Inflammation - Topic 2 PDF

INFLAMMATION The material is intended for educational purpose only. The images and videos used in this presentation do not belong to the lecturer and are obtained from various sources to facilitate discussion. ACUTE AND CHRONIC INFLAMMATION INFLAMMATION  protective response invol...

INFLAMMATION The material is intended for educational purpose only. The images and videos used in this presentation do not belong to the lecturer and are obtained from various sources to facilitate discussion. ACUTE AND CHRONIC INFLAMMATION INFLAMMATION  protective response involving:  host cells  blood vessels  proteins and other mediators  Purpose:  a) to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult  b) initiate the process of repair INFLAMMATION  Protective mission accomplished by:  Dilution  Destruction  Neutralization of harmful agents (e.g., microbes, toxins)  Isolation  Repair Remember!  Although inflammation helps clear infections and other noxious stimuli and initiates repair, the inflammatory reaction and the subsequent repair process can themselves cause considerable harm.* Inflammation  Agents of host defense include Cells and molecules Plasma Proteins Leukocytes ( WBC )  Goal of the inflammatory reaction: to bring those agents to the site of infection or tissue damage.  The steps of the inflammatory response can be remembered as the five Rs:  (1) Recognition of the injurious agent,  (2) Recruitment of leukocytes,  (3) Removal of the agent,  (4) Regulation (control) of the response  (5) Resolution (repair). Inflammation  Acute inflammation is rapid in onset and of short duration few minutes to as long as a few days characterized by fluid and plasma protein exudation predominantly neutrophilic leukocyte accumulation. Inflammation Chronic Inflammation  more insidious  longer duration (days to years)  influx of lymphocytes and macrophages  with associated:  tissue destruction  vascular proliferation  fibrosis (scarring) Cardinal Signs of Inflammation  Calor - heat, resulting from vasodilation of blood vessels  Rubor - redness, resulting from vasodilation of blood vessels  Tumor - swelling, resulting from edema  Dolor - pain. resulting from local release of prostaglandin and kinins  Functio laesa - loss (or impairment) of function  in some situations, the inflammatory reaction becomes the cause of disease, and the damage it produces is its dominant feature  Inflammation is terminated when the offending agent is eliminated. ACUTE INFLAMMATION  Inflammation  controlled and self-limited  Major components of acute inflammation:  1. Vascular changes  Vasodilation  Increased vascular permeability - edema  Endothelial cell activation - increased adhesion of leukocytes and migration of leukocytes through vessel walls.  2. Cellular events – cellular emigration  Cellular recruitment  Activation of leukocytes STIMULI FOR ACUTE INFLAMMATION  1. Infections (bacterial, viral, fungal, parasitic) and microbial toxins  2. Trauma (blunt and penetrating) and various physical and chemical agents  3. Tissue necrosis ( from any cause) including ischemia and physical and chemical changes  4. Foreign bodies - (splinters, dirt, sutures, crystal deposits)  5. Immune reactions (hypersensitivity reactions) Immune-mediated inflammatory reactions  The steps of the inflammatory response can be remembered as the five Rs:  (1) recognition of the injurious agent,  (2) recruitment of leukocytes,  (3) removal of the agent,  (4) regulation (control) of the response  (5) resolution (repair).  I. Recognition (OF MICROBES, NECROTIC CELLS, AND FOREIGN SUBSTANCES) I. Recognition of Microbes, Necrotic Cells, and Foreign Substances  *Cells that express receptors to sense the presence of infectious pathogens and substances released from dead cells.  Phagocytes  dendriticcells (cells in connective tissue and organs that capture microbes and initiate responses to them)  many other cells such as epithelial cells,  Receptors are known as “pattern recognition receptors” I. Recognition of Microbes, Necrotic Cells, and Foreign Substances Two most important families of these receptors: 1.Toll-like receptors – ten mammalian TLRs 2.Inflammasome - multi-protein cytoplasmic complex  recognizes products of dead cells:  uric acid  extracellular ATP  crystals and some microbial products. VASCULAR EVENTS II. RECRUITMENT OF LEUKOCYTES  The steps of the inflammatory response can be remembered as the five Rs:  (1) recognition of the injurious agent,  (2) recruitment of leukocytes,  (3) removal of the agent,  (4) regulation (control) of the response  (5) resolution (repair). II. RECRUITMENT OF LEUCOCYTES Vascular changes: I. changes in vascular caliber and flow II. increased vascular permeability III. responses of lymphatic vessels II. RECRUITMENT OF LEUCOCYTES  A. Vascular Changes:  1. Changes in vascular caliber and blood flow ❖ Initially: interaction between the injurious agent and the macrophages and other host defense cells ❖ Followed by: triggering vascular response  The main vascular reactions of acute inflammation:  a. Vasodilation – to increase blood flow  b. Increased vascular permeability  bothdesigned to bring blood cells and proteins to sites of infection or injury. II. RECRUITMENT OF LEUCOCYTES  (I. Changes in vascular caliber and flow) A. Initiated rapidly after infection or injury Transient vasoconstriction (seconds only) Arteriolar vasodilation Locally increased blood flow Engorgement of down-stream capillary bed Vascular expansion –redness (erythema), & warmth II. RECRUITMENT OF LEUCOCYTES B. Microvasculature becomes more permeable protein-rich fluid moves into the extravascular tissues RBC become concentrated in the blood Increasing viscosity Slowing of blood flow - STASIS II. RECRUITMENT OF LEUCOCYTES C. Margination: As stasis develops leukocytes particularly neutrophils begin to accumulate along the vascular endothelial surface (first step in the journey of leukocytes through the vascular wall into the interstitial tissues). II. RECRUITMENT OF LEUCOCYTES Vascular changes  II. Increased vascular permeability Movement of protein-rich fluid and cells into the extravascular tissues Increase in osmotic pressure on the interstitial fluid More outflow of water from blood into tissues Exudates (high protein content with wbc and rbc  Transudate – interstitial fluid accumulation caused by increased hydrostatic pressure Due to reduce VR  Exudate – protein-rich fluid accumulation in the extravascular compartment, typical of inflammation due to increased vascular permeability. Edema – fluid accumulation in extravascular spaces, either from an exudate or a transudate.  Mechanisms that contribute to vascular permeability  1. Endothelial cell contraction leading to intercellular gaps in postcapillary venules (most common cause of increased vascular permeability).  2. Endothelial injury resulting in endothelial cell necrosis and detachment.  3. Increased transcytosis of proteins  4. Leakage from new blood vessels.  Mechanisms that contribute to vascular permeability  1. Endothelial cell contraction leading to intercellular gaps in postcapillary venules (most common cause of increased vascular permeability).  2. Endothelial injury (results in vascular leakage by causing endothelial cell necrosis and detachment).  3. Increased transcytosis of proteins  4. Leakage from new blood vessels.  Mechanisms that contribute to vascular permeability  1. Endothelial cell contraction leading to intercellular gaps in postcapillary venules (most common cause of increased vascular permeability).  2. Endothelial injury (results in vascular leakage by causing endothelial cell necrosis and detachment).  3. Increased transcytosis of proteins  4. Leakage from new blood vessels.  Mechanisms that contribute to vascular permeability  1. Endothelial cell contraction leading to intercellular gaps in postcapillary venules (most common cause of increased vascular permeability).  2. Endothelial injury (results in vascular leakage by causing endothelial cell necrosis and detachment).  3. Increased transcytosis of proteins  4. Leakage from new blood vessels. VASCULAR LEAKAGE Vascular changes III. Responses of lymphatic vessels Lymph flow is increased helping drain edema fluid, leukocytes, and cell debris from the extravascular space. In severe cases, offending agents are carried by the lymphatics dissemination – secondary inflammation: Lymphangitis Lymphadenitis ❖Reactive or inflammatory lymphadenitis CELLULAR EVENTS II. LEUKOCYTE RECRUITMENT ACTIVATION  The steps of the inflammatory response can be remembered as the five Rs:  (1) recognition of the injurious agent,  (2) recruitment of leukocytes,  (3) removal of the agent,  (4) regulation (control) of the response  (5) resolution (repair). Leukocyte cellular events  Leukocytes leave the vasculature routinely through the following sequence of events: 1. Margination and rolling along the vessel wall 2. Adhesion to the endothelium 3. Transmigration between endothelial cells 4. Migration in interstitial tissues toward a chemotactic stimulus  Leukocyte cellular events  Margination - process of leukocyte accumulation at the periphery of vessels.  Rolling – process wherein leukocytes attached loosely to the adhesion molecules produced by the endothelial cells tumble on the endothelial surface.  Leukocyte cellular events  Margination - process of leukocyte accumulation at the periphery of vessels.  Rolling – process wherein leukocytes attached loosely to the adhesion molecules produced by the endothelial cells tumble on the endothelial surface.  Adhesion Ligands –  1. intercellular adhesion molecule-1 (ICAM-1)  Binds to integrins:  LFA-1 also called CD11a/CD18  Mac-1 antigen (CD11b/CD18)  2. vascular cell adhesion molecule-1 (VCAM-1)  Binds to integrin VLA-4 Stable attachment of leukocytes to endothelial cells at the site of injury is influenced by: 1. cytokine-stimulated increased integrin affinity 2. increased expression of integrin ligands Adhesion  Mediated by integrins expressed on leukocyte cell surfaces interacting with their ligands on endothelial cells.  Integrins – transmembrane heterodynamic glycoproteins expressed on the leukocyte plasma membrane.  Chemokines – chemoattractant cytokines secreted by cells on the site of inflammation, and displayed on the endothelial cell surface.  Ligands – attachment molecules for integrins secreted and displayed by the endothelial cells for the attachment of the integrins to the endothelial cell surface. Transmigration (diapedesis)  A process of extravasation of leukocytes wherein leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions.  Occurs mainly in the venules of the systemic vasculature  Noted also in capillaries in the pulmonary circulation. Transmigration (diapedesis)  Migration is driven by:  1. chemokines produced in extravascular tissues  2.platelet endothelial cell adhesion molecule-1 (PECAM-1) (also called CD31), a cellular adhesion molecule expressed on leukocytes and endothelial cells  Collagenases – secreted by leukocytes that enable them to pass through the basement membrane.  Chemotaxis  Leukocyte locomotion along chemical gradient to the site of injury.  extends pseudopods or filopodia that pull the back of the cell in the direction of extension  Chemoattractants:  1. Exogenous substances  Soluble bacterial products  2. Endogenous substances  Complement components particularly C5  Cytokines (chemokine family e.g., IL-8)  Arachidonic acid metabolites (AA) mainly Leukotriene B4 (LTB4)  Chemotactic agents bind surface receptors inducing calcium mobilization and assembly of cytoskeletal contractile elements. Chemotaxis  Neutrophils migrate to the area first for the first 6 to 24 hours, and replaced by monocytes in 24 to 48 hours.  Reasons for the early preponderance:  1. Neutrophils > other leukocytes in the blood  2. More rapid response to chemokines  3. More firm attachment to the adhesion molecules that are rapidly induced on endothelial cells ( P- and E-selectins). ACTIVATION  Stimuli for activation include  microbes  products of necrotic cells  several mediators  undergo activation:  Prepare AA metabolites from phospholipids  Prepare for degranulation and release of lysosomal enzymes (oxidative burst)  Regulate leukocyte adhesion molecule affinity as needed Nature of Leukocyte in an Inflammatory Reaction iii. Removal of the AGENT  The steps of the inflammatory response can be remembered as the five Rs:  (1) recognition of the injurious agent,  (2) recruitment of leukocytes,  (3) removal of the agent,  (4) regulation (control) of the response  (5) resolution (repair). ACTIVATION  Activation results in recognition of the offending agents by TLRs and other receptors, which deliver signals  activate the leukocytes to phagocytose and destroy the offending agents. III. REMOVAL OF THE AGENT PHAGOCYTOSIS  Steps in phagocytosis:  1. Recognition and attachment of the particle to be ingested  2. Engulfment with subsequent formation of phagocytic vacuole  3. Killing or degradation of the ingested material III. REMOVAL OF THE AGENT: PHAGOCYTOSIS - ENGULFMENT Binding of opsonized particles to these receptors Triggers engulfment , pseudopods are extended around the object, Formation of a phagocytic vacuole Fusion of the membrane of the vacuole with the lysosomal granule Degranulation - discharge of the granule’s contents into the phagolysosome III. REMOVAL OF THE AGENT PHAGOCYTOSIS - RECOGNITION  Leukocyte receptors for phagocytosis:  1. Mannose receptors  2. Scavenger receptors  3. Opsonins  Opsonization – process wherein receptor proteins known as opsonins coat the microbes for recognition by the phagocytes. III. REMOVAL OF THE AGENT: PHAGOCYTOSIS – KILLING AND DEGRADATION  The key steps in this reaction:  1. Production of microbicidal substances within lysosomes  2. Fusion of the lysosomes with phagosomes  3. Exposing the ingested particles to the destructive mechanisms of the leukocytes  4. Lysosomal sequestration of the degraded material ▪ The most important microbicidal substances: ▪ Reactive oxygen species (ROS or reactive oxygen intermediates) ▪ Reactive nitrogen species ( derived from Nitric Oxide) ▪ Lysosomal enzymes. III. REMOVAL OF THE AGENT: PHAGOCYTOSIS – KILLING AND DEGRADATION  Phagocyte oxidase is active only after its cytosolic subunit translocates to the membrane of the phagolysosome; thus, the reactive end products are generated mainly within the vesicles, and the phagocyte itself is not damaged.  H2O2 is eventually broken down to water and O2 by the actions of catalase, and the other ROS also are degraded. Reactive nitrogen species, particularly nitric oxide (NO), act in the same way as that described for ROS. III. REMOVAL OF THE AGENT: PHAGOCYTOSIS – KILLING AND DEGRADATION  Dead microorganisms - degraded by the action of lysosomal acid hydrolases.  Most important lysosomal enzyme involved in bacterial killing - elastase. III. REMOVAL OF THE AGENT: PHAGOCYTOSIS – KILLING AND DEGRADATION  Other leukocyte granules that are capable of killing organisms (in addition to the ROS and enzymes):  bactericidal permeability-increasing protein (causing phospholipase activation and membrane phospholipid degradation)  lysozyme (causing degradation of bacterial coat oligosaccharides)  major basic protein (an important eosinophil granule constituent that is cytotoxic for parasites)  defensins (peptides that kill microbes by creating holes in their membranes). III. REMOVAL OF THE AGENT: PHAGOCYTOSIS – SECRETION OF MICROBICIDAL SUBSTANCES  The contents of lysosomal granules are secreted by leukocytes into the extracellular milieu by several mechanisms:  1. regurgitation during feeding  2. frustrated phagocytosis  3. Phagolysosome membrane may be damaged if potentially injurious substances, such as silica particles, are phagocytosed. III. REMOVAL OF THE AGENT: PHAGOCYTOSIS – SECRETION OF MICROBICIDAL SUBSTANCES  Neutrophil Extracellular Traps (NETs)  are “traps,” are extracellular fibrillar networks that are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (such as chemokines, cytokines, complement proteins, and ROS). Defects of leukocyte function  Defects of adhesion:  LFA-1 and Mac-1 subunit defects lead to impaired adhesion (LAD-1)  Absence of sialyl-Lewis X, and defect in E- and P-selectin sugar epitopes (LAD-2)  Defects of chemotaxis/phagocytosis:  Microtubule assembly defect leads to impaired locomotion and lysosomal degranulation (Chediak-Higashi Syndrome) Defects of leukocyte function  Inherited defects in leukocyte adhesion  LAD-1 - defective synthesis of the CD18 β  LAD-2 - defect in fucose metabolism resulting in the absence of sialyl–Lewis X  Inherited defects in phagolysosome function  Chédiak-Higashi syndrome  Inherited defects in microbicidal activity  chronic granulomatous disease  Acquired deficiencies Defects of leukocyte function 1. Inherited defects in leukocyte adhesion 2. Inherited defects in phagolysosome function 3. Inherited defects in microbicidal activity  4. Defective host defenses carrying mutations in TLR signaling pathways.  5. Gain-of-function mutations in genes encoding some components of the inflammasome, one of which is called cryo- pyrin MORPHOLOGIC PATTERNS OF INFLAMMATION  1. Serous inflammation  2. Fibrinous inflammation  3. Purulent or suppurative inflammation  4. Ulcers SEROUS INFLAMMATION  characterized by the outpouring of a watery, relatively protein-poor fluid that, depending on the site of injury, derived either from the  Plasma  Secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities (effusion).  Ex. Skin blister from burn or viral infection  FIBRINOUS INFLAMMATION  a consequence of more severe injuries, resulting in greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial barrier.  appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum  SUPPURATIVE OR PURULENT INFLAMMATION, ABSCESS ◆ manifested by the collection of large amounts of purulent exudate (pus) consisting of neutrophils, iquefied debris necrotic cells, and edema fluid. ◆ Abscesses are focal collections of pus that may be caused by seeding of pyogenic organ- isms into a tissue or by secondary infections of necrotic foci.  Ulcers local defect, or excavation, of the surface of an organ or tissue that is produced by necrosis of cells and sloughing (shedding) of necrotic and inflammatory tissue  most commonly encountered in  (1) the mucosa of the mouth, stomach, intestines, or genito- urinary tract  (2) in the subcutaneous tissues of the lower extremities in older persons who have circulatory disturbances predisposing affected tissue to extensive necrosis Morphologic Patterns of Acute Inflammation Outcomes of Acute Inflammation  1. Complete resolution: Regeneration and repair  2. Healing by connective tissue replacement (scarring, or fibrosis).  3. Progression of the response to chronic inflammation  Mediators of Inflammation Chemical mediators  Plasma-derived:  Complement, kinins, coagulation factors  Many in “pro-form” requiring activation (enzymatic cleavage)  Cell-derived:  Preformed, sequestered and released (mast cell histamine)  Synthesized as needed (prostaglandin) Chemical mediators  May or may not utilize a specific cell surface receptor for activity  May also signal target cells to release other effector molecules that either amplify or inhibit initial response (regulation)  Are tightly regulated:  Quickly decay (AA metabolites), are inactivated enzymatically (kininase), or are scavenged (antioxidants) CHRONIC INFLAMMATION Sequence of events in Vascular Changes ↑ Vascular permeability ↑ blood flow Exudate – protein-rich dilation extravascular fluid Acute Erythema & warmth Tissue edema Inflammation Leukocyte cellular Events Phagocytosis, killing, Margination & rolling and degradation of the Adhesion offending agent follow. Transmigration Chemotaxis Outcomes Genetic or acquired Resolution defects in leukocyte Chronic Inflammation functions give rise to Fibrosis recurrent infections. CHRONIC INFLAMMATION  inflammation of prolonged duration (weeks to years) in which continuing inflammation, tissue injury, and healing, often by fibrosis, proceed simultaneously.  is the persistence of inflammation with attempts of repair resulting from persistence of the injurious agent.  Characteristics:  1. Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells  2. Tissue destruction, largely induced by the products of the inflammatory cells  3. Repair, involving new vessel proliferation (angiogenesis) and fibrosis  Chronic inflammation  Arises in the following settings:  1. Persistent infections  2. Immune-mediated inflammatory diseases (hypersensitivity diseases)  3. Prolonged exposure to potentially toxic agents, either exogenous or endogenous.  4. Some forms of chronic inflammation may be important in the pathogenesis of diseases that are not conventionally thought of as inflammatory disorders MORPHOLOGIC FEATURES  Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells  Tissue destruction, induced by the persistent offending agent or by the inflammatory cells  Attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis  Chronic Inflammatory Cells and Mediators MACROPHAGES, LYMPHOCYTES AND OTHER CELLS: EOSINOPHILS AND MAST CELLS CHRONIC INFLAMMATION  The dominant cells in most chronic inflammatory reactions = macrophages  contribute to the reaction by: secreting cytokines and growth factors that act on various cells by destroying foreign invaders and tissues by activating other cells, notably T lymphocytes.  Macrophages in the mononuclear phagocyte system (RES)  Liver – kupffer cells  Spleen and lymph nodes – sinus histiocytes  CNS – microglial cells  Lungs – alveolar macrophages ; dust cells The Players (mononuclear phagocyte system)  Macrophages  Circulate as monocytes and reach site of injury within 24 – 48 hrs and transform  Become activated by T cell-derived cytokines, endotoxins, and other products of inflammation CHRONIC INFLAMMATION Major pathways of macrophage activation 1. classical 2. alternative Classical macrophage activation may be induced by:  microbial products such as endotoxin, which engage TLRs and other sensors  T cell–derived signals, importantly the cytokine IFN-γ, in immune responses  foreign substances including crystals and particulate matter. * CHRONIC INFLAMMATION  Alternative macrophage activation  induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells.  Not actively microbicidal instead, the principal function of alternatively activated (M2) macrophages is in tissue repair. secrete growth factors that:  promote angiogenesis activate fibroblasts  stimulate collagen synthesis. Maturation of mononuclear phagocytes  Roles of Macrophage in inflammation:  1. ingest and eliminate microbes and dead tissues.  2. initiate the process of tissue repair and are involved in scar formation and fibrosis.  3. secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines, and others) and eicosanoids.  4. display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that is essential for defense against many microbes by cell-mediated immune responses.  Fate of macrophages after inflammation abates:  eventually die or wander off into the lymphatics.  In chronic inflammatory sites, however, macrophage accumulation persists, because of continued recruitment from the blood and local proliferation  Macrophages fuse into large, multinucleate giant cells induced by IFN-γ. Chronic Inflammatory Cells  T and B lymphocytes  Antigen-activated (via macrophages and dendritic cells)  Release macrophage-activating cytokines (in turn, macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed)  Plasma cells  Terminally differentiated B cells  Produce antibodies  Eosinophils  Found especially at sites of parasitic infection, or at allergic (IgE-mediated) sites  Granulomatous Inflammation  a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis.  The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called epithelioid cells.  Some activated macrophages may fuse, forming multinucleate giant cells.  SYSTEMIC EFFECTS OF INFLAMMATION  1. Fever  2. Elevated levels of acute phase proteins  CRP – C reactive proteins  Fibrinogen  Serum amyloid A  ESR  3. Leukocytosis/leukopenia  Neutrophilia  Lymphocytosis, eosinophilia  4. S/Sx : inc. HR, inc BP, sweating, rigors, chills, anorexia, somnolence, malaise  5. Signs of sepsis: inc TNF, IL-12, IL-1, , acidosis, hypovolemic shock.  THANK YOU This PPT was prepared by GenPath and Histopath Professors- Rubio, Ahmad, Pagud, and Maria Jose. Updated by the current cluster.