Inflammation & edema

Inflammation & edemaNindya ShintaIntroductionInjurious stimuli cause a protective vascular connective tissue reaction called inflammationDiluteDestroyIsolateInitiate repairAcute and chronic forms2Acute inflammationImmediate and early response to tissue injury (physical, chemical, microbiologic, etc.)VasodilationVascular leakage and edemaLeukocyte emigration (mostly PMNs)3

4VasodilationBrief arteriolar vasoconstriction followed by vasodilationAccounts for warmth and rednessOpens microvascular bedsIncreased intravascular pressure causes an early transudate (protein-poor filtrate of plasma) into interstitium (vascular permeability still not increased yet)

5Vascular leakageVascular permeability (leakiness) commencesTransudate gives way to exudate (protein-rich)Increases interstitial osmotic pressure contributing to edema (water and ions)

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7Vascular leakageFive mechanisms known to cause vascular leakinessHistamines, bradykinins, leukotrienes cause an early, brief (15 30 min.) immediate transient response in the form of endothelial cell contraction that widens intercellular gaps of venules (not arterioles, capillaries)Cytokine mediators (TNF, IL-1) induce endothelial cell junction retraction through cytoskeleton reorganization (4 6 hrs post injury, lasting 24 hrs or more)

8Vascular leakageSevere injuries may cause immediate direct endothelial cell damage (necrosis, detachment) making them leaky until they are repaired (immediate sustained response), or may cause delayed damage as in thermal or UV injury, or some bacterial toxins (delayed prolonged leakage)Marginating and endothelial cell-adherent leukocytes may pile-up and damage the endothelium through activation and release of toxic oxygen radicals and proteolytic enzymes (leukocyte-dependent endothelial cell injury) making the vessel leaky

9Vascular leakageCertain mediators (VEGF) may cause increased transcytosis via intracellular vesicles which travel from the luminal to basement membrane surface of the endothelial cellAll or any combination of these events may occur in response to a given stimulus

10Leukocyte cellular eventsLeukocytes leave the vasculature routinely through the following sequence of events:Margination and rollingAdhesion and transmigrationChemotaxis and activationThey are then free to participate in:Phagocytosis and degranulationLeukocyte-induced tissue injury11Margination and RollingWith increased vascular permeability, fluid leaves the vessel causing leukocytes to settle-out of the central flow column and marginate along the endothelial surfaceEndothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium like a tumbleweed until it eventually comes to a stop as mutual adhesion reaches a peak12Margination and RollingEarly rolling adhesion mediated by selectin family:E-selectin (endothelium), P-selectin (platelets, endothelium), L-selectin (leukocytes) bind other surface molecules (i.e.,CD34, Sialyl-Lewis X-modified GP) that are upregulated on endothelium by cytokines (TNF, IL-1) at injury sites

13AdhesionRolling comes to a stop and adhesion resultsOther sets of adhesion molecules participate:Endothelial: ICAM-1, VCAM-1 Leukocyte: LFA-1, Mac-1, VLA-4(ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4) Ordinarily down-regulated or in an inactive conformation, but inflammation alters this14Transmigration (diapedesis)Occurs after firm adhesion within the systemic venules and pulmonary capillaries via PECAM 1 (CD31) Must then cross basement membraneCollagenasesIntegrins15Transmigration (diapedesis)Early in inflammatory response mostly PMNs, but as cytokine and chemotactic signals change with progression of inflammatory response, alteration of endothelial cell adhesion molecule expression activates other populations of leukocytes to adhere (monocytes, lymphocytes, etc)16Chemotaxis Leukocytes follow chemical gradient to site of injury (chemotaxis)Soluble bacterial productsComplement components (C5a)Cytokines (chemokine family e.g., IL-8)LTB4 (AA metabolite)Chemotactic agents bind surface receptors inducing calcium mobilization and assembly of cytoskeletal contractile elements17Chemotaxis and ActivationLeukocytes: extend pseudopods with overlying surface adhesion molecules (integrins) that bind ECM during chemotaxisundergo activation:Prepare AA metabolites from phospholipidsPrepare for degranulation and release of lysosomal enzymes (oxidative burst)Regulate leukocyte adhesion molecule affinity as needed18

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Leukocytes Rolling Within a Venule20

Neutrophil Pavementing (lining the venule)21

Leukocyte Margination and Diapedesis22

Neutrophil Transendothelial Migration (Diapedesis)23Phagocytosis and DegranulationOnce at site of injury, leukocytes:Recognize and attachEngulf (form phagocytic vacuole)Kill (degrade)24Recognition and BindingOpsonized by serum complement, immunoglobulin (C3b, Fc portion of IgG)Corresponding receptors on leukocytes (FcR, CR1, 2, 3) leads to binding

25Phagocytosis and DegranulationTriggers an oxidative burst (next slide) engulfment and formation of vacuole which fuses with lysosomal granule membrane (phagolysosome)Granules discharge within phagolysosome and extracellularly (degranulation)

26Degradation and Clean-upReactive end-products only active within phagolysosomeHydrogen peroxide broken down to water and oxygen by catalaseDead microorganisms degraded by lysosomal acid hydrolases27

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29Leukocyte granulesOther antimicrobials in leukocyte granules:Bactericidal permeability increasing protein (BPI)LysozymeLactoferrinDefensins (punch holes in membranes)

30Leukocyte-induced tissue injuryDestructive enzymes may enter extracellular space in event of:Premature degranulationFrustrated phagocytosis (large, flat)Membranolytic substances (urate crystals)Persistent leukocyte activation (RA, emphysema)

31Chemical mediatorsPlasma-derived:Complement, kinins, coagulation factorsMany in pro-form requiring activation (enzymatic cleavage)Cell-derived:Preformed, sequestered and released (mast cell histamine)Synthesized as needed (prostaglandin)

32Chemical mediatorsMay or may not utilize a specific cell surface receptor for activityMay also signal target cells to release other effector molecules that either amplify or inhibit initial response (regulation)Are tightly regulated:Quickly decay (AA metabolites), are inactivated enzymatically (kininase), or are scavenged (antioxidants)33Specific mediatorsVasoactive aminesHistamine: vasodilation and venular endothelial cell contraction, junctional widening; released by mast cells, basophils, platelets in response to injury (trauma, heat), immune reactions (IgE-mast cell FcR), anaphylatoxins (C3a, C5a fragments), cytokines (IL-1, IL-8), neuropeptides, leukocyte-derived histamine-releasing peptides 34Specific mediatorsSerotonin: vasodilatory effects similar to those of histamine; platelet dense-body granules; release triggered by platelet aggregationPlasma proteasesClotting systemComplementKinins

35Clotting cascadeCascade of plasma proteasesHageman factor (factor XII)Collagen, basement membrane, activated platelets converts XII to XIIa (active form)Ultimately converts soluble fibrinogen to insoluble fibrin clotFactor XIIa simultaneously activates the brakes through the fibrinolytic system to prevent continuous clot propagation

36Kinin systemLeads to formation of bradykinin from cleavage of precursor (HMWK)Vascular permeabilityArteriolar dilationNon-vascular smooth muscle contraction (e.g., bronchial smooth muscle)Causes painRapidly inactivated (kininases)

37Complement systemComponents C1-C9 present in inactive formActivated via classic (C1) or alternative (C3) pathways to generate MAC (C5 C9) that punch holes in microbe membranesIn acute inflammationVasodilation, vascular permeability, mast cell degranulation (C3a, C5a)Leukocyte chemotaxin, increases integrin avidity (C5a)As an opsonin, increases phagocytosis (C3b, C3bi)

38Specific MediatorsArachidonic acid metabolites (eicosanoids)Prostaglandins and thromboxane: via cyclooxygenase pathway; cause vasodilation and prolong edema; but also protective (gastric mucosa); COX blocked by aspirin and NSAIDS

39Specific MediatorsLeukotrienes: via lipoxygenase pathway; are chemotaxins, vasoconstrictors, cause increased vascular permeability, and bronchospasmPAF (platelet activating factor)Derived also from cell membrane phospholipid, causes vasodilation, increased vascular permeability, increases leukocyte adhesion (integrin conformation)40More specific mediators CytokinesProtein cell products that act as a message to other cells, telling them how to behave.IL-1, TNF- and -, IFN- are especially important in inflammation.Increase endothelial cell adhesion molecule expression, activation and aggregation of PMNs, etc., etc., etc.41Specific mediatorsNitric Oxideshort-acting soluble free-radical gas with many functionsProduced by endothelial cells, macrophages, causes:Vascular smooth muscle relaxation and vasodilationKills microbes in activated macrophagesCounteracts platelet adhesion, aggregation, and degranulation

42Specific mediatorsLysosomal componentsLeak from PMNs and macrophages after demise, attempts at phagocytosis, etc.Acid proteases (only active within lysosomes).Neutral proteases such as elastase and collagenase are destructive in ECM.Counteracted by serum and ECM anti-proteases.

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Table 32. Mediators of Acute Inflammation.

MediatorVasodilationImmediateSustainedChemotaxisOpsoninPainHistamine++++Serotonin (5HT)++Bradykinin++++Complement 3a+Complement 3b+++Complement 5a++++Prostaglandins+++++?Leukotrienes++++?+++Lysosomal proteases++1Oxygen radicals++1

4444Possible outcomes of acute inflammationComplete resolutionLittle tissue damageCapable of regenerationScarring (fibrosis)In tissues unable to regenerateExcessive fibrin deposition organized into fibrous tissueAbscess formation occurs with some bacterial or fungal infectionsProgression to chronic inflammation

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47Chronic inflammationLymphocyte, macrophage, plasma cell (mononuclear cell) infiltrationTissue destruction by inflammatory cellsAttempts at repair with fibrosis and angiogenesis (new vessel formation)When acute phase cannot be resolvedPersistent injury or infection (ulcer, TB)Prolonged toxic agent exposure (silica)Autoimmune disease states (RA, SLE)

48The Players (mononuclear phagocyte system)MacrophagesScattered all over (microglia, Kupffer cells, sinus histiocytes, alveolar macrophages, etc.Circulate as monocytes and reach site of injury within 24 48 hrs and transformBecome activated by T cell-derived cytokines, endotoxins, and other products of inflammation49The PlayersT and B lymphocytesAntigen-activated (via macrophages and dendritic cells)Release macrophage-activating cytokines (in turn, macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed)Plasma cellsTerminally differentiated B cells50The PlayersProduce antibodiesEosinophils Found especially at sites of parasitic infection, or at allergic (IgE-mediated) sites

51Patterns of acute and chronic inflammationSerousWatery, protein-poor effusion (e.g., blister)Fibrinous Fibrin accumulationEither entirely removed or becomes fibroticSuppurativePresence of pus (pyogenic staph spp.)Often walled-off if persistentUlcerationNecrotic and eroded epithelial surfaceUnderlying acute and chronic inflammationTrauma, toxins, vascular insufficiency

52Systemic effectsFeverOne of the easily recognized cytokine-mediated (esp. IL-1, IL-6, TNF) acute-phase reactions includingAnorexiaSkeletal muscle protein degradationHypotensionLeukocytosisElevated white blood cell countBacterial infection (neutrophilia)Parasitic infection (eosinophilia)Viral infection (lymphocytosis)

5353Types of edemaDependent bilateral edema (usuallypitting)LymphedemaLocalized edemaMyxedema54Pitting dependent edema: causesDecreased serum proteinIncreased systemic venous pressureCapillary edema (increased permeability)55Edema due to hypoalbuminemia:common causesImpaired protein synthesisDecreased protein intake: starvation, kwashiokorDecreased absorption of proteins: malabsorptionImpaired hepatic synthesis due to liver diseaseIncreased loss of proteinSkin loss: burns, weeping skin diseasesUrinary loss: nephrotic syndromeFecal loss: bowel disease56Edema due to venous pressure:common causesSystemic venous hypertensionCongestive heart failurePericardial diseases, tricuspid valve diseaseRegional venous hypertensionInferior vena cava syndromeVenous thrombosisLower extremity venous insufficiency57Edema due to capillary permeabilityVasculitisIdiopathic cyclic edema of womenVaries with menstrual cyclePost-anoxic encephalopathy58Pitting recovery timeTechnique:Press firmly to boneShine light and determine time to resolution of shadowInterpretationAcute edema (< 3 months)< 40 seconds associated with low serum albumin59Rapid pitting recovery: < 40 seconds protein synthesis protein intake: dietary history absorption of proteins: diarrhea hepatic synthesis due to liver disease: alcohol, other hepatotoxins, hepatitis loss of proteinSkin loss: skin lesions such as burns, ulcersUrinary loss: foamy urine with high proteinFecal loss: diarrhea, sticky, oily stools60Rapid pitting recovery: < 40 secondsImpaired protein synthesis protein intake: starvation, kwashiokor absorption of proteins: malabsorption hepatic synthesis due to liver diseaseIncreased loss of proteinSkin loss: burns, weeping skin diseasesUrinary loss: nephrotic syndromeFecal loss: bowel disease61Slow pitting time (> 40 seconds)normoalbuminemic edemaSystemic venous hypertensionCongestive heart failurePericardial diseases, tricuspid valve diseaseRegional venous hypertensionInferior vena cava syndromeVenous thrombosisLower extremity venous insufficiency62Venous hypertension & edema:systemic vs regionalSystemic venous hypertensionElevated neck veinsThird heart sound in heart failureRegional venous hypertensionNeck veins not elevatedThird heart sound63

64Lymphedema: nonpitting edemaProtein-rich edema due to abnormality of lymphatic drainageCharacteristicsNontender, painlessDoes not vary much during the dayUlceration rareHyperkeratosis, thickening of skin65Lymphedema: nonpitting edemaUpper extremitybreast cancer or surgery/radiation for breast cancerNewborn baby, Turners syndrome (X0)Lower extremityIdiopathic: aplasia/dysplasia of lymphatics3 types: congenital, praecox, form tardeAssociated with yellow nails, pleural effusionsSecondaryInflammatoryObstructive66Lymphedema: secondary causesInflammatoryTropical: filariasis + recurrent strep infectionNontropical: recurrent streptococcal cellulitisObstructiveUnilateral in 95%Usually due to malignancyProstate cancer most common in menLymphoma most common in womenAny pelvic tumor or major pelvic surgery67Miscellaneous causes of edemaHot days: bilateral edema due to venous pooling + compensatory salt and water retention (aldosterone)Localized edemaFacial edemaTrichinosis, hypothyroidism, allergies, nephrotic syndromePretibial myxedema from Graves thyrotoxicosisLipedemaadiposity of the legsPseudothrombophlebitisA form of unilateral edema with elevated venous pressure due to a popliteal cyst68

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