Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

INFLAMMATION OVERVIEW
1. A protective response 2. Get rid of damaged/necrotic tissue and foreign invaders such as microbes i. Destroy -->infectious agents ii. Dilutes -->infectious agents iii. Walls off -->infectious agents Initial cause : microbes / toxins Injurious consequence : necrotic cell / tissue 3. Complex reaction in tissue -> responses of blood vessels and leukocytes (plasma proteins) 4. Inflammatory stimulus generate/activate -> various cells / plasma proteins to produce -> soluble factors -> trigger vascular and cellular reactions 5. Termination of inflammation: a. When offending agent is eliminated b. Rxn resolves rapidly, mediators are broken down and dissipated c. Leukocytes have short lifespan in tissues d. Anti-inflammatory mechanism activated i. controls inflammatory response ii. Prevent excessive host tissue damage 6. Intertwined with Repair Process Repair Process: a. Heal damaged tissue b. Repair begins at inflammation c. Completed when injurious agent is neutralized d. Replaces damage tissue through: i. Regeneration of native parenchymal cells ii. Filling of defective tiss. w/ fibrous tiss. (called Scarring) iii. Or combination of these 2 processes 7. Inflammation can be harmful in most situations a. Inflamm Mechanism has intrinsic ability to destroy both: i. Foreign invaders ii. Normal tissues b. Can cause injury or disease c. Underlies common chronic disease: i. Rheumatoid arthritis ii. Atherosclerosis iii. Lung Fibrosis iv. Hypersensitivity rxns (insect bites, drugs, toxins d. Anti-inflamm drugs: i. Control harmful effects of Inflammation ii. Not interfere on beneficial effects e. Abnormal host responses contributes to disease (usually in chronic inflammation) i. Atherosclerosis ii. Type-2 Diabetes iii. Alzheimer disease iv. Cancer f. Referred to as silent-killer

Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. 8. Has 2 Types: a. Acute Inflammation i. Rapid onset (minutes) ii. Short duration (hours or days) Main features: 1. Exudation of fluid and plasma proteins (edema) 2. Emigration of leukocytes (neutrophils / polymorphonuclear leukocytes) Successful -> subsides Fail -> progress to chronic phase b. Chronic Inflammation i. Onset: 1. Follow acute inflammation 2. Insidious ii. Longer duration iii. Associated w/ Lymphocytes or Macrophages iv. Characterized by: 1. Proliferation of blood vessels 2. Fibrosis 3. Tissue destruction

CPU MD 2014

HISTORICAL HIGHLIGHTS
1. Described in Egyptian Papyrus (3000 BC) 2. Celsus, roman writer: 4 Cardinal Signs of Inflammation (more prominent in acute inflamm) i. Rubor (redness) ii. Tumor (swelling) iii. Calor (heat) iv. Dolor (pain) 3. Rudolf Virchow (19th cent) 5th Sign: loss of function (function laesa) 4. John Hunter Inflammation is not a disease but a nonspecific response w/ salutary effect on host 5. Elie Metchnikoff (Russian, 1880s) a. Described Phagocytosis b. Purpose of Inflammation bring phagocytic cells to site and engulf invading bacteria 6. George Bernard Shaw a. Doctor s Dilemma b. To cure-all disease -> stimulate the phagocytes 7. Thomas Lewis a. Chemical substances (eg. Histamine) mediate vascular changes in inflammation b. Lead to important discoveries of: i. Chemical mediators in inflammation ii. Use of anti-inflammatory drugs

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

ACUTE INFLAMMATION
1. Rapid host response 2. Deliver leukocytes and plasma proteins (antibodies) to site of infection 3. 3 Components: a. Alteration of vascular calibre lead to inc. blood flow b. Structural changes in microvasculature permit plasma proteins and leukocytes to leave circulation c. Emigration of leukocytes from microcirc, leukocyte accumulation in site of injury, and leukocyte activation

4. Stimuli of Acute Inflamm: a. Infections (bacterial, viral, fungal, parasitic) and microbial toxins i. most common and medically important ii. Sensing mechanisms (receptors) engagement triggers signalling pathways -> stimulate production of mediators 1. Toll-like receptors (TLRs) / Drosophila protein Toll - for microbial products 2. Several cytoplasmic receptors detect bacteria, viruses, and fungi b. Tissue necrosis i. From different causes: 1. Ischemia (myocardial infarct) 2. Trauma 3. Physical and Chemical Injury ii. Releases several chemicals that cause Inflamm Response 1. Uric Acid a purine metabolite 2. Adenosine Triphosphate normal energy store 3. HMGB-1 - DNA-binding protein of unknown function 4. DNA released into the cytoplasm 5. HIF-1 (hypoxia-induced factor-1 ) hypoxia a. produced by cells deprived of oxygen b. activates the transcription of many genes - including vascular endothelial growth factor (VEGF) -> increases vascular permeability

Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 c. Foreign bodies (eg. splinters, dirt, sutures) i. cause traumatic tissue injury ii. carry microbes d. Immune/Hypersensitivity Reactions i. normally protective immune system damages the individual's own tissues ii. injurious immune responses: 1. directed against self-antigens ->autoimmune diseases 2. excessive reactions against environmental substances or microbes iii. associated with chronic inflammation 1. autoimmune reactions are persistent and difficult to cure 2. stimuli for the inflammatory responses cannot be eliminated iv. induced by cytokines from T Lymphocytes and other immune system cells v. common in immune-mediated inflammatory disease 5. Sequence of Events in Acute Inflammation a. Reaction of Blood Vessels - series of changes designed to maximize the movement of plasma proteins and circulating cells out of the circulation i. Exudation - escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities Exudate - Presence implies inc. in permeability of small blood vessels -> Inflammatory Response - Extravascular fluid that has: a. high protein concentration b. cellular debris c. high specific gravity Transudate - An ultrafiltrate of blood plasma <- osmotic or hydrostatic imbalance + inc . vasc. perm - Fluid: a. low protein content (mostly albumin) b. little or no cellular material c. low specific gravity Edema - excess of fluid in the interstitial tissue or serous cavities - either exudate or transudate Pus - purulent exudate - rich in : o leukocytes (mostly neutrophils) o debris of dead cells o microbes b. Changes in Vascular Flow and Caliber i. begin early after injury ii. consist of: 1. vasodilation a. earliest manifestations of acute inflammation b. follows a transient constriction of arterioles c. involves the arterioles (leads to opening of new capillary beds in the area) d. results in: inc. blood flow (cause heat and redness ERYTHEMA) e. induced by action of mediators on vasc. smooth muscle i. Histamine ii. NO (nitric oxide) 4

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 2. Inc. perm. of microvasculature w/ outpouring of protein-rich fluid in extravasc. tissues 3. Loss of fluid and inc. vessel diameter lead to: a. slower blood flow b. concentration of red cells in small vessels c. increased viscosity of the blood 4. Statis (vascular congestion) - dilation of small vessels that are packed with slowly moving red cells; localized redness 5. Accumulation of blood leukocytes (neutrophils) 6. Activation of endothelial cells by mediators (produced at sites of infection and tissue damage) -> inc. levels of adhesion molecules 7. Adherence of leukocytes to endothelium 8. Migration of leukocytes through vascular wall into interstitial tissue iii. Increased Vascular Permeability (Vascular Leakage) Mechanisms: a. Contraction of endothelial cells (immediate transient response) i. increases interendothelial spaces ii. occurs rapidly after exposure to mediator iii. short-lived (15 30 minutes) Delayed prolonged leakage - begins after a delay of 2-12 hrs - lasts for several hours or days - caused by contraction of endothelial cells or mild endothelial damage - in mild injury eg. late-appearing sunburn Elicited by: 1. Histamine 2. Bradykinin 3. Leukotrienes 4. neuropeptide substance P 5. many other chemical mediators b. Endothelial injury ->results to endothelial cell necrosis and detachment - Usually by direct damage to endothelium - Neutrophil adhesion can injure endothelium c. Transcytosis -> inc. transport of fluids and proteins through endothelial cell - Involve vesiculovacuolar organelle channels consisting of interconnected, uncoated vesicles and vacuoles located close to intercellular junctions factors such as VEGF promote vascular leakage by inc. number and size of these channels

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

iv. Responses of Lymphatic Vessels (Reactive or Inflammatory Lymphadenitis) 1. lymphatics and lymph nodes a. filters and polices the extravascular fluids b. proliferate during inflammatory reactions i. to handle the increased load ii. increased numbers of lymphocytes and macrophages c. enlarged -> caused by hyperplasia of lymphoid follicles 2. In inflammation -> lymph flow is increased -> helps drain edema fluid that accumulates due to increased vascular permeability 3. presence of red streaks near a skin wound -> sign of infection 4. lymphadenitis / lymphangitis a. indicated by streaking that follows the course of lymphatic channels b. infection of lymph channels c. painful enlargement of draining lymph nodes c. Reaction of leukocytes in Inflammation i. Deliver leukocytes to site of injury ii. Activate leukocytes to eliminate offending agents iii. Phagocytic leukocytes are important (neutrophils and macrophages) 1. Ingest and kill bacteria and other microbes 2. Eliminate necrotic tissue and foreign substances 3. Produce growth factors for repair iv. When strongly activated: 1. induce tissue damage and prolonged inflammation 2. leukocyte products that destroy microbes and necrotic tissues -> injure normal host tissues

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

v. Mechanism: 1. Recruitment of Leukocytes to Sites of Infection and Injury (Extravasation) a. Margination - leukocyte redistribution; Mechanism: Stasis (slow blood flow) -> change in hemodynamic conditions (wall shear stress decreases) -> WBC assume peripheral position (RBC in central axial column) b. Rolling i. adhere to endothelium, detach and bind again ii. at some point leukocytes adhere firmly iii. mediated by SELECTINS - Types: L-selectin (leukocytes) E-selectin (endothelium) P-selectin (platelets and endothelium) - Ligands: sialylated oligosaccharides bound to mucin-like glycoprotein backbones - expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury c. Adhesion i. mediated by complementary adhesion molecules (CAM) ii. expression is enhanced by secreted proteins called Cytokines iii. cytokines secreted by tissues in response to injurious agents iv. Tissue macrophages, mast cells, and endothelial cells - encounter microbes and dead tissues - respond by secreting Cytokines: tumor necrosis factor (TNF) interleukin-1 (IL-1) chemokines (chemoattractant cytokines) > enter the blood vessel > bind to endothelial cell proteoglycans > displayed at high concentrations on the endothelial surface > bind to and activate the rolling leukocytes - Integrins family of heterodimeric leukocyte surface proteins mediates firm adhesion TNF and IL-1 -- induce endothelial expression of ligands for integrins > vascular cell adhesion molecule 1 (VCAM-1, the ligand for the VLA-4 integrin) > intercellular adhesion molecule-1 (ICAM-1, the ligand for the LFA-1 and Mac-1 integrins) v. firm integrin-mediated binding of the leukocytes to the endothelium - results from: combination of cytokine-induced expression of integrin ligands on the endothelium activation of integrins on the leukocytes d. Leukocytes stop rolling -> their cytoskeleton is reorganized -> spread out on endothelial surface 7

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 e. Leukocyte migration through endothelium (TRANSMIGRATION/DIAPEDESIS) i. Occurs mainly on post-capillary venules ii. Chemokine stimulation -> migration toward chemical concentration gradient (site of injury or infection) iii. Adhesion molecules are also involved - Present in intercellular junctions bet. Endothelial cells - PECAM-1 (platelet endothelial cell adhesion molecule) or CD31 iv. Leukocytes 1. traverse the endothelium 2. pierce the basement membrane (by secreting collagenases) 3. enter the extravascular tissue 4. migrate toward the chemotactic gradient created by chemokines 5. accumulate in the extravascular site (retained in the site where they are needed) Leukocyte Adhesion Molecules Genetic Deficiencies: 1. Leukocyte adhesion deficiency type 1 - defect in the biosynthesis of the 2 chain shared by the LFA-1 and Mac-1 integrins 2. Leukocyte adhesion deficiency type 2 - defect in a fucosyl transferase (enzyme that attaches fucose moieties to protein backbones); caused by absence of sialyl-Lewis X, the fucosecontaining ligand for E- and P-selectins f. Chemotaxis of Leukocytes i. Chemoattractants - exogenous bacterial products > peptides that possess an N-formylmethionine terminal amino acid - endogenous chemical mediators > cytokines > components of the complement system (particularly C5a) > arachidonic acid (AA) metabolites leukotriene B4 (LTB4) ii. chemotactic agents bind to specific seven-transmembrane G protein coupled receptors (surface of leukocytes) iii. receptors activate -> second messengers -> increase cytosolic calcium -> activate small guanosine triphosphatases of the Rac/Rho/cdc42 family and numerous kinases -> induce polymerization of actin -> increased amounts of polymerized actin at leading edge of the cell -> localization of myosin filaments -> leukocyte moves by extending filopodia -> leukocytes migrate toward the inflammatory stimulus

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 g. Nature of Leukocyte Infiltrate varies with: i. age of inflamm response - 6-24hrs neutrophils predominate more numerous in the blood respond rapidly to chemokines attach more firmly to adhesion molecules but short lived, apoptosis and disappear after after 24hrs - 24-48hrs monocytes replace Survive longer May proliferate in tissues ii. type of stimulus - bacteria neutrophils - viral lymphocytes - hypersensitivity eosinophils 2. Recognition of Microbes and Dead Tissues Leukocyte receptors that recognize external stimuli and deliver activating signals: i. Toll-like receptors (TLRs) microbial products - recognize components of different types of microbes ii. G protein coupled receptors found on neutrophils, macrophages, and most other types of leukocytes - recognize short bacterial peptides containing Nformylmethionyl residues iii. Receptors for opsonins - Opsonization coat microbes with opsonin; enhance phagocytosis Antibodies Complement proteins Lectins iv. Receptors for cytokines - Leukocytes express receptors for cytokines (produced in response to microbes) interferon- (IFN- ) - secreted by: > natural killer cells > antigen-activated T lymphocytes (adaptive immune responses) 3. Phagocytosis a. Sequential Steps: i. recognition and attachment of the particle to be ingested by the leukocyte - Mannose receptors - Scavenger receptors - Opsonin receptors ii. engulfment, with subsequent formation of a phagocytic vacuole - extensions of the cytoplasm (pseudopods) wrap foreign particle - plasma membrane pinches off to form a vesicle (phagosome) that encloses particle - phagosome then fuses with a lysosomal granule - discharge of the granule's contents into the phagolysosome 9

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 iii. killing or degradation of the ingested material - accomplished by: reactive oxygen species (ROS) reactive nitrogen species (RNS) derived from NO respiratory burst - Phagocyte granules contain: Elastase Defensin Cathelicidins Lysozyme Lactoferrin Major basic protein Bactericidal/permeability increasing protein d. Other functional responses of Activated Leukocytes i. Produce growth factors induce tissue repair after injury 1. stimulate the proliferation of endothelial cells and fibroblasts 2. synthesis of collagen, and enzymes that remodel connective tissues ii. secrete inhibitors of the inflammatory response - amplify and control the reaction 6. Termination of Acute Inflammatory Response a. inflammation declines: i. mediators of inflammation are produced in rapid bursts ii. mediators are produced only as long as the stimulus persists iii. mediators have short half-lives iv. mediators are degraded after their release b. neutrophils i. short half-lives in tissues a ii. die by apoptosis within a few hours after leaving the blood c. inflammation process triggers a variety of stop signals that serve to actively terminate the reaction d. arachidonic acid metabolite i. pro-inflammatory leukotrienes ii. anti-inflammatory lipoxins e. anti-inflammatory cytokines i. transforming growth factor- (TGF- ) ii. IL-10 f. anti-inflammatory lipid mediators i. resolvins ii. protectins g. neural impulses (cholinergic discharge) - inhibit the production of TNF in macrophages

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Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

MEDIATORS OF INFLAMMATION
The Actions of the Principal Mediators of Inflammation Mediator Principal Sources Actions CELL-DERIVED Histamine Serotonin Prostaglandins Leukotrienes Platelet-activating factor Reactive oxygen species Nitric oxide Cytokines (TNF, IL-1) Mast cells, basophils, platelets Platelets Mast cells, leukocytes Mast cells, leukocytes Leukocytes, mast cells Leukocytes Endothelium, macrophages Macrophages, endothelial cells, mast cells Leukocytes, activated macrophages Vasodilation, increased vascular permeability, endothelial activation Vasodilation, increased vascular permeability Vasodilation, pain, fever Increased vascular permeability, chemotaxis, leukocyte adhesion and activation Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst Killing of microbes, tissue damage Vascular smooth muscle relaxation, killing of microbes Local endothelial activation (expression of adhesion molecules), fever/pain/anorexia/hypotension, decreased vascular resistance (shock) Chemotaxis, leukocyte activation

Chemokines

PLASMA PROTEIN DERIVED Complement products Plasma (produced in (C5a, C3a, C4a) liver) Kinins Proteases activated during coagulation Plasma (produced in liver) Plasma (produced in liver) Leukocyte chemotaxis and activation, vasodilation (mast cell stimulation) Increased vascular permeability, smooth muscle contraction, vasodilation, pain Endothelial activation, leukocyte recruitment

IL-1, interleukin-1; MAC, membrane attack complex; TNF, tumor necrosis factor

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Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

Properties and General Principles of Mediator Production and Action

1. Generated either from cells or from plasma proteins a. sequestered in intracellular granules b. rapidly secreted by granule exocytosis c. synthesized de novo in response to a stimulus d. Produced by: i. Platelets ii. Neutrophils iii. monocytes/macrophages iv. mast cells v. endothelium vi. smooth muscle vii. fibroblasts viii. Liver: 1. Plasma-derived mediators 2. present in the circulation as inactive precursors (must be activated) 2. Active mediators are produced in response to various stimuli Stimuli include: i. microbial products ii. substances released from necrotic cells iii. proteins of the complement, kinin, and coagulation systems 3. One mediator can stimulate the release of other mediators a. cytokine TNF acts on endothelial cells -> stimulate the production of another cytokine, IL-1, and many chemokines b. provide mechanisms for amplifying or counteracting the initial action of a mediator 4. Mediators vary in their range of cellular targets 5. Once activated and released from the cell, most of these mediators are short-lived Cell-Derived Mediators 1. Vasoactive Amines a. important actions on blood vessels b. stored as preformed molecules in cells c. first mediators to be released during inflammation d. Histamine i. richest sources: mast cells; also in blood basophils and platelets ii. present in mast cell granules iii. released by mast cell degranulation iv. in response to a variety of stimuli 1. physical injury such as trauma, cold or heat 2. binding of antibodies to mast cells (allergic reactions) 3. anaphylatoxins (C3a and C5a) 4. histamine-releasing proteins derived from leukocytes 5. neuropeptides (substance P) 6. cytokines (IL-1, IL-8) v. causes dilation of arterioles and increases the permeability of venules

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Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 e. Serotonin (5-hydroxytryptamine) i. preformed vasoactive mediator ii. actions similar to histamine iii. present in platelets and certain neuroendocrine cells (GIT) iv. Release of serotonin from platelets <- stimulated when platelets aggregate after contact with collagen, thrombin, adenosine diphosphate, and antigenantibody complexes v. increased vascular permeability 2. Arachidonic Acid (AA) Metabolites a. 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) b. derived from: i. dietary sources ii. conversion from the essential fatty acid linoleic acid c. normally esterified in membrane phospholipids d. Prostaglandins (PGs) i. produced by: 1. mast cells 2. macrophages 3. endothelial cells ii. produced by the actions of two cyclooxygenases (COX-1 and COX-2) iii. important PGs in inflammation: 1. PGE2 2. PGD2 3. PGF2 4. PGI2 (prostacyclin) 5. TxA2 (thromboxane) e. Leukotrienes i. lipoxygenase enzymes - responsible for production ii. secreted mainly by leukocytes iii. chemoattractants for leukocytes iv. have vascular effects v. Types: 1. 5-lipoxygenase a. predominant in neutrophils b. converts AA to 5-hydroxyeicosatetraenoic acid c. chemotactic for neutrophils d. precursor of the leukotrienes 2. LTB4 a. potent chemotactic agent and activator of neutrophils b. effects: i. aggregation and adhesion of the cells to venular endothelium ii. generation of ROS iii. release of lysosomal enzymes 3. cysteinylcontaining leukotrienes C4, D4, and E4(LTC4, LTD4, LTE4) a. intense vasoconstriction b. bronchospasm (important in asthma) c. increased vascular permeability

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Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 f. Lipoxins i. generated from AA by the lipoxygenase pathway ii. inhibitors of inflammation iii. neutrophils produce intermediates in lipoxin synthesis iv. inhibit: 1. leukocyte recruitment and cellular components of inflammation 2. neutrophil chemotaxis and adhesion to endothelium Anti-inflammatory drugs: Cyclooxygenase inhibitors- inhibit both COX-1 and COX-2 (inhibit prostaglandin synthesis) y Aspirin y Nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin o Lipoxygenase inhibitors  inhibit leukotriene production - Zileuton  block leukotriene receptors Montelukast o Broad-spectrum inhibitors corticosteroids  act by reducing the transcription of genes encoding COX-2, phospholipase A2, proinflammatory cytokines (such as IL-1 and TNF), and iNOS 3. Platelet-Activating Factor (PAF) a. phospholipid-derived mediator b. causes platelet aggregation c. multiple inflammatory effects d. produced by: (in both secreted and cell-bound form) i. platelets ii. basophils iii. mast cells iv. neutrophils v. macrophages vi. endothelial cells e. causes: i. vasoconstriction ii. bronchoconstriction iii. increased leukocyte adhesion to endothelium (by enhancing integrin-mediated leukocyte binding) iv. chemotaxis v. degranulation vi. oxidative burst f. extremely low concentrations -> causes vasodilation and increased venular permeability g. PAF elicit most of vascular and cellular reactions of inflammation h. boosts the synthesis of other mediators (eicosanoids) 4. Reactive Oxygen Species a. production is dependent on the activation of the NADPH oxidase system b. increase the expression of chemokines, cytokines and endothelial leukocyte adhesion molecules -> amplifying the inflammatory response

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Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. 5. Nitric Oxide (NO) a. released from endothelial cells b. endothelium -derived relaxing factor c. synthesized from L-arginine by the enzyme nitric oxide synthase (NOS) d. three different types of NOS: i. endothelial (eNOS) ii. neuronal (nNOS) iii. inducible (iNOS) e. relaxes vascular smooth muscle and promotes vasodilation f. inhibitor of: i. cellular component of inflammatory responses ii. platelet aggregation and adhesion iii. several features of mast cell induced inflammation iv. leukocyte recruitment

CPU MD 2014

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Pathology - Inflammation 6. Cytokines Cytokine Principal Sources IN ACUTE INFLAMMATION TNF IL-1 IL-6 Chemokines

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

Principal Actions in Inflammation

Macrophages, mast cells, T lymphocytes Macrophages, endothelial cells, some epithelial cells Macrophages, other cells Macrophages, endothelial cells, T lymphocytes, mast cells, other cell types

Stimulates expression of endothelial adhesion molecules and secretion of other cytokines; systemic effects Similar to TNF; greater role in fever Systemic effects (acute-phase response) Recruitment of leukocytes to sites of inflammation; migration of cells to normal tissues

IN CHRONIC INFLAMMATION IL-12 IFNIL-17 Dendritic cells, macrophages T lymphocytes, NK cells T lymphocytes Increased production of IFNActivation of macrophages (increased ability to kill microbes and tumor cells) Recruitment of neutrophils and monocytes

IFN- , interferon- ; IL-1, interleukin-1; NK cells, natural killer cells; TNF, tumor necrosis factor.

7. Chemokines a. family of small (8 to 10 kD) proteins b. chemoattractants for specific types of leukocytes c. four major groups (according to the arrangement of the conserved cysteine (C) residues in the mature proteins): i. C-X-C chemokines ( chemokines) 1. act primarily on neutrophils 2. secreted by activated macrophages, endothelial cells, and other cell types 3. causes activation and chemotaxis of neutrophils ii. C-C chemokines ( chemokines) 1. Include: a. monocyte chemoattractant protein (MCP-1) b. eotaxin c. macrophage inflammatory protein-1 (MIP-1 ) d. RANTES (regulated and normal T-cell expressed and secreted) e. attract monocytes, eosinophils, basophils, and lymphocytes iii. C chemokines ( chemokines) - specific for lymphocytes iv. CX3C chemokines 1. Fractalkine 2. exists in two forms: a. the cell surface-bound protein i. can be induced on endothelial cells by inflammatory cytokines ii. promotes strong adhesion of monocytes and T cells b. soluble form i. derived by proteolysis of the membrane-bound protein ii. has potent chemoattractant activity for monocytes and T cells 16

Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. d. two main function: i. they stimulate leukocyte recruitment in inflammation ii. control the normal migration of cells through various tissues 8. Neuropeptides a. secreted by sensory nerves and various leukocytes b. initiation and propagation of an inflammatory response

CPU MD 2014

Plasma-Protein Derived Mediators 1. Complement System a. consists of more than 20 proteins b. functions in both innate and adaptive immunity for defense against microbial pathogens c. causes: i. increased vascular permeability ii. chemotaxis iii. opsonization d. Pathways: i. classical pathway - triggered by fixation of C1 to antibody (IgM or IgG) ii. alternative pathway Triggered by: (in the absence of antibody) o microbial surface molecules (eg. endotoxin, or LPS) o complex polysaccharides o cobra venom o and other substances iii. lectin pathway - plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1 e. Functions: i. Inflammation ii. Phagocytosis iii. Cell lysis f. tightly controlled by cell-associated and circulating regulatory proteins

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Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. CPU MD 2014 2. Coagulation and Kinin Systems a. Bradykinin, C3a, and C5a - mediators of increased vascular permeability b. C5a - mediator of chemotaxis c. Thrombin - has effects on endothelial cells and many other cell types d. C3a and C5a can be generated by several types of reactions: i. immunologic reactions - involving antibodies and complement (the classical pathway) ii. activation of alternative and lectin complement pathways by microbes (absence of antibodies) iii. agents not directly related to immune responses: 1. plasmin 2. kallikrein 3. serine proteases e. Activated Hageman factor (factor XIIa) initiates four systems involved in the inflammatory response: i. kinin system - produces vasoactive kinins ii. clotting system 1. induces formation of thrombin 2. has inflammatory properties iii. fibrinolytic system - induce inflammation 1. produces plasmin 2. degrades fibrin to produce fibrinopeptides iv. complement system 1. produces anaphylatoxins and other mediators 2. kallikreinby feedback -> activate Hageman factor (amplification of the reaction)

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Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. Role of Mediators in Different Reactions of Inflammation Role in Inflammation Mediators Vasodilation Prostaglandins Nitric oxide Histamine Increased vascular permeability Histamine and serotonin

CPU MD 2014

C3a and C5a (by liberating vasoactive amines from mast cells, other cells) Bradykinin Leukotrienes C4, D4, E4 PAF Substance P Chemotaxis, leukocyte recruitment and activation TNF, IL-1 Chemokines C3a, C5a Leukotriene B4 (Bacterial products, e.g., N-formyl methyl peptides) Fever IL-1, TNF Prostaglandins Pain Prostaglandins Bradykinin Tissue damage Lysosomal enzymes of leukocytes Reactive oxygen species Nitric oxide

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Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

OUTCOMES OF ACUTE INFLAMMATION

1. Complete resolution - restoration of the site of acute inflammation to normal; injury is limited or short-lived 2. Healing by connective tissue replacement (fibrosis) - involves tissues that are incapable of regeneration; connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue (Organization) 3. Progression to chronic inflammation

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Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION

1. Serous inflammation a. outpouring of a thin fluid that may be derived from: i. plasma ii. secretions of mesothelial cells b. usually in: i. peritoneal cavities ii. pleuralcavities iii. pericardial cavities c. accumulation of fluid in these cavities ->effusion d. skin blister <- from a burn or viral infection : large accumulation of serous fluid 2. Fibrinous inflammation a. fibrinogen pass the vascular barrier b. fibrinous exudate development i. characteristic of inflammation in the lining of body cavities 1. meninges 2. pericardium 3. pleura ii. removed by: 1. fibrinolysis 2. clearing of debris by macrophages c. fibrin appearance: (histologically) i. eosinophilic meshwork of threads ii. amorphous coagulum 3. Suppurative or Purulent Inflammation: Abscess a. production of large amounts of pus or purulent exudate i. Consisting of: 1. Neutrophils 2. liquefactive necrosis 3. edema fluid b. pyogenic(pus-producing) bacteria staphylococci c. eg. acute appendicitis d. Abscesses i. localized collections of purulent inflammatory tissue ii. caused by suppuration buried in a tissue, an organ, or a confined space iii. produced by deep seeding of pyogenic bacteria into a tissue iv. central region 1. mass of necrotic leukocytes and tissue cells 2. zone of preserved neutrophils around v. vascular dilation occur vi. parenchymal and fibroblastic proliferation occur vii. indicates chronic inflammation and repair 21

Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

4. Ulcer a. b. c. d.

local defect, or excavation, of surface of an organ or tissue produced by the sloughing (shedding) of inflamed necrotic tissue tissue necrosis and resultant inflammation exist on or near a surface most commonly encountered in: i. mucosa of the mouth, stomach, intestines, or genitourinary tract ii. skin and subcutaneous tissue of lower extremities (older persons who have circulatory disturbances that predispose to extensive ischemic necrosis)

CHRONIC INFLAMMATION
1. Causes of Chronic Inflammation a. Persistent infections i. microorganisms that are difficult to eradicate 1. mycobacteria 2. viruses 3. fungi 4. parasites ii. delayed-type hypersensitivity iii. granulomatous reaction - specific pattern of inflammatory response b. Immune-mediated inflammatory diseases i. caused by excessive and inappropriate activation of immune system ii. autoimmune diseases - immune reactions develop against own tissues 1. rheumatoid arthritis 2. multiple sclerosis iii. unregulated immune responses against microbes - inflammatory bowel disease iv. Immune responses against common environmental substances - allergic diseases(bronchial asthma) c. Prolonged exposure to potentially toxic agentseither: i. exogenous - inflammatory lung disease; Silicosis-silica inhaled for prolonged periods ii. endogenous Atherosclerosis - chronic inflammatory process in arterial wall byendogenous toxic plasma lipid components 2. Morphologic features a. Infiltration with mononuclear cells i. Macrophages ii. Lymphocytes iii. Plasma cells b. Tissue destruction - induced by the persistent offending agent or by the inflammatory cells c. Attempts at healing by connective tissue replacement of damaged tissue i. Angiogenesis - proliferation of small blood vessels ii. Fibrosis 22

Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. 3. Role of Macrophages in Chronic Inflammation a. Macrophages i. one component of mononuclear phagocyte system/reticuloendothelial system ii. cells of bone marrow origin 1. blood monocytes 2. tissue macrophages a. liver (Kupffer cells) b. spleen and lymph nodes (sinus histiocytes) c. lungs (alveolar macrophages) d. central nervous system (microglia) b. Extravasation of monocytes i. governed by the same factors that are involved in neutrophil emigration 1. adhesion molecules 2. chemical mediators with chemotactic and activating properties ii. monocyte ->macrophage (upon reaching extravascular tissue) iii. activatedby a variety of stimuli 1. microbial products that engage TLRs 2. cellular receptors 3. cytokines (eg. IFN- ) secreted by: a. sensitized T lymphocytes b. natural killer cells 4. chemical mediators

CPU MD 2014

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Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

iv. products of activated macrophages 1. eliminate injurious agents such as microbes 2. nitiate the process of repair 3. responsible for tissue injury in chronic inflammation v. Activation of macrophagesincrease levels of: 1. lysosomal enzymes 2. reactive oxygen and nitrogen species 3. production of cytokines 4. growth factors 5. mediators of inflammation 4. Other cell types involved in Chronic Inflammation a. Lymphocytes i. mobilized in both antibody-mediated and cell-mediated immune reactions ii. Antigen-stimulated (effector and memory) lymphocytes of different types (T and B cells) b. Plasma cells i. develop from activated B lymphocytes ii. produce antibodies directed against persistent foreign or self antigens iii. tertiary lymphoid organs - lymphoid organogenesis (patients with long-standing rheumatoid arthritis) 24

Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. c. Eosinophils i. abundant in immune reactions mediated by IgE and in parasitic infections ii. eotaxin - chemokine important for eosinophil recruitment d. Mast cells i. widely distributed in connective tissues ii. participate in both acute and chronic inflammatory reactions iii. occurs during: 1. allergic reactions to foods 2. insect venom 3. drugs 4. anaphylactic shock iv. ability to both promote and limit inflammatory reactions in different situations

CPU MD 2014

5. Granulomatous Inflammation a. distinctive pattern of chronic inflammation b. Immune reactions are usually involved in the development of granulomas c. granuloma -> cellular attempt to contain an offending agent that is difficult to eradicate i. strong activation of T lymphocytes leading to macrophage activation ii. can cause injury to normal tissues d. microscopic aggregation of macrophages -> transformed into epithelium-like cells i. surrounded by a collar of mononuclear leukocytes ii. principally lymphocytes iii. occasionally plasma cells e. Older granulomas develop an enclosing rim of fibroblasts and connective tissue f. epithelioid cells fuse -> form giant cells i. periphery ii. center of granulomas

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Pathology - Inflammation Giant Cells:

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

1. Langhans-type giant cell peripheral 2. Foreign body type giant cell haphazard g. 2 types: i. Foreign body granulomas ii. Immune granulomas Examples of Diseases with Granulomatous Inflammation Disease Cause Tissue Reaction Tuberculosis Mycobacterium tuberculosis Caseating granuloma (tubercle): focus of activated macrophages (epithelioid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cells; central necrosis with amorphous granular debris; acid-fast bacilli Acid-fast bacilli in macrophages; noncaseating granulomas Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells necrotic without loss of cellular outline Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon Noncaseating granulomas with abundant activated macrophages Occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate

Leprosy Syphilis

Mycobacterium leprae Treponema pallidum

Cat-scratch disease Sarcoidosis

Gram-negative bacillus Unknown etiology

Crohn disease Immune reaction against (inflammatory bowel intestinal bacteria, selfdisease) antigens

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Pathology - Inflammation

Chapter 2 Summary Robbins and Cotran 8th ed.

CPU MD 2014

SYSTEMIC EFFECTS OF INFLAMMATION

1. Fever a. elevation of body temperature ( 1 - 4C) b. manifestations of acute-phase response c. in response to pyrogens i. act by stimulating prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus ii. exogenous pyrogens - bacterial products iii. endogenous pyrogens -cytokines such as IL-1 and TNF iv. increase the enzymes (cyclooxygenases) that convert AA into prostaglandins v. prostaglandins (PGE2)in hypothalamus -> stimulateproduction of neurotransmitters (cyclic adenosine monophosphate) - function to reset the temperature set point at a higher level vi. NSAIDs (aspirin) reduce fever by inhibiting prostaglandin synthesis 2. Acute-phase proteins a. C-reactive protein (CRP) i. opsonins and fix complement ii. Elevated serum levels of CRP - marker for increased risk of myocardial infarction in patients with coronary artery disease b. Fibrinogen i. binds to red cells and causes them to form stacks ii. basis for measuring the erythrocyte sedimentation rate- simple test for the systemic inflammatory response c. Serum amyloid A (SAA) protein i. opsonins and fix complement ii. replaces apolipoprotein A iii. alter the targeting of high-density lipoproteins from liver cells to macrophages iv. source of energy-producing lipids v. causes secondary amyloidosis 3. Leukocytosis a. leukocyte count climbs to 15,000 or 20,000 cells/ L b. high levels of 40,000 to 100,000 cells/ L - extreme elevations (leukemoid reaction) c. neutrophilia - increase in the blood neutrophil count d. lymphocytosis - viral infections; increase in the number of lymphocytes e. eosinophilia - bronchial asthma, allergy, and parasitic infestations; inc. eosinophils f. leukopenia - decreased number of circulating white cells (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa)

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Pathology - Inflammation Chapter 2 Summary Robbins and Cotran 8th ed. 4. Manifestations: a. increased pulse and blood pressure b. decreased sweating (redirection of blood flow from cutaneous to deep vascular beds) c. rigors (shivering) d. chills (search for warmth) e. anorexia f. somnolence g. malaise 5. In severe bacterial infections (sepsis) - septic shock; high levels of cytokines a. disseminated intravascular coagulation b. cardiovascular failure c. metabolic disturbance

CPU MD 2014

CONSEQUENCES OF DEFECTIVE OR EXCESSIVE INFLAMMATION

1. Defective inflammation a. results in increased susceptibility to infections b. associated with delayed wound healing 2. Excessive inflammation a. unregulated immune responses against common environmental antigens Allergy b. immune responses develop against normally tolerated self-antigens Autoimmune Diseases

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