Presentation on theme: "Acute and Chronic Inflammation"— Presentation transcript:
1 Acute and Chronic Inflammation Chapter 2Lisa Stevens, D.O.
2 Background Inflammation Acute inflammation Acute or chronic Depends on the nature of the stimulusEffectiveness of the initial reaction in eliminating the stimulus or the damaged tissuesAcute inflammationRapid in onset (minutes)Short duration (hours or a few days)Exudation of fluid and plasma proteins (edema)Emigration of leukocytes (neutrophils)
3 Background Chronic inflammation May follow acute inflammation May be insidious in onsetLonger durationPresence of lymphocytes and macrophagesProliferation of blood vessels and fibrosisTissue destruction
4 Historical Highlights Clinical features of inflammationEgyptian papyrus dated around 3000 bcCelsusRoman writer of the first century adFirst listed the four cardinal signs of inflammationRubor (redness)Tumor (swelling)Calor (heat)Dolor (pain)Signs are typically more prominent in acute inflammation
5 Historical Highlights Fifth clinical signLoss of function (functio laesa)Added by Rudolf Virchow in the 19th centurySir Thomas LewisStudied the inflammatory response in skinChemical substances (histamine), mediate the vascular changes of inflammation
6 Acute Inflammation Rapid host response Delivers leukocytes and plasma proteinsSites of infection or tissue injuryThree major componentsAlterations in vascular caliberStructural changes in the microvasculatureEmigration of the leukocytes
7 Figure 2-1 The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth); (2) extravasation and extravascular deposition of plasma fluid and proteins (edema); (3) leukocyte emigration and accumulation in the site of injury.
8 Stimuli For Acute Inflammation Infections (bacterial, viral, fungal, parasitic) and microbial toxinsMost common and medically important causesTissue necrosisIschemiaTrauma,Physical and chemical injuryForeign bodiesImmune reactions
9 Definitions Exudate Transudate Inflammatory extravascular fluid High protein concentrationSpecific gravity > 1.020Usually due to permeabilityTransudateFluid with low protein concentration (albumin)Specific gravity < 1.012Permeability usually not increased (due to a pressure response)
10 Definitions Edema Pus Excess interstitial fluid Can be either an exudate or transudatePusPurulent exudateLeukocytes (neutrophils)Debris of dead cellsMicrobes
11 Figure 2-2 Formation of transudates and exudates Figure 2-2 Formation of transudates and exudates. A, Normal hydrostatic pressure (blue arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. B, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. C, An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces.
12 Seen here is vasodilation with exudation that has led to an outpouring of fluid with fibrin into the alveolar spaces, along with PMN's. The series of events in the process of inflammation are: Vasodilation: leads to greater blood flow to the area of inflammation, resulting in redness and heat.Vascular permeability: endothelial cells become "leaky" from either direct endothelial cell injury or via chemical mediators.Exudation: fluid, proteins, red blood cells, and white blood cells escape from the intravascular space as a result of increased osmotic pressure extravascularly and increased hydrostatic pressure intravascularlyVascular stasis: slowing of the blood in the bloodstream with vasodilation and fluid exudation to allow chemical mediators and inflammatory cells to collect and respond to the stimulus.
13 Vascular Changes Vasodilation Earliest manifestations of acute inflammationFollows a transient constriction of arteriolesLasts a few secondsFirst involves the arteriolesLeads to opening of new capillary bedsResult is increased blood flowCause of heat and redness (erythema) at the site of inflammationInduced by the action of several mediatorsHistamine and nitric oxide
14 Vascular Changes Vasodilation Followed by increased permeability of the microvasculatureOutpouring of protein-rich fluid into the extravascular tissuesLoss of fluid and increased vessel diameterLeads to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the bloodChanges result in dilation of small vesselsPacked with slowly moving red cellsStasis
15 Vascular Changes As stasis progresses…. Leukocytes (neutrophils) accumulate along the vascular endotheliumEndothelial cells are activated by mediators produced at sites of infection and tissue damageExpress increased levels of adhesion moleculesLeukocytes then adhere to the endotheliumMigrate through the vascular wall into the interstitial tissue
16 Increased Vascular Permeability Hallmark of acute inflammationIncreased vascular permeabilityLeads to the escape of a protein-rich exudate into the extravascular tissueCauses edema
17 Increased Vascular Permeability MechanismsContraction of endothelial cellsResults in increased interendothelial spacesMost common mechanism of vascular leakageElicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other mediatorsCalled the immediate transient responseOccurs rapidly after exposure to the mediatorUsually short-lived (15-30 minutes)
18 Increased Vascular Permeability MechanismsEndothelial injuryResults in endothelial cell necrosis and detachmentDirect damage to the endotheliumTranscytosisIncreased transport of fluids and proteins through the endothelial cell
19 Figure 2-3 Principal mechanisms of increased vascular permeability in inflammation, and their features and underlying causes. NO, nitric oxide; VEGF, vascular endothelial growth factor.
20 Figure 2-3 Principal mechanisms of increased vascular permeability in inflammation, and their features and underlying causes. NO, nitric oxide; VEGF, vascular endothelial growth factor.
21 Responses of the Lymphatics Lymphatics and lymph nodesFilters and polices the extravascular fluidsNormally drain the small amount of extravascular fluid that leaked out of capillariesInflammationLymph flow is increased and helps drain edema fluidAccumulates due to increased vascular permeabilityLymphatic vessels proliferate during inflammatory reactionsLymphatics may become secondarily inflamed (lymphangitis)Draining lymph nodes may become inflamed (lymphadenitis)Hyperplasia of the lymphoid folliclesIncreased numbers of lymphocytes and macrophages
22 Reactions of Leukocytes in Inflammation Processes involving leukocytes in inflammationRecruitment from the blood into extravascular tissuesRecognition of microbes and necrotic tissuesRemoval of the offending agent
23 Recruitment of Leukocytes to Sites of Infection and Injury ExtravasationJourney of leukocytesVessel lumen to the interstitial tissueLumenMargination, rolling, and adhesion to endotheliumMigration across endothelium and vessel wallMigration in the tissues toward a chemotactic stimulus
24 Figure 2-4 The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process-selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. Neutrophils express low levels of L-selectin; they bind to endothelial cells predom in antly via P- and E-selectins. ICAM-1, intercellular adhesion molecule 1; TNF, tumor necrosis factor.
25 Recruitment of Leukocytes to Sites of Infection and Injury MarginationBlood flow slows early in inflammation (stasis)Hemodynamic conditions change (wall shear stress decreases)More white cells assume a peripheral position along the endothelial surfaceRolling on the vessel wallIndividual and then rows of leukocytes adhere transiently to the endotheliumDetach and bind again
26 Recruitment of Leukocytes to Sites of Infection and Injury AdhereCells finally come to rest at some pointFirmly attachResembling pebbles over which a stream runs without disturbing them
27 Leukocyte Migration through Endothelium Body Migration of the leukocytes through the endotheliumTransmigration or diapedesisOccurs mainly in post-capillary venulesChemokines act on the adherent leukocytesStimulate the cells to migrate through interendothelial spaces toward the chemical concentration gradientToward the site of injury or infection where the chemokines are being produced
28 Leukocyte Migration through Endothelium Body After traversing the endotheliumLeukocytes pierce the basement membraneEnter the extravascular tissueCells then migrate toward the chemotactic gradientCells accumulate in the extravascular site
29 Chemotaxis of Leukocytes After exiting the circulationLeukocytes emigrate in tissues toward the site of injuryChemotaxisLocomotion oriented along a chemical gradientChemoattractantsExogenous substancesBacterial productsLipidsEndogenous substancesChemical mediatorsCytokinesComponents of the complement systemArachidonic acid (AA)
30 Chemotaxis of Leukocytes Leukocyte movementExtending filopodiaPull the back of the cell in the direction of extensionExample: Automobile with front-wheel drive is pulled by the wheels in frontMigrate toward the inflammatory stimulus
31 Figure 2-6 Scanning electron micrograph of a moving leukocyte in culture showing a filopodium (upper left) and a trailing tail. (Courtesy of Dr. Morris J. Karnovsky, Harvard Medical School, Boston, MA.)
32 Leukocytic Infiltrate Nature of the leukocyte infiltrateVaries with the age of the inflammatory responseVaries with the type of stimulusAcute inflammationNeutrophils predominate in the inflammatory infiltrateDuring the first 6 to 24 hoursReplaced by monocytes in 24 to 48 hoursSurvive longerMay proliferate in the tissuesBecome the dominant population in chronic inflammatory reactions
33 Leukocytic Infiltrate ExceptionsPseudomonas bacteriaCellular infiltrate is dominated by continuously recruited neutrophils for several daysViral infectionsLymphocytes may be the first cells to arriveHypersensitivity reactionsEosinophils may be the main cell type
34 Recognition of Microbes and Dead Tissues Leukocyte recruitment to site of infectionMust be activated to perform their functionsRecognition of the offending agentsDeliver signalsActivate the leukocytes to ingest and destroy the offending agents and amplify the inflammatory reaction
35 Figure 2-7 Nature of leukocyte infiltrates in inflammatory reactions Figure 2-7 Nature of leukocyte infiltrates in inflammatory reactions. The photomicrographs are representative of the early (neutrophilic) (A) and later (mononuclear) cellular infiltrates (B) seen in an inflammatory reaction in the myocardium following ischemic necrosis (infarction). The kinetics of edema and cellular infiltration (C) are approximations.
36 Removal of the Offending Agents Leukocyte activationResults from signaling pathwaysIncreases in cytosolic Ca2+Activation of enzymesProtein kinase CPhospholipase A2Functional responses that are most important for destruction of microbesPhagocytosisIntracellular killing
37 Phagocytosis Phagocytosis Involves three sequential steps Recognition and attachment of the particle to be ingested by the leukocyteIts engulfment, with subsequent formation of a phagocytic vacuoleKilling or degradation of the ingested material
38 Engulfment After a particle is bound to phagocyte receptors Extensions of the cytoplasm (pseudopods) flow around itPlasma membrane pinches off to form a vesicle (phagosome)Encloses the particleFuses with a lysosomal granuleDischarge of the granule's contents into the phagolysosome
39 Killing and Degradation Final step in the elimination of infectious agents and necrotic cellsOccurs within neutrophils and macrophagesMicrobial killing is accomplished largely by reactive oxygen species and reactive nitrogen species
40 Microbial killingCan also occur through the action of other substances in leukocyte granulesGranules contain many enzymesElastaseDefensinsCationic arginine-rich granule peptides that are toxic to microbesCathelicidinsAntimicrobial proteins found in neutrophils and other cellsLysozymeHydrolyzes the muramic acid-N-acetylglucosamine bond, found in the glycopeptide coat of all bacteria
41 Microbial killing Leukocyte granules Granules contain many enzymes LactoferrinIron-binding protein present in specific granulesMajor basic proteinCationic protein of eosinophilsLimited bactericidal activityCytotoxic to many parasitesBactericidal/permeability increasing proteinBinds bacterial endotoxinBelieved to be important in defense against some gram-negative bacteria
42 Functional Responses of Activated Leukocytes Leukocytes play several other roles in host defenseProduce a number of growth factorsStimulate the proliferation of endothelial cells and fibroblastsStimulate the synthesis of collagenStimulate enzymes that remodel connective tissuesThese products drive the process of repair after tissue injury
43 Release of Leukocyte Products and Leukocyte-Mediated Tissue Injury Leukocytes are important causes of injury to normal cells and tissues under several circumstancesPart of a normal defense reaction against infectious microbesInfections that are difficult to eradicate (TB) and certain viral diseasesProlonged host response contributes more to the pathology than does the microbe itselfInappropriately directed inflammatory responseAgainst host tissues, as in certain autoimmune diseasesExcessive host reactionAgainst usually harmless environmental substancesAllergic diseases, including asthma
44 Defects in Leukocyte Function Inherited and acquiredLead to increased vulnerability to infectionsImpairments of leukocyte functionInherited defects in leukocyte adhesionInherited defects in phagolysosome functionChédiak-Higashi syndromeAutosomal recessive conditionCharacterized by defective fusion of phagosomes and lysosomes in phagocytesCausing susceptibility to infections
45 Defects in Leukocyte Function Impairments of leukocyte functionInherited defects in leukocyte adhesionInherited defects in phagolysosome functionChédiak-Higashi syndromeAbnormalities in melanocytes (leading to albinism)Cells of the nervous system (associated with nerve defects)Platelets (causing bleeding disorders)Leukocyte abnormalitiesNeutropenia (decreased numbers of neutrophils)Defective degranulationDelayed microbial killing
46 Defects in Leukocyte Function Impairments of leukocyte functionInherited defects in microbicidal activityChronic granulomatous disease (group of congenital diseases)Characterized by defects in bacterial killingRender patients susceptible to recurrent bacterial infectionInherited defects in the genes encoding components of phagocyte oxidaseName of this disease comes from the macrophage-rich chronic inflammatory reactionTries to control the infection when the initial neutrophil defense is inadequateLeads to collections of activated macrophages that wall off the microbesAggregates called granulomas
47 Defects in Leukocyte Function Impairments of leukocyte functionAcquired deficienciesMost frequent cause of leukocyte defectsBone marrow suppressionDecreased production of leukocytesSeen following therapies for cancer (radiation and chemotherapy)Seen when the marrow space is compromised by tumorsArise in the marrowLeukemiasMetastatic from other sites
48 Acute and Chronic Inflammation PART 2Chapter 2Lisa Stevens, D.O.
49 Mediators of Inflammation Mediators are generated either from cells or from plasma proteinsCell-derived mediatorsNormally sequestered in intracellular granulesCan be rapidly secreted by granule exocytosisHistamine in mast cell granulesSynthesized de novo in response to a stimulusProstaglandins, cytokines
50 Mediators of Inflammation Cells that produce mediatorsPlatelets, neutrophils, monocytes/macrophages, and mast cellsMesenchymal cells (endothelium, smooth muscle, fibroblasts)Most epitheliaPlasma-derived mediatorsComplement proteins, kininsProduced mainly in the liverPresent in the circulation as inactive precursorsMust be activated to acquire their biologic properties
51 Mediators of Inflammation Active mediatorsProduced in response to various stimuliMicrobial productsSubstances released from necrotic cellsProteins of the complement, kinin, and coagulation systemsActivated by microbes and damaged tissuesEnsures that inflammation is normally triggered only when and where it is needed
52 Mediators of Inflammation Mediators are short-livedOnce activated and released from the cellQuickly decayArachidonic acid metabolitesInactivated by enzymesKininase inactivates bradykininOtherwise scavenged or inhibitedAntioxidants scavenge toxic oxygen metabolitesInhibited: complement regulatory proteins break up and degrade activated complement components
53 Cell-Derived Mediators Vasoactive aminesTwo major vasoactive aminesHistamine and SerotoninStored as preformed molecules in cells and areAmong the first mediators to be released during inflammation
54 Histamine Richest sources Found in blood basophils and platelets Mast cellsNormally present in the connective tissue adjacent to blood vesselsFound in blood basophils and plateletsPresent in mast cell granules
55 Histamine Released by mast cell degranulation in response to: Physical injury such as trauma, cold, or heatBinding of antibodies to mast cells (allergic reactions)Fragments of complement called anaphylatoxinsC3a and C5aHistamine-releasing proteins derived from leukocytesNeuropeptides (substance P)Cytokines (IL-1, IL-8)
56 Histamine Causes dilation of arterioles Increases the permeability of venulesConsidered to be the principal mediator of the immediate transient phase of increased vascular permeabilityProducing interendothelial gaps in venules
57 Serotonin Preformed vasoactive mediator Actions similar to those of histaminePresent in plateletsStimulated when platelets aggregateAfter contact with collagen, thrombin, adenosine diphosphate, and antigen-antibody complexesPlatelet release reactionKey component of coagulationPresent in certain neuroendocrine cellsGastrointestinal tract
58 Arachidonic Acid (AA) Metabolites Prostaglandins, Leukotrienes, and LipoxinsArachidonic acid20-carbon polyunsaturated fatty acidDerived from dietary sourcesConversion from the essential fatty acid linoleic acid
59 Arachidonic Acid (AA) Metabolites Does not occur free in the cellNormally esterified in membrane phospholipidsMechanical, chemical, and physical stimuliRelease AA from membrane phospholipids through the action of cellular phospholipasesPhospholipase A2
60 Arachidonic Acid (AA) Metabolites AA-derived mediators (eicosanoids)Synthesized by two major classes of enzymesCyclooxygenasesGenerate prostaglandinsLipoxygenasesProduce leukotrienes and lipoxinsBind to G protein-coupled receptors on many cell typesCan mediate virtually every step of inflammation
61 ProstaglandinsProduced by mast cells, macrophages, endothelial cells, and many othersInvolved in the vascular and systemic reactions of inflammationProduced by the actions of two cyclooxgenasesConstitutively expressed COX-1Inducible enzyme COX-2
62 Prostaglandins Divided into series based on structural features Coded by a letterPGD, PGE, PGF, PGG, and PGHSubscript numeral1, 2Indicates the number of double bonds in the compound
63 Prostaglandins Most important ones in inflammation Prostacyclin PGE2, PGD2, PGF2α, PGI2 (prostacyclin), and TxA2 (thromboxane)ProstacyclinVasodilatorPotent inhibitor of platelet aggregationMarkedly potentiates the permeability- increasing and chemotactic effects of other mediators
64 Prostaglandins PGD2 PGF2α Major prostaglandin made by mast cells Along with PGE2 (which is more widely distributed)Causes vasodilationIncreases the permeability of post-capillary venulesPotentiating edema formationPGF2αStimulates the contraction of uterine and bronchial smooth muscle and small arterioles
65 Prostaglandins PGD2 PGE2 Chemoattractant for neutrophils Hyperalgesic Makes skin hypersensitive to painful stimuliInvolved in cytokine-induced fever during infections
66 Leukotrienes Produced by lipoxygenase enzymes Secreted mainly by leukocytesChemoattractants for leukocytesVascular effects
67 Leukotrienes Three different lipoxygenases 5-lipoxygenase Predominant one in neutrophilsConverts AA to 5-hydroxyeicosatetraenoic acidChemotactic for neutrophilsPrecursor of the leukotrienes
68 Leukotrienes Three different lipoxygenases LTB4 Potent chemotactic agent and activator of neutrophilsCauses aggregation and adhesion of the cells to venular endotheliumGeneration of ROSReleases lysosomal enzymes
69 Leukotrienes Three different lipoxygenases Cysteinyl-containing leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4)Intense vasoconstriction, bronchospasm and increased vascular permeability
70 Lipoxins Generated from AA by the lipoxygenase pathway Inhibitors of inflammationTwo cell populations are required for their biosynthesisLeukocytes (esp. neutrophils)Produce intermediates in lipoxin synthesisConverted to lipoxins by platelets interacting with the leukocytes
71 Lipoxins Principal actions of lipoxins Inhibit leukocyte recruitment and the cellular components of inflammationInhibit neutrophil chemotaxis and adhesion to endotheliumInverse relationship between the production of lipoxin and leukotrienesSuggests that lipoxins may be endogenous negative regulators of leukotrienesMay thus play a role in the resolution of inflammation
72 Inhibition of Eicosanoid Synthesis Anti-inflammatory drugs work by inhibiting the synthesis of eicosanoidsCyclooxygenase inhibitorsAspirinNon-steroidal anti-inflammatory drugsIndomethacinInhibit both COX-1 and COX-2Inhibit prostaglandin synthesis
73 Inhibition of Eicosanoid Synthesis Lipoxygenase inhibitors5-lipoxygenase is not affected by NSAIDsInhibit leukotriene production (Zileuton)Block leukotriene receptors (Montelukast)Useful in the treatment of asthmaBroad-spectrum inhibitorsCorticosteroidsPowerful anti-inflammatory agentsReduces the transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF)
74 Inhibition of Eicosanoid Synthesis Modify the intake and content of dietary lipidsIncreasing the consumption of fish oilPolyunsaturated fatty acids in fish oilServe as poor substrates for conversion to active metabolitesExcellent substrates for the production of anti-inflammatory lipid productsResolvins and protectins
75 Platelet-Activating Factor (PAF) Phospholipid-derived mediatorCauses platelet aggregationKnown to have multiple inflammatory effectsVariety of cell types can elaborate PAFPlatelets, basophils, mast cells, neutrophils, macrophages, and endothelial cells
76 Platelet-Activating Factor (PAF) Causes vasoconstriction and bronchoconstrictionAt extremely low concentrations…Induces vasodilationIncreased venular permeabilityCauses increased leukocyte adhesion, chemotaxis, degranulation, and the oxidative burstBoosts the synthesis of other mediators (eicosanoids)
77 Reactive Oxygen Species Oxygen-derived free radicalsMay be released extracellularly from leukocytesAfter exposure to microbes, chemokines, and immune complexesFollowing a phagocytic challengeProduction is dependent on the activation of the NADPH oxidase systemSuperoxide anion, hydrogen peroxide, and hydroxyl radicalMajor species produced within cellsCombine with nitric oxide to form reactive nitrogen species
78 Reactive Oxygen Species Implicated in responses in inflammationEndothelial cell damage, with resultant increased vascular permeabilityInjury to other cell types (parenchymal cells, red blood cells)Inactivation of antiproteases (α1-antitrypsin)
79 Antioxidants Superoxide dismutase Catalase Glutathione peroxidase Found in or can be activated in a variety of cell typesCatalaseDetoxifies H2O2Glutathione peroxidasePowerful H2O2 detoxifierCeruloplasminCopper-containing serum proteinSerum transferrinIron-free fraction
80 Nitric Oxide (NO)Discovered as a factor released from endothelial cellsCaused vasodilationCalled endothelium-derived relaxing factorSoluble gasProduced by endothelial cells, macrophages and some neuronsActs in a paracrine manner on target cellsRelaxation of vascular smooth muscle cellsIn vivo half-life of NO is only secondsGas acts only on cells in close proximity to where it is produced
81 Nitric Oxide (NO) Has dual actions in inflammation Relaxes vascular smooth musclePromotes vasodilationInhibitor of the cellular component of inflammatory responses
82 Nitric Oxide (NO) Reduces platelet aggregation and adhesion Inhibits several features of mast cell- induced inflammationInhibits leukocyte recruitmentNO and its derivatives are microbicidalNO is a mediator of host defense against infection
83 Figure 2-12 Functions of nitric oxide (NO) in blood vessels and macrophages. NO is produced by two NO synthase (NOS) enzymes. It causes vasodilation, and NO-derived free radicals are toxic to microbial and mammalian cells.
84 Cytokines and Chemokines Proteins produced by many cell typesPrincipally activated lymphocytes and macrophagesAlso endothelial, epithelial, and connective tissue cellsInvolved in cellular immune responses
85 Cytokines and Chemokines Tumor Necrosis Factor and Interleukin-1Major cytokines that mediate inflammationProduced mainly by activated macrophagesSecretion of TNF and IL-1Stimulated by endotoxin and other microbial products, immune complexes, physical injury, and a variety of inflammatory stimuli
86 Cytokines and Chemokines Tumor Necrosis Factor and Interleukin-1EndotheliumInduce a spectrum of changesReferred to as endothelial activationInduce the expression of endothelial adhesion moleculesSynthesis of chemical mediators, including other cytokines, chemokines, growth factors, eicosanoids, and NOProduction of enzymes associated with matrix remodelingIncreases in the surface thrombogenicity of the endotheliumAugments responses of neutrophils to other stimuliBacterial endotoxin
87 Figure 2-13 Principal local and systemic actions of tumor necrosis factor (TNF) and interleukin-1 (IL-1).
88 Tumor Necrosis Factor and IL-1 Induce the systemic acute-phase responsesAssociated with infection or injuryRegulates energy balance by promoting lipid and protein mobilization and by suppressing appetiteSustained production contributes to cachexiaPathologic state characterized by weight loss and anorexiaAccompanies some chronic infections and neoplastic diseases
89 Chemokines Family of small (8 to 10 kD) proteins Act primarily as chemoattractants for specific types of leukocytes40 different chemokines20 different receptorsTwo main functionsStimulate leukocyte recruitment in inflammationControl the normal migration of cells through various tissues
90 Chemokines Classified into four major groups According to the arrangement of the conserved cysteine (C) residues in the mature proteinsC-X-C chemokines (α chemokines)One amino acid residue separating the first two conserved cysteine residuesAct primarily on neutrophilsIL-8 is typical of this groupSecreted by activated macrophages, endothelial cells, and other cell typesCauses activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophilsMost important inducers are microbial products and other cytokines, mainly IL-1 and TNF
91 Chemokines Classified into four major groups C-C chemokines (β chemokines)First two conserved cysteine residues adjacentGenerally attract monocytes, eosinophils, basophils, and lymphocytes but not neutrophilsC chemokines (γ chemokines)Lack two (the first and third) of the four conserved cysteinesLymphotactinRelatively specific for lymphocytes
92 Chemokines Classified into four major groups CX3C chemokines Contain three amino acids between the two cysteinesFractalkineTwo formsCell surface-bound proteinSoluble form
93 Lysosomal Constituents of Leukocytes Neutrophils and monocytes contain lysosomal granulesNeutrophils have two main types of granulesSmaller specific (or secondary) granulesContain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphataseLarger azurophil (or primary) granulesContain myeloperoxidase, bactericidal factors (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases
94 Lysosomal Constituents of Leukocytes Neutrophils have two main types of granulesBoth types of granules can fuse with phagocytic vacuoles containing engulfed materialGranule contents can be released into the extracellular space
95 Neuropeptides Secreted by sensory nerves and various leukocytes Play a role in the initiation and propagation of inflammationSubstance P and neurokinin AFamily of tachykinin neuropeptidesProduced in the central and peripheral nervous systemsBiologic functionsTransmission of pain signalsRegulation of blood pressureStimulation of secretion by endocrine cellsIncreasing vascular permeability
96 Plasma Protein-Derived Mediators Three interrelated systems: the complement, kinin, and clotting systemsComplement SystemConsists of more than 20 proteinsNumbered C1 through C9Functions in both innate and adaptive immunity for defense against microbial pathogensSeveral cleavage products of complement proteins are elaboratedCause increased vascular permeability, chemotaxis, and opsonizationCritical step in complement activationProteolysis of the third (and most abundant) component, C3
97 Complement System Functionally divided into three general categories InflammationC3a, C5a, and, to a lesser extent, C4a are cleavage products of the corresponding complementStimulate histamine release from mast cellsIncrease vascular permeability and cause vasodilationCalled anaphylatoxinsC5aPowerful chemotactic agent for neutrophils, monocytes, eosinophils, and basophilsActivates the lipoxygenase pathway of AA metabolism in neutrophils and monocytesCauses further release of inflammatory mediators
98 Complement System Functionally divided into three general categories PhagocytosisC3b and its cleavage product iC3b (inactive C3b)When fixed to a microbial cell wall, act as opsoninsPromote phagocytosis by neutrophils and macrophagesCell lysisDeposition of the MAC on cellsCells permeable to water and ionsResults in death (lysis) of the cells
99 Complement System C3a and C5a Most important inflammatory mediators Can be cleaved by several proteolytic enzymes present within the inflammatory exudateInclude plasmin and lysosomal enzymes released from neutrophilsInitiate a self-perpetuating cycle of neutrophil recruitment
100 Figure 2-14 The activation and functions of the complement system Figure 2-14 The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC).
101 Coagulation and Kinin Systems Culminate in the activation of thrombin and the formation of fibrinIntrinsic clotting pathwaySeries of plasma proteinsActivated by Hageman factor (factor XII)Protein synthesized by the liver that circulates in an inactive formActivated upon contact with negatively charged surfaces
102 Kinins Vasoactive peptides Derived from plasma proteins (kininogens) Action of specific proteases (kallikreins)Active form of factor XII (factor XIIa)Converts plasma prekallikrein into an active proteolytic form (kallikrein)Cleaves a plasma glycoprotein precursor high-molecular-weight kininogen, to produce bradykininBradykininIncreases vascular permeabilityCauses contraction of smooth muscleDilation of blood vesselsPain when injected into the skinShort-lived---quickly inactivated by an enzyme called kininase
103 KininsAt the same time factor XIIa is inducing fibrin clot formation, it activates the fibrinolytic systemCascade counterbalances clotting by cleaving fibrinSolubilizing the clotKallikreinCleaves plasminogenPlasma protein that binds to the evolving fibrin clot to generate plasminMultifunctional protease
104 Kinins Fibrinolytic system Primary function of plasmin Lyse fibrin clotsCleaves the complement protein C3 to produce C3 fragmentsDegrades fibrin to form fibrin split productsActivate Hageman factorTrigger multiple cascades
105 Figure 2-15 Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces inflammation by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells. HMWK, high molecular weight kininogen.
106 Summary Bradykinin, C3a, and C5a C5a Thrombin Mediators of increased vascular permeabilityC5aMediator of chemotaxisThrombinEffects on endothelial cells and many other cell types
107 Summary C3a and C5a Generated by several types of reactions Immunologic reactions, involving antibodies and complement (the classical pathway)Activation of the alternative and lectin complement pathways by microbes, in the absence of antibodiesAgents not directly related to immune responsesPlasmin, kallikrein, and some serine proteases
108 Summary Activated Hageman factor (factor XIIa) Initiates four systems (inflammatory response)Kinin systemProduces vasoactive kininsClotting systemInduces formation of thrombinFibrinolytic systemProduces plasminDegrades fibrin to produce fibrinopeptidesComplement systemProduces anaphylatoxins and other mediators
109 Acute and Chronic Inflammation PART 3Chapter 2Lisa Stevens, D.O.
110 Outcomes of Acute Inflammation Variables that may modify the basic process of inflammationNature and intensity of the injurySite and tissue affectedResponsiveness of the host
111 Outcomes of Acute Inflammation Inflammatory reactions--outcomesComplete resolutionRestoration of site of acute inflammation to normalUsual outcomeInjury is limited or short-livedLittle tissue destruction and the damaged parenchymal cells can regenerateRemoval of cellular debris and microbes by macrophagesResorption of edema fluid by lymphatics
112 Outcomes of Acute Inflammation Inflammatory reactions--outcomesHealing by connective tissue replacementFibrosisOccurs after substantial tissue destructionInflammatory injury involves tissues that are incapable of regenerationAbundant fibrin exudation in tissue or serous cavities that cannot be adequately clearedConnective tissue grows into the area of damageConverts it into a mass of fibrous tissueOrganization
113 Outcomes of Acute Inflammation Inflammatory reactions--outcomesProgression of the response to chronic inflammationMay follow acute inflammationResponse may be chronic from the onset
114 Outcomes of Acute Inflammation Progression of the response to chronic inflammationAcute to chronic transitionAcute inflammatory response cannot be resolvedPersistence of injurious agentInterference with normal process of healingBacterial infection of the lungFocus of acute inflammation (pneumonia)Extensive tissue destruction and formation of a cavityChronic lung abscess
115 Figure 2-16 Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation. The components of the various reactions and their functional outcomes are listed.
116 Morphologic Patterns of Acute Inflammation Morphologic hallmarks of acute inflammationDilation of small blood vesselsSlowing of blood flowAccumulation of leukocytes and fluidExtravascular tissue
117 Figure 2-17 The characteristic histopathology of acute inflammation Figure 2-17 The characteristic histopathology of acute inflammation. A, Normal lung shows thin (virtually invisible) blood vessels in the alveolar walls and no cells in the alveoli. B, The vascular component of acute inflammation is manifested by congested blood vessels (packed with erythrocytes), resulting from stasis. C, The cellular component of the response is manifested by large numbers of leukocytes (neutrophils) in the alveoli.
118 Serous Inflammation Marked by outpouring of thin fluid Derived from plasma/secretions of mesothelial cellsPeritoneal, pleural, and pericardial cavitiesAccumulation of fluid in these cavitiesEffusionSkin blisterBurn or viral infectionLarge accumulation of serous fluid
120 Figure 2-18 Serous inflammation Figure 2-18 Serous inflammation. Low-power view of a cross-section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous effusion.
124 Fibrinous Inflammation Fibrinous exudateVascular leaks are largeLocal procoagulant stimulus (e.g., cancer cells)Characteristic of inflammationLining of body cavitiesMeninges, pericardium and pleura
126 Fibrinous Inflammation Fibrinous exudateMicroscopic examinationFibrin appears as an eosinophilic meshwork of threadsAmorphous coagulumRemoved by fibrinolysis and clearing of other debris by macrophages
127 Microscopic appearance of fibrinous inflammation
128 Fibrinous Inflammation Fibrinous exudateIf fibrin is not removedStimulates ingrowth of fibroblasts and blood vesselsLeads to scarringConversion of the fibrinous exudate to scar tissue (organization)Pericardial sacOpaque fibrous thickening of the pericardium and epicardiumObliteration of the pericardial space
129 Figure 2-19 Fibrinous pericarditis Figure 2-19 Fibrinous pericarditis. A, Deposits of fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P).
130 Suppurative Inflammation Large amounts of purulent exudateNeutrophils, liquefactive necrosis, and edema fluidBacteria (e.g., staphylococci) produce this localized suppurationPyogenic (pus-producing) bacteriaExampleAcute appendicitis
131 Suppurative inflammation of the pericardial cavity
134 Photomicrograph of suppurative inflammation within the alveolar spaces.
135 Photomicrograph of suppurative inflammation of the alveolar space.
136 Suppurative Inflammation AbscessesLocalized collections of purulent inflammatory tissueSuppuration buried in a tissue, an organ, or a confined spaceProduced by deep seeding of pyogenic bacteria into a tissue
139 Suppurative Inflammation AbscessesCentral regionAppears as mass of necrotic leukocytes and tissue cellsNecrotic focus…Around it---zone of preserved neutrophilsOutside it---vascular dilation and parenchymal and fibroblastic proliferation
140 Figure 2-20 Purulent inflammation Figure 2-20 Purulent inflammation. A, Multiple bacterial abscesses in the lung, in a case of bronchopneumonia. B, The abscess contains neutrophils and cellular debris, and is surrounded by congested blood vessels.
141 Higher power view of the last photomicrograph---marked acute inflammation within the abscess cavity.
142 UlcersLocal defect, or excavation, of the surface of an organ or tissueProduced by the sloughing (shedding) of inflamed necrotic tissueMost commonly encounteredMucosa of the mouth, stomach, intestines, or genitourinary tractSkin and subcutaneous tissue of the lower extremitiesOlder persons who have circulatory disturbances
146 “Gangrenous necrosis” with a large cutaneous ulceration.
147 Figure 2-21 The morphology of an ulcer. A, A chronic duodenal ulcer Figure 2-21 The morphology of an ulcer. A, A chronic duodenal ulcer. B, Low-power cross-section of a duodenal ulcer crater with an acute inflammatory exudate in the base
148 Figure 2-21 The morphology of an ulcer. A, A chronic duodenal ulcer Figure 2-21 The morphology of an ulcer. A, A chronic duodenal ulcer. B, Low-power cross-section of a duodenal ulcer crater with an acute inflammatory exudate in the base
149 Esophageal ulceration secondary to a viral infection.
150 Summary of Inflammation Vascular phenomena of acute inflammationCharacterized by increased blood flow to the injured areaResults mainly from arteriolar dilation and opening of capillary bedsInduced by mediators such as histamine
151 Summary of Inflammation Vascular phenomena of acute inflammationIncreased vascular permeabilityAccumulation of protein-rich extravascular fluid (exudate)Plasma proteins leave the vessels (widened interendothelial cell junctions of the venules)Redness (rubor), warmth (calor), and swelling (tumor)Increased blood flow and edema
152 Summary of Inflammation Vascular phenomena of acute inflammationCirculating leukocytesAdhere to the endothelium via adhesion moleculesTraverse the endotheliumMigrate to the site of injury under the influence of chemotactic agentsActivated leukocytes release toxic metabolites and proteases extracellularlyCauses tissue damageProstaglandins, neuropeptides, and cytokines releasedLocal symptom---pain (dolor)
153 Chronic Inflammation Inflammation of prolonged duration Weeks or monthsMay follow acute inflammationMay begin insidiously
154 Causes of Chronic Inflammation Persistent infections by microorganismsMycobacteria, and certain viruses, fungi, and parasitesImmune reaction (delayed-type hypersensitivity)Immune-mediated inflammatory diseasesAutoimmune diseasesAtherosclerosisChronic inflammatory process of the arterial wallInduced by endogenous toxic plasma lipid components
155 Morphology of Chronic Inflammation Infiltration with mononuclear cellsMacrophages, lymphocytes, and plasma cellsTissue destructionInduced by the persistent offending agent or by the inflammatory cellsProliferation of small blood vesselsAngiogenesisFibrosis
156 Figure 2-22 A, Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows). B, By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.
157 Figure 2-22 A, Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows). B, By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.
158 Chronic inflammation as demonstrated by infiltrating lymphocytes and plasma cells.
159 Macrophages in Chronic Inflammation Component of the mononuclear phagocyte systemAlso known as the reticuloendothelial systemConsists of closely related cells of bone marrow originBlood monocytesTissue macrophages
160 Macrophages in Chronic Inflammation Component of the mononuclear phagocyte systemTissue macrophagesDiffusely scattered in the connective tissueLiver (Kupffer cells)SpleenLymph nodes (sinus histiocytes)Lungs (alveolar macrophages)Central nervous system (microglia)
161 Macrophages in Chronic Inflammation Mononuclear phagocytesArise from a common precursor in the bone marrowGives rise to blood monocytesFrom the blood, monocytes migrate into tissuesHalf-life of blood monocytes is about 1 dayDifferentiate into macrophagesLife span of tissue macrophages is several months or years
162 Macrophages in Chronic Inflammation Monocytes emigrate into extravascular tissuesEarly in acute inflammationWithin 48 hours--predominant cell typeWhen it reaches the extravascular tissue…Undergoes transformation into the macrophageActivated by a variety of stimuliMicrobial productsCytokinesOther chemical mediators
163 Macrophages in Chronic Inflammation Products of activated macrophagesServe to eliminate injurious agents (microbes)Initiate the process of repairResponsible for tissue injury in chronic inflammationActivation of macrophagesIncreased levels of lysosomal enzymes and reactive oxygen and nitrogen speciesProduction of cytokines, growth factors, and other mediators of inflammationTissue destructionHallmark of chronic inflammation
164 Macrophages with surrounding acute and chronic inflammation.
165 Figure 2-23 Maturation of mononuclear phagocytes Figure 2-23 Maturation of mononuclear phagocytes. (From Abbas AK et al: Cellular and Molecular Immunology, 5th ed. Philadelphia, WB Saunders, 2003.)
166 Figure 2-24 The roles of activated macrophages in chronic inflammation Figure 2-24 The roles of activated macrophages in chronic inflammation. Macrophages are activated by nonimmunologic stimuli such as endotoxin or by cytokines from immune-activated T cells (particularly IFN-γ). The products made by activated macrophages that cause tissue injury and fibrosis are indicated. AA, arachidonic acid; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; TGFβ, transforming growth factor β.
167 Other Cells in Chronic Inflammation LymphocytesPlasma cellsDevelop from activated B lymphocytesProduce antibodiesDirected either against persistent foreign or self antigens
168 Other Cells in Chronic Inflammation EosinophilsAbundant in immune reactionsMediated by IgEParasitic infectionsChemokine for eosinophil recruitmentEotaxinGranules that contain major basic proteinHighly cationic protein that is toxic to parasitesCauses lysis of mammalian epithelial cellsBenefit in controlling parasitic infectionsContribute to tissue damage in immune reactionsAllergies
169 Other Cells in Chronic Inflammation Mast cellsWidely distributed in connective tissuesParticipate in acute and chronic inflammatory reactionsDegranulation and release of mediatorsHistamine and prostaglandinsAllergic reactions to foods, insect venom, or drugsCatastrophic results (e.g. anaphylactic shock)
170 Figure 2-25 Macrophage-lymphocyte interactions in chronic inflammation Figure 2-25 Macrophage-lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines) and others that activate macrophages (IFNγ). Different subsets of T cells (called TH1 and TH17) may produce different sets of cytokines; these are described in Chapter 6. Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines (such as IL-12).
171 Figure 2-26 A focus of inflammation showing numerous eosinophils.
172 Granulomatous Inflammation Distinctive pattern of chronic inflammationCellular attempt to contain an offending agent that is difficult to eradicateStrong activation of T lymphocytesLeading to macrophage activationCause injury to normal tissues
173 Granulomatous Inflammation Most commonly seenTuberculosisSarcoidosisCat-scratch diseaseLymphogranuloma inguinaleLeprosyBrucellosisSyphilisMycotic infectionsBerylliosis
174 Granuloma Focus of chronic inflammation Consists of a microscopic aggregation of macrophagesTransformed into epithelium-like cellsSurrounded by a collar of mononuclear leukocytesLymphocytes and occasionally plasma cells
179 Granuloma Two types of granulomas Foreign body granulomas Incited by relatively inert foreign bodiesForm around materialTalc (IV drug abuse)SuturesForeign material can be identified in the center of the granulomaRefractile
180 Foreign body giant cell reaction to aspirated vegetable matter.
181 Foreign body giant cell reaction to suture material.
182 Foreign body giant cell reaction to talc powder (heroin/IV drug user).
183 Granuloma Immune granulomas Caused by a variety of agents that are capable of inducing a cell-mediated immune responseProduces granulomas usually when the inciting agent is poorly degradable or particulatePrototype is caused by infection with Mycobacterium tuberculosisGranuloma is referred to as a tuberclePresence of central caseous necrosisrare in other granulomatous diseases
184 Figure 2-27 Typical tuberculous granuloma showing an area of central necrosis surrounded by multiple Langhans-type giant cells, epithelioid cells, and lymphocytes
186 Systemic Effects of Inflammation Collectively called the acute-phase responseAlso known as the systemic inflammatory response syndromeReactions to cytokines whose production is stimulated by bacterial productsConsists of several clinical and pathologic changesFeverElevation of body temperature (1° to 4°C)One of the most prominent manifestationsProduced in response to substances called pyrogens
187 Systemic Effects of Inflammation Consists of several clinical and pathologic changesAcute-phase proteinsPlasma proteinsSynthesized in the liverConcentrate in the plasma in response to inflammatory stimuliThree best-known proteinsC-reactive protein (CRP)FibrinogenSerum amyloid A (SAA) protein
188 Systemic Effects of Inflammation Consists of several clinical and pathologic changesLeukocytosisCommon feature of inflammatory reactionsEspecially those induced by bacterial infectionsLeukocyte count usually climbs to 15,000 or 20,000 cells/μL
189 Systemic Effects of Inflammation Consists of several clinical and pathologic changesLeukocytosisMay reach extraordinarily high levels of 40,000 to 100,000 cells/μLLeukemoid reactionsSimilar to the white cell counts observed in leukemiaAccelerated release of cells from the bone marrowRise in the number of more immature neutrophils in the blood (shift to the left)
190 Systemic Effects of Inflammation Consists of several clinical and pathologic changesBacterial infectionsIncrease in the blood neutrophil count (neutrophilia)Viral infections (infectious mono, mumps, and German measles)Absolute increase in the number of lymphocytes (lymphocytosis)
191 Systemic Effects of Inflammation Consists of several clinical and pathologic changesBronchial asthma, allergy, and parasitic infestationsIncrease in the absolute number of eosinophils (eosinophilia)Infections (typhoid fever and viruses, rickettsiae, and certain protozoa)Decreased number of circulating white cells (leukopenia)
192 Systemic Effects of Inflammation Consists of several clinical and pathologic changesIncreased pulse and blood pressureDecreased sweatingRedirection of blood flow from cutaneous to deep vascular bedsMinimizes heat loss through the skinRigors (shivering)Chills (search for warmth)AnorexiaSomnolence
193 Consequences of Defective or Excessive Inflammation Defective inflammationResults in increased susceptibility to infectionsAssociated with delayed wound healingProvides the necessary stimulus to get the repair process startedExcessive inflammationBasis of many types of human diseaseAllergiesDisorders in which the fundamental cause of tissue injury is inflammation