphylatoxin and from NO), as well as lysosomal enzymes that destroy phagocytosed debris release kinin-like peptide from kininogen  This is the final step in the elimination of infectious agents and necrotic cells - Neutrophil elastase – degrade virulence factors of bacteria and  Killing and degradation of microbes and dead cells w/in neutrophils and macrophage combat bacterial infections occur most efficiently after activation of the phagocytes sequestered in lysosomes - Macrophage also contain acid hydrolase, collagenase, elastase, phospholipase, and plasminogen activator - A1-antitrypsin – major inhibitor of neutrophil elastase ROS - Produced by rapid activation of NADPH oxidase (aka phagocyte - A2-macroglobulin – antiprotease found ins erum and various oxidase), w/c oxidizes NADPH  reduces O2 to superoxide anion secretions - Neutrophils  oxidative reaction is triggered by activating - Defensin – cationic arginine-rich granule peptides that are toxic signals and phagocytosis  called respiratory burst to microbes - Phagocyte oxidase – enzyme complex; consist of at least seven - Cathelicidins – antimicrobial proteins found in neutrophils and proteins ; located in plasma membrane and cytoplasm other cells - ROS are produced within the lysosome and phagolysosome - Lysozyme – hydrolyzes the muramic acid-N-acetylglucosamone - O2- is converted to H2O2 bond, found in the glycopeptides coat of all bacteria - H202 + MPO + Cl- = hypochlorite (OCl2-) potent microbial - Lactoferrin – iron-binding protein present in specific granules agent; destroys microbes by halogenations or by oxidation - Major basic protein – cationic protein of eosinophils; has limited - H2O2-MPO-halide system  most efficient bacterial system of bactericidal activity but is cytotoxic to many parasites neutrophils - H2O2 is also converted to hydroxyl radical (-OH)  destructive agent  bind to and modify cellular lipids, proteins, and nucleic acids, and destroy microbes Neutrophil Extracellular Traps - Serum, tissue fluids and cells possess antioxidant mechanisms: 1. Superoxide dismutase  NETs are extracellular fibrillar networks that provide a high concentration of 2. Catalase (detoxify H2O2) antimicrobial substances at sites of infection and prevent the spread of the microbes 3. Glutathione peroxidise (detoxify H2O2) by trapping them in the fibrils 4. Ceruloplasmin  Produced by neutrophils in response to infectious pathogens (bacteria and fungi) 5. Transferrin and inflammatory mediators (chemokines, cytokines (IF), complement proteins, ROS) Nitric Oxide - Soluble gas produced from arginine by the action of NO  Extracellular traps consists of viscous meshwork of nuclear chromatin that binds and synthase (NOS); three diff. types of NOS: o eNOS (endothelial) concentrates granule proteins such as antimicrobial peptides and enzymes o nNOS (neurnonal)  NET formation  nuclei of neutrophils are lost  lead to death of cells o iNOS (inducible) o Seen in blood during sepsis - eNOS and nNOS  expressed at low levels; NO they generate o Dependent on platelet activation maintain vascular tone and as a neurotransmitter, respectively o Nuclear chromatin is a source of nuclear antigens  systemic autoimmune - iNOS  involved in microbial killing; induced when macrophage disease and neutrophils are activated by cytokines or microbial products - NO reacts with superoxide in macrophage to generate the highly reactive free radical peroxynitrite (ONOO-)  attack and damage the lipids, CHONs, and nucleic acids of microbes and host cells abmrmtmd Leukocyte-Meidated Tissue Injury Mediators of Inflammation Leukocytes are important causes of injury to normal cells under several circumstances:  The mediators of inflammation – initiate and regulate inflammatory reactions  As part of a normal defense reaction against infectious microbes, when adjacent  Most important mediators of acute inflammation are vasoactive amines, lipid products tissues suffer collateral damage (prostaglandins and leukotrienes), cytokines (chemokines), and products of complete  When the inflammatory response is inappropriately directed against host tissues activation (autoimmune diseases)  Mediators are either secreted by cells or generated from plasma proteins  When the host reacts excessively against harmless environmental substances o Cell-derived mediators – sequestered in intracellular granules and can be (allergic diseases, asthma) rapidly secreted by granules exocytosis (e.g., histamine in mast cell granules) or synthesized de novo (prostaglandin, leukotrienes, cytokine)  During activation and phagocytosis  neutrophils and macrophages produce microbial o The major cell types that produce mediators of acute inflammation are the substances w/in phagolysosome  released and able to damage normal tissues sentinels that detect invaders and damage in tissue, that is, macrophage, (leukocyte-dependent tissue injury) dendritic cells and mast cells o Plasma-derived mediators – (complement proteins); produced manly in Other Functional Responses of Activated Leukocytes the liver; present in circulation as inactive precursors  Most of the mediators are short-lived  Macrophage – critical cells of chronic inflammation and tissue repair; produce: o Cytokines – amplify or limit inflammatory reactions Vasoactive Amines: Histamine and Serotonin o Growth factors – stimulate proliferation of endothelial cells, fibroblast  Histamine and serotonin – two major vasoactive amines; important actions on and collagen blood vessels  Neutrophils and macrophage – important in acute inflammation  Stored as preformed molecules; first mediators to be released  T-lymphocytes also contribute to acute inflammation  Mast cells – richest source of histamine;  Histamine is also found in basophils and plate lets; released by mast cells  IL-7 (TH17 cells) – induce secretion of chemokines that recruit other leukocytes degranulation in response to: o Absence of TH17 responses  susceptible to fungal and bacterial 1. Physical injury (trauma, cold, heat) infections 2. Binding of antibodies to mast cells (immediate hypersensitivity/allergic rxns) o Skin abscess that develop are “cold abscesses”  lack classic features of 3. Anaphylatoxins (C3a, C5a) – products of complement acute inflammation such as warmth and redness  Neuropeptides (substance P) and cytokines (IL-1, IL-8) may also trigger release of histamine Histamine - Cause dilation of arterioles and increases permeability of venules Termination of the Acute Inflammatory Response - Principal mediator of the immediate transient phase of increased vascular permeability, producing endothelial gaps in venules  Inflammation declines after agents are removed because mediators are produced in - Vasoactive effects are mediated by binding to H1 receptors on rapid burst, have short half-lives and degraded after release microvascular endothelial cells  Active termination mechanism include a switch in the type of arachidonic acid - Antihistamine drugs – H1 receptor antagonist metabolite produced, from proinflammatory leukotrienes to anti-inflammatory lipoxins, - Histamine also causes contraction of smooth muscles and the liberation of anti-inflammatory cytokines, including TGF-b, and IL-10 from Serotonin - 5-hydroxytryptamine; preformed vasoactive mediator present in macrophage and other cells platelets and neuroendocrine cells (GIT) - Primary function: neurotransmitter in GIT  Neural impulses (cholinergic response)  inhibit production of TNF in macrophages - Also a vasoconstrictor KEY CONCEPTS: Leukocyte Activation and Removal of Offending Agents  Leukocytes can eliminate microbes and dead cells by phagocytosis, followed by destruction in phagolysosomes  Destruction is caused by free radicals (ROS, NO) generated in activated leukocytes and lysosomal enzymes  Neutrophils can extrude their nuclear contents to form extracellular nets that trap and destroy microbes  Enzymes and ROS may be released into the extracellular environment  The mechanism that function to eliminate microbes and dead cells (the physiologic role of inflammation) are also capable of damaging normal tissues (the pathologic consequence of inflammation) abmrmtmd Arachidonic Acid Metabolites Leukotrienes  The lipid mediators prostaglandins and leukotrienes are produced from arachidonic  Leukotrienes are produced by leukocytes and mast cells by the action of acid (AA) present in membrane phospholipids, and stimulate vascular and cellular lipoxygenase; involve in vascular & smooth muscle reaction & leukocyte recruitment reactions in acute inflammation  Three different lipoxygenase:  AA  20-carbon polyunsaturated fatty acid; derived from dietary sources or by o 5-lipoxygenase – predominant in neutrophils; converts AA to 5-HETA conversion from the essential fatty acid linoleic acid which is a chemotactic for neutrophils and the precursor of the leukotrienes  Does not occur free; esterified in membrane phospholipids  LTB4 – potent chemotactic agent and activator of neutrophils; cause aggregation and  Phospholipase A2 – release AA from membrane phospholipids adhesion of the cells to venular endothelium, generation of ROS, and release of  Eicosanoids – AA-derived mediators; synthesized by two major classes of enzymes: lysosomal enzymes o Cyclooxygenase (generate prostaglandins)  LTC4, LTD4, LTE4 – cysteinyl-containing leukotrienes; cause intense o Lipooxygenase (produce leukotrienes and lipoxins) vasoconstrictions, bronchospasm (asthma), and increased permeability of venules  Eicosanoids bind to GPCR; can mediate virtually every step of inflammation  Leukotrienes are more potent than is histamine in increasing vascular permeability and causing bronchospasm Lipoxins  Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes  Inhibit neutrophil chemotaxis and adhesion to endothelium  Unusual because they require two cell population for transcellular biocynthesis  Leukocytes (neutrophils) produce intermediates in lipoxin synthesis and these are converted to lipoxins by platelets interacting with the leukocytes Prostaglandins  Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and Pharmacologic Inhibitors of Prostaglandins and Leukotrienes many other cell types, and are involved in the vascular and systemic reactions of Cyclooxygenase - Aspirin and NSAIDs (ibuprofen) inflammation Inhibitors - Inhibit COX-1 and COX-2  inhibit prostaglandin  Generated by the actions of two cyclooxygenases  COX-1 and COX-2 synthesis  treat pain and fever  COX-1 – produced in response to inflammatory stimuli; expressed in most tissues; - Aspirin irreversibly acetylate and inactivates cyclooxygenases serve a homeostatic function (e.g., fluid and electrolyte balance in kidneys and GIT) - Selective COX-2 inhibitors – 200-300 fold more potent in  COX-2 – induced by inflammatory stimuli and generates the prostaglandins involved blocking COX-2 than COX-1 in inflammatory reactions; low or absent in most normal tissues - COX-1  responsible for production of prostaglandin  PGD, PGE, PGF, PGG, PGH involved in both inflammation and homeostatic functions  PGE2, PGD2, PGF2a, PGI, TxA2  most important ones in inflammation (fluid balance in kidney and cytoprotection in GIT) o TxA2 – found in platelets; potent platelet-aggregating agent and - COX-2  generates prostaglandins that are involved only in vasoconstrictor; (inactive form  TxB2) inflammatory reactions o PGI2 – vascular endothelium; (PGF1a  stable end product); vasodilator - COX-2 inhibitors – anti-inflammatory w/o toxicities of the and a potent inhibitor of platelet-aggregation non selective inhibitors such as gastric ulceration  Markedly potentiates the permeability-increasing and chemotactic - Selective COX-2 inhibitors may increase the risk of effects of other mediators cardiovascular and cerebrovascular events  impair o Thromboxane-prostacyclin imbalance – early event in thrombus endothelial cell production of PGI2 (vasodilator and inhibitor formation in coronary and cerebral blood vessels of platelet aggregation), but leave intact the COX-1 o PGD2 – major prostaglandin made by mast cells along w/ PGE2 (more production by platelets of TxA2 (important mediator of widely distributed); causes vasodilation and increases the permeability of platelet aggregation and vasoconstriction) postcapillary venules  potentiates edema formation - Selective COX-2 inhibition promote vascular thrombosis o PGF2a  stimulates the contraction of uterine and bronchial smooth Lipoxygenase - 5-lipoxygenase is not affected by NSAIDs muscle and small arterioles Inhibitors - Inhibitors of leukotriene production (Zileuton)  useful in o PGD2 – chemoattractant for neutrophils the treatment of asthma  Prostaglandins are involved in pathogenesis of pain and fever in inflammation Corticosteroids - Broad-spectrum anti-inflammatory agents  PGE2 – hyperalgesic and maked the skin hypersensitive to painful stimuli (intradermal - Reduce transcription of genes encoding COX-2, injection of histamine and bradykinin)  cytokine induced fever phospholipase A2, proinflammatory cytokines (IL-1 and TNF) and iNOS abmrmtmd  Leukotriene - Block leukotriene receptors and prevent the action of the Receptor leukotrienes Antagonist - Useful in the treatment of asthma (montelukast) Modify intake - Increase consumption of fish oil and content of - Polyunsaturated fatty acids are poor substrates for dietary lipids conversion to active metabolites by COX and LOX pathways - Better substrates for the production of anti-inflammatory lipid products Cytokines and Chemokines  Cytokines are proteins that mediate and regulate immune and inflammatory reactions and produced by many cell types: Chemokines o Activated lymphocytes, macrophage and dendritic cells  Chemokines - family of small (8-10kD) proteins that act as chemoattractants for WBC o Endothelial, epithelial and connective tissue cells  Classified to four groups accord. to arrangement of cysteine residues:  Growth factors that act on epithelial and mesenchymal cells are not grouped under C-X-C - One amino acid residue separating the first two of the four cytokines chemokines conserved cysteine residues  Cytokines involved in acute inflammation: - Act primarily on neutrophils o TNF and IL-1 - IL-8 – secreted by activated macrophages, endothelial cells, and o Chemokines (CXC, CC, C, CX3C) causes activation and chemotaxis of neutrophils; limited activity on monocytes and eosinophils - Most important inducers: microbial products, cytokines (IL-1 and TNF and IL-1 TNF)  TNF and IL-1 serve critical in leukocyte recruitment by promoting leukocyte adhesion C-C - Have first two conserved cysteine residues adjacent and migration p roduced mainly by activated macrophages and dendritic cells chemokines - MCP-1, eotaxin, MIP-1a, RANTES – attract monocytes,  TNF is also produced by T-lymphocytes and mast cells; induced through TLRs eosinophils, basophils and lymphocytes  IL-1 is also produced by epithelial cells; activation is dependent w/ inflammasome - Eotaxin selectively recruits eosinophils  Important roles: C - Lack the first and third of the four conserved cysteines Endothelial - Both induce spectrum of changes  endothelial activation: chemokines - Lymphotactin Relatively specific for lymphocytes activation o ↑ expression of endothelial adhesion molecules (E & P selectins, ligands for integrins) CX3C - Has three amino acids between the two cysteines o ↑ of various mediators (cytokine, chemokine, GF, chemokines - Fractalkine – only known member eicosanoids) - Exist in two forms: o ↑ procoagulant activity of the endothelium - Cell surface-bound protein induced on endothelial cells  Activation of - TNF – augments response of neutrophils to other stimuli promotes strong adhesion of monocytes and T-cells leukocytes and (endotoxin) and stimulate microbicidal activity of - Soluble form derived by proteolysis of the membrane-bound other cells macrophage by inducing production of NO protein; has potent chemoattractant activity for the same cells - IL-1 – activates fibroblast to synthesize collagen and  Chemokines mediate their activity by binding to GPCR stimulates proliferation of synovial and other mesenchymal  Receptors (CXCR or CCR) usually exhibit overlapping ligand specificities; leukocytes cells; stimulate TH17 response express more than one receptor type Systemic acute- - IL-1, IL-6, TNF – induce the systemic APR asso. w/  CXCR-4, CCR-5 – act as coreceptors for a viral envelope glycoprotein of HIV phase response infection (including fever)  Chemokines is displayed at high concentrations attached to proteoglycans on the - Seen in sepsis  disseminated bacterial infection surface of endothelial cells and in ECM; two main functions: - TNF – regulates energy balance; promote lipid and protein In acute - Inflammatory chemokines – stimulate leukocyte mobilization by suppressing apetite inflammation attachment to endothelium by acting on leukocytes to - Sustained TNF production  cachexia (pathologic state cxd increase affinity of integrins; stimulate chemotaxis by weight loss and anorexia; chronic infxn and neoplastic dx) (migration) of leukocytes in tissues to the site of infection  TNF antagonist have been remarkably effective in the treatment of chronic - Induced y microbes and other stimuli inflammatory disease (e.g., RA, psoriasis, IBD) Maintenance of - Hemostatic chemokines – organize cell types in different  Complications of therapy: susceptibility to mycobacterial infection  reduced ability of tissue anatomic regions of the tissues (e.g., T & B lymphocytes in macrophages to kill intracellular microbes architecture spleen and lymph nodes)  IL-1 antagonist are not as effective - Produced in tissues  Blocking either cytokine has no effect on the outcome of sepsis abmrmtmd Other Cytokines in Acute Inflammation  The activation of complement is tightly controlled by cell-associated and circulating  IL-6 – made by macrophages and other cells; involved in local systemic reactions regulatory proteins:  IL-17 – produced mainly by T-lymphocytes; promotes neutrophil recruitment  Antagonist against both  efficacious in the tx of inflammatory disease C1 INH - Blocks the activation of C1  Type interferons – inhibit viral replication; contribute to some of the systemic - Inherited deficiency  hereditary angioedema manifestations of inflammation DAF and - Two proteins linked to plasma membranes by a GPI anchor  Cytokines also play key roles in chronic inflammation CD59 - DAF – prevents formation of C3 convertase - CD59 – inhibits formation of the MAC - Acquired deficiency of enzyme that creates GPI anchors  Complement System deficiency of these regulators and excessive complement activation and lysis of RBC (sensitive to complement-mediated cell lysis) in the  Complement system - collection of soluble proteins and membrane receptors; function disease called Paroxysmal Nocturnal Hemoglobinuria (PNH) mainly in host defense ; 20 proteins; C1 to C9 Other Mediators of Inflammation  Functions in both innate and adaptive immunity against microbial pathogens  Cleavage products cause increased vascular permeability, chemotaxis and Platelet- - Phospholipid-derived mediator; has multiple inflammatory effect opsonisation Activating - Platelets, basophils, mast cells, neutrophils, macrophages,  Present in inactive forms in plasma  activated to become proteolytic enzymes Factors (PAF) endothelial cells  can elaborate PAF  C3 – most abundant; proteolysis of C3 is the critical step in complement aactivation - Cause vasoconstriction and bronchoconstriction  Cleavage of C3 can occur by one of three pathways: - At low concentration it induces vasodilation and increased venular permeability Classical - Triggered by fixation of C1 to antibody (IgM or IgG) that has Products of - PARs – activated by thrombin; expressed on platelets and pathway combined with antigen Coagulation leukocytes; major role in platelet activation during clotting Alternative - Triggered by microbial surface molecules (e.g., endotoxin, LPS), Kinins - Kinins are vasoactive peptides derived from kininogen by the pathway complex polysaccharides, cobra venom, and other substances, in action of kallikreins the absence of antibody - Kallikrein cleaves HMWK to produce bradykinin Lectin - Plasma mannose-binding lectin binds to carbohydrates on - Bradykinin – increases vascular permeability and causes pathway microbes and directly activates C1 contraction of smooth muscle, dilation of blood vessels, and pain  All three pathways of complement activation lead to the formation of an active when injected into the skin (effects are similar to histamine) enzyme called the C3 covertase, which splits C3 into two functionally distinct o Action is short-lived  quickly inactivated by kininase Neuropeptides - Secreted by sensory nerves and leukocytes fragments, C3a and C3b - Role in the initiation and regulation of inflammatory response o C3a is released C3b binds to C5 convertase - Substance P and neurokinin A – produced in CNS and PNS o C5 convertase cleaves C5 to release C5a and leave C5b attached to the - Nerve fibers w/ substance P – prominent in the lung and GIT cell surface C5b binds to C6-C9  formation of MAC - Substance P – function in transmission of pain signals,  Three main functions of complement system regulation of BP, stimulation of hormone secretion by endocrine cells, and increase vascular permeability Inflammation - C3a, C5a, C4a – cleavage products; stimulate histamine release from mast cells, increase vascular permeability & cause vasodilation o Called anaphylatoxins  involved in anaphylaxis Role of Mediators in Different Reactions of Inflammation - C5a – chemotactic agent for neutrophils, monocytes, eosinophils, Reaction of Inflammation Principal Mediators basophils Vasodilation Histamine & Prostaglandin o Also activates lipoxygenase pathway of AA metabolism in ↑ Vascular Permeability Histamine and serotonin neutrophils and monocytes  release of inflammatory C3a and C5a mediators Leukotrienes C4, D4, E4 Opsonization - C3b, iC3b – acts as opsonins and promote phagocytosis by Chemotaxis, Leukocyte recruitment & TNF, IL-1 and neutrophils and macrophages, which bear cell surface receptors for activation Chemokines Phagocytosis the complement fragments C3a, C5a Cell lysis - Deposition of MAC on cells  ↑ permeability to water and ions  Leukotriene B4 cell lysis Fever IL-1, TNF - This role is important in killing microbes with thin walls (e.g., Prostaglandins Neisseria) Pain Prostaglandins & Bradykinin - Deficiency of the terminal components of complement predisposes Tissue Damage Lysosomal enzymes of leukocytes to Neisseria infections ROS abmrmtmd KEY CONCEPTS: Action of the Principal Mediators of Inflammation o Zone of preserved neutrophils around necrotic focus  Vasoactive amines (histamine): vasodilation and ↑ vascular permeability o Outside: vascular dilation, parenchymal and fibroblastic  AA metabolites (prostaglandins and leukotrienes): vascular reactions, proliferation  indicates chronic inflammation and repair leukocyte chemotoaxis, other rxns of inflammation; antagonized by lipoxins Ulcers - Local defect/excavation of the surface of an organ or tissue that is  Cytokines: proteins produced by many cell types; usually act at short-range; mediate produced by the sloughing of inflamed necrotic tissue multiple effects, mainly in leukocyte recruitment and migration; principal ones in acute - Occur when tissue necrosis and inflammation exist on or near a inflammation are TNF, IL-1 and chemokines surface  Complement proteins: activation of the complement system by microbes or - Most encountered in: antibodies leads to the generation of multiple breakdown products, which are o Mucosa of the mouth, stomach, intestines, genitourinary responsible for leukocyte chemotaxis, opsonisation, and phagocytosis of microbes and tract other particles, and cell killing o Skin and subcutaneous tissue of the lower extremities  Kinins: produced by proteolytic cleavage of precursors; mediate vascular rxn, pain (older person w/ circulatory disturbances  ischemic necrosis) - Peptic ulcer  intense polymorphonuclear infiltration and Morphologic Patterns of Acute Inflammation vascular dilation (acute stage)  fibroblastic proliferation, scarring, accumulation of lymphocytes, macrophage, plasma cell (chronic stage  Morphologic hallmarks of acute inflammatory reactions: dilation of small blood vessels and accumulation of leukocytes and fluid in the extravascular Outcomes of Acute Inflammation tissues  Importance of recognizing the gross and microscopic patterns is that they often  All acute inflammatory reactions typically have one of three outcomes: provide valuable clues about the underlying cause 1. Complete resolution Serous - Marked by exudation of cell-poor fluid into spaces into body o Resolution – usual outcome when injury us limited, short-lived, or with Inflammation cavities lined by peritoneum , pleura or pericardium - Fluid is not infected w/ destructive organism; does not contain little tissue destruction large # of leukocytes o Involves removal of cellular debris and microbes by macrophages, and - Fluid may be derived from: resorption of edema fluid by lymphatics o Plasma (as a result of ↑ vascular permeability) 2. Healing by connective tissue replacement (scarring, or fibrosis) o Secretions of mesothelial cells (as a result of local o Occurs after substantial tissue destruction which involves tissue that are irritation) incapable of regeneration, or when there is abundant fibrin exudation in - Effusion – accumulation of fluid in cavities; occur in tissue or in serous cavities (pleura, peritoneum) that cannot be fully cleared noninflammatory conditions - Skin blister from burn or viral infection  accumulation of serous o Connective tissue grown into area of damage or exudates, converting it to a fluid w/in or beneath the damaged epidermis of the skin mass of fibrous tissue, a process called organization Fibrinous - Fibrinous exudates – develops when the vascular leaks are 3. Progression to chronic inflammation Inflammation large or there is a local procoagulant stimulus o Occurs when acute response cannot be resolved  result of persistence o Cx of inflammation in the lining of body cavities injurious agent or interference with the normal process of healing (meninges, pericardium, pleura) o Dissolved by fibrinolysis and cleared by macrophages Summary of Acute Inflammation - Fibrin – eosinophilic meshwork of threads; amorphous coagulum - Conversion of fibrinous exudates to scar tissue w/in pericardial sacs leads to opaque fibrous thickening of pericardium and  The vascular and cellular reactions account for the signs and symptoms of the epicardium  obliteration of pericardial space inflammatory response Purulent - Cxd by the production of pus, an exudates consisting of  Edema - ↑blood flow and ↑ vascular permeability lead to accumulation of extravascular (Suppurative) neutrophils, the liquefied debris of necrotic cells and edema fluid fluid rich in plasma proteins Inflammation, - Most frequent cause of purulent (suppurative) inflammation  o Rubor – redness Abscess infection w/ bacteria that cause liquefactive tissue necrosis (e.g., o Calor – warmth Staphylococci)  known as pyogenic bacteria o Tumor – swelling - Example of acute suppurative inflammation  acute appendicitis  During the damage, and in part as a result of the liberation of prostaglandins, - Abscesses – localized collections of purulent inflammatory tissue caused by suppuration buried in a tissue, an organ, or a confined neuropeptides, and cytokines, one of the local symptoms is pain (dolor) space  produced by seeding bacteria in tissue o Have a central region that appears as mass of necrotic leukocytes and tissue cells