1、InflammationDept. of Pathol. 2015.4Inflammation is Most common pathological change, involving all tissues and organsBasic pathological changes of most disease, infection, allergy, autoimmune diseaseParticipating in almost all pathological conditions, wound healing, ischemic, tumorImportant functions

2、overviewFuruncle（癤）SARS: Severe Acute Respiratory SyndromenormalSARSEtiology：SARS冠狀病毒（SARS CoV）Allergy - EdemaAcute proliferative glomerulonephritisEMSubepithelial “hump” depositSkin blister result from burningSerous effusion accumulated within and underneath the epidermis of skinOutlines of Inflamm

3、ationPart 1：General Considerations of inflammation - Definition - Inflammatory agents（致炎因子） - Basic pathological changes （基本病變）Part 2：Acute inflammation - vascular and cellular events - Inflammatory mediator (炎癥介質） - Classification and outcomesPart 3：Chronic inflammation Part 4：Local and systemic ma

4、nifestations Part 1 General ConsiderationsHistorical aspects of inflammation Contributor (country)TimeContributionCelsus (Italy)1st ADFour cardinal signs: redness, swelling, heat, painJohn Hunter (Scotland)1793Inflammation as a host defense and not a disease processJulius Cohnheim (Germany) 1839-188

5、4Observed inflamed vessels microscopicallyElie Metchnikoff (Russia) 1882Observed and described phagocytosisRudolf Virchow (Germany)1821-1902Fifth cardinal sign: loss of functionSir Thomas Lewis (England) 1927Determined chemicals (histamine) induce vascular changes1.1 Definition具有血管系統的活體組織對損傷因子發生的防御反

6、應。Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult. Repairing the defect concomitantly (regeneration of parenchymal cells and connective tissue cells) (Basic Pathology)本質：損傷 - 抗損傷

7、（包括修復） 炎癥作用的雙面性致炎因子損傷抗損傷炎癥 不利： - 抗損傷的同時，纖維化，瘢痕，過敏反應,炎癥對組織也造成一定程度的損傷。 有利：防御及抗損傷1.2 Inflammatory agents任何能夠引起組織損傷的因素：生物性 ( Infectious ) :最常見，=感染創傷和物理性免疫反應：4 種類型變態反應化學性 ( Chemical )：外源性、內源性缺血 ( Ischemic ) 壞死 ( necrosis )異物 ( Foreign particle ) Herpes simplex單純皰疹Tinea癬Differentiate the following 3 condi

8、tions：Inflammatory diseases 炎癥性疾病Infectious diseases 感染性疾病Communicable diseases 傳染病InflammationInfectionCommunicablediseasePerniosis凍瘡多形性日光疹Contact dermatitis接觸性皮炎隆乳后異物反應1.3 Basic pathological changes同時存在，某一具體炎癥常以某一病變為主。急性炎癥或炎癥早期一般變質和滲出較顯著；慢性炎癥或炎癥后期，增生較顯著。Alteration（變質）Exudation（滲出）Proliferation（增生）

9、Basic pathological changes - AlterationDefinition：degeneration and necrosis at sites of injury 1) degeneration hydropic, Fatty, hyaline and mucoid 2) necrosis coagulative, liquifactive and fibrinoidBoth parenchymal and stromal cells are involvedAlteration inflammation-Viral hepatitisMechanism of the

10、 alterationDirect injury from inflammatory agentsInflammatory results - vascular circulation problem - inflammatory mediators， O-radicalsExudationDefinition: extravasation of blood components in inflammationBlood components: plasma fluidproteins leukocytesHallmark of inflammationExudation of plasmaE

11、xudation of plasmaExudation of fibrin該患者的胸腔積液是滲出液(exudates)還是漏出液(transudates)？流體靜壓膠體滲透壓Transudate: passive an ultrafiltrate of plasma, little protein and cellsExudate: active protein-rich and cell-rich fluid，extravagate due to high vascular permeabilityExudate（滲出液）Transudate（漏出液）Causeinflammationnon

12、-inflammationGrosscloudyclearGravity1.01830g/L100/mm3100/mm3Coagulation+-Mucoprotein（Rivalta試驗）+-Exudation of leukocytes （inflammatory cells）neutrophils (acute and purulent )lymphocytes ( chronic )monocytes ( macrophages, chronic ) eosinophils (allergic and parasitic )basophils and mast cell Mononuc

13、lear cells ( monocytes + lymphocytes )Neutrophil (polymorphonuclear cell)Hallmark for purulent and acute inflammationQuick response (extravasation in 15min)Short life span (24h)Pus cell: degenerative and necrotic neutrophilsFunction： - microphage, strong phagocytosis and killing ability - Azurophili

14、c granule (acid protease, neutal protease, myeloperoxidase, phospholipase) - Specific granule (enzyme)Neutrophils37Smallest white blood cellshas a large, dark-staining nucleus with little cytoplasmDivided into T, B, NKMainly seen in chronic inflammation and virus infectionLymphocyte38Monocytes/Macro

15、phages Bone marrowMonocytes in circulating bloodMacrophages after extravasating from the bloodMacrophagesThe heart of chronic inflammation Extravasation within 24hLong life span: half-life in circulation is 1d, in tissue could be 1m-1yr. Strong ability of phagocytosis and killing after activation.re

16、ciprocal activation of T cell and macrophagesMacrophages:Antigens processed by macrophages activate T cellsRelease cytokines ( IL-1 and TNF) to activate T and other cells.T lymphocytes:Produce mediators (such as IFN-) to activate and transform macrophages into epithelioid cell, Aschoff cell, typhoid

17、 cell , foamy cell, multinuclear giant cell特殊部位的巨噬細胞名稱：結締組織-組織細胞；肝竇-枯否細胞；腦組織-小膠質細胞巨噬細胞：吞噬不同物質后，名稱不同吞噬脂質泡沫細胞吞噬炭末塵細胞心衰時吞噬RBC 心衰細胞吞噬結核桿菌類上皮細胞和Langhans巨細胞風濕熱時吞噬壞死物質風濕細胞（Aschoff細胞）吞噬異物異物巨細胞，相互融合成多核巨細胞epithelioid cell in tuberculosisEosinophilsCharacteristic of parasitic infections and IgE mediated immune

18、 responsesMajor basic protein (MBP), a cation protein, is toxic to both parasites and epithelial cells血吸蟲感45支氣管哮喘：大量嗜酸性粒細胞浸潤Basophil and Mast CellWidely distributed in connective tissuesSentinel cells in both acute and chronic inflammationRelease histamine and arachidonic acid (AA) metabolites that

19、elicit the early vascular changesarmed by IgE to certain antigens play central role in anaphylatic shock靜止肥大細胞活化肥大細胞Protective function: 1) Limit & clear up invading microbes ( 消滅敵人) 2) Break down & absorb necrotic tissues ( 打掃戰場) 3) Beneficial to regeneration and repair ( 戰后建設) Negative function of

20、 over- exudation 1）Edema：brain, pulmonary 2）Hydrops ：hydrothorax, ascites, hydropericardium, hydronephrosis, hydrocephalus 3）fibrous exudation：organization and adhesionBasic pathological changes - Exudation致炎因子粘附分子類型趨化因子類型炎癥細胞壽命MCP（單核細胞趨化因子）Definition: reproduction of cells during inflammationCompon

21、ents： 1) Parenchymal cells 2) Mesenchymal cells 3) Inflammatory cellsFunction: 1) repair 2) limit the spread of inflammationBasic pathological changes- ProliferationProliferationPart 2 Acute inflammationCharacteristics of Acute InflammationShort duration: days to 1 monthsAcute injuries induced by in

22、flammatory agentsExudation: fluid, plasma proteins, neutrophils2.1 The Process of Acute Inflammation Vascular events Cellular eventsVascular Events（1）(1) Changes in vascular caliber and flow Arterioles transient vasoconstriction at the site of injury neurogenic and chemical mediator systems within s

23、econds to minutes Vasodilation of arterioles neurogenic and specific mediator increases blood flow to the capillary bed- inflammatory hyperemia redness and warmth. increased intravascular hydrostatic pressure transudate Stasis： increased blood viscosity and slowed circulation margination (2) Increas

24、ed vascular permeability Vascular Events（2）(1) Changes in vascular caliber and flow (2) Increased vascular permeability exudate of protein-rich extravascular fluid- Increasing interstitial osmotic pressure Outflow of water, ions and proteins into interstitum- Allowing the movement of cells into the

25、interstitum, even erythrocytesEdema, extravasation of plasma and leukocytesTransudate Exudate Mechanism of Increased Vascular Permeability1) Endothelial cell contraction and retraction - Common, reversible - Postcapillary venules (more receptors) Contraction: - Induced by histomine, bradykinin, leuk

26、otrienes - Immediate transient response (fast and short-lived, min or h) Retraction: - Induced by TNF, IL-1 - a structural reorganization of the endothelial cytoskeleton, takes 4-6 h to develop and persist for more than 24 h 2) Direct endothelial injury Caused by severe injuries or infection Arterio

27、les, capillaries and venules Endothelial necrosis and detachment, usually associated with platelet adhesion and thrombosis Immediate sustained response (severe burn) or delayed prolonged response (mild thermal injury, bacterial toxin, sunburn)Mechanism of Increased Vascular Permeability (cont.)Mecha

28、nism of Increased Vascular Permeability (cont.)3) Leukocyte-dependent endothelial injuryInduced by toxic oxygen and proteolytic enzymes released by leukocytesSystemic venules and pulmonary capillaries 4) Increased transcytosis via intracellular vesicular pathway In venules induced by VEGF5) Leakage

29、from new blood vessels Insufficient formation of intercellular junctionMore receptors for chemical mediators and angiogenic factor (VEGF)Above mechanisms are stated separately, however, they all participate in the setting of a particular inflammatory agent Increased Vascular Permeability1. Extravasa

30、tionCellular Events of Leukocytes2. Accumulation in the site of injury 3 steps3. Phagocytosis and killing of Leukocytes (1) Margination (2) Rolling (3) Adhesion (4) Transmigration 1) Margination: Leukocyte are pushed out of the central axial column and accumulation at the periphery of vessels. 2) Ro

31、lling: Leukocytes tumble on the endothelial surface and transiently sticking along endothelial cells. mediated by binding between selectin and selected sialyl-Lewis-X-modified glycoprotein. up-regulated or redistributed after stimulation loose and transient adhesion1. Leukocytes extravasationMechani

32、sms mediating increased leukocyte-endothelial adhesion L、P和E分別表示leukocyte,platelet和endothelium1. Leukocytes extravasation3) Adhesion the leukocytes firmly stick to endothelial surfaces. binding of integrin on leukocyte with ICAM and VCAM on endothelial egrin undergo conformational change to

33、 higher affinity1. Leukocytes extravasation - squeezing between cells at intercellular junctions Leukocytes diapedesis （阿米巴運動 ） - occurs in venules of systemic circulation and in capillaries of pulmonary circulation - Mediated by CD31 (PECAM-1) , belong to Ig superfamily 4) TransmigrationEndothelial

34、-neutrophil interaction 炎癥時內皮細胞和白細胞粘附分子的表達增加，親和性增強，表達新的粘附分子Chemotaxis（趨化作用）: after extravasating from the blood, leukocytes migrate toward sites of injury along a chemical gradient. Chemotactic agents （趨化因子） : include bacterial products, chemokines, C5a, leukotriene B4specific binding of the chemota

35、ctic agents with their receptors on the specific leukocytes 2. Leukocytes accumulation in the site of injury 白細胞滲出血管的機制 Neutrophil margination and adhesion to the endothelium 血吸蟲病1) Recognition and Attachment to microbeby opsonins binding with opsonin receptors on leukocytesOpsonin (調理素) ：血清中的促進細胞吞噬

36、功能的蛋白質。Fc portion of IgGC3b and C3bicarbohydrate-binding lectins：collectins (集結素)3. Phagocytosis and killing - 3 stepsDifferent classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes.白細胞滲出 白細胞激活3. Pha

37、gocytosis and killing - 3 steps 2) Engulfment : pseudopods are extended around microbes, subsequently forming a phagocytic vacuolephagosomelysosomephagolysosome酸性水解酶中性蛋白酶髓過氧化物酶陽離子蛋白溶菌酶磷脂酶A23) Killing and Degradation oxygen dependent mechanism - oxidative burst：Rapid activation of leukocyte NADPH oxi

38、dase, produce O2- 、H2O2 - MPO in azuophilic granules converts H2O2 into HOCL - O2- 、H2O2 、HOCl：powerful oxidant and antimicrobial agent - Fortunately NADPH oxidase activation and end products are limited in phagolysosome.oxygen independent mechanism bactericidal permeability-increasing protein (BPI)

39、, lysozymePhagocytosis白細胞吞噬過程示意圖Leukocytes products (eg lysosomal enzymes, ROS, chemical mediators)released into the extracellular environmentcause injury to normal cells and tissuesLeukocyte-induced tissue injuryDefects in Leukocytes FunctionGenetic or acquiredIncreased vulnerability of infectionRe

40、current and life-threatening infectionAlthough rare, highlighting the complex series of molecular events in vivoDefects in Leukocytes FunctionLeukocyte adhesion deficiency 1(LAD-1): Defect in chain of CD11/CD18 integrin, impaired adhesion and spreadingLeukocyte adhesion deficiency 2(LAD-2):Defect in

41、 fucose metabolism resulting in the absence of sialyl-Lewis X(墨角藻糖基轉移酶突變使唾液酸化Lewis X缺乏 ), impaired rolling and loose adhesion to endothelial cellsDefects in Leukocytes FunctionChronic granulomatous disease (CGD): Defects in several components of NADPH oxidase, impaired killing of engulfed microbesCh

42、ediak-Higashi syndrome: autosomal recessive disease, defects in phagolysome formation resulting from intracellular trafficking of organelles, impairing lysomal degranulation into phagosomes, secretion of cytotoxic T cell is also damaged, severe immunodeficiency occurs.2.2 Inflammatory Mediator (chem

43、ical mediators)Function: mediate the vascular and cellular events in inflammation 參與炎癥反應（血管擴張、通透性增加、白細胞滲出等）的內源性化學因子稱為炎癥介質Characteristics of Inflammatory MediatorInduce effects by binding specific receptors on target cells（配體-受體特異性結合）Stimulate target cells to release secondary effecter molecules (級聯反

44、應)Act on only one or few targets, or having widespread activityBeing potential to cause harmful effects, so mediator function is tightly regulated in vivo. Various Chemical MediatorsPlasma derived Chemical mediatorscirculate as inactive precursors that must undergo proteolytic cleavage to acquire ac

45、tivity. 凝血系統 纖溶系統 補體系統 激肽系統activation of factor XII by contacting with collagens, basement membrane, or activated platelets. Clotting and fibrinolytic systemIncrease permeability and leukocyte emigrationEnhance leukocyte adhesion Increase permeabilitychemotaxis Increase permeabilityIncrease permeabi

46、lityComplement system anaphylatoxin（過敏毒素） inducing mast cells release histamineactivating AA metabolismstrong chemotaxin for leucocytes except eosinophils anaphylatoxin（過敏毒素） inducing mast cells release histamine opsoninKinin systemBradykinin is the ultimate product - Vessel dilation - Increase vasc

47、ular permeability - Bronchial smooth muscle contraction - Pain KininogenBradykinin緩激肽Function: arteriole dilation, increased permeability類型釋放細胞刺激因素Histamine mast cells basophils plateletsPhysicalimmune (IgE)C3a and C5a,leukocyte-derived histamine released proteinsNeuropeptideIL-1 and IL-85-droxytryp

48、tamine (5-HT)/Serotonin) plateletsVasoactive AminesCyclooxygenasepathwayPLArachidonic acid花生四烯酸Phospholipase A2LipoxygenasepathwayLTB4LTA4LTB4, LTC4, LTE4PGI2TxA2PGD2, PGE2, PGG2Arachidonic Acid Metabolism (AA)activated by physical and chemical stimuli, or by inflammatory mediators such as C5aA 22-c

49、arbon polyunsaturated fatty acidReleased via phospholipases which activated by physical and chemical stimuli, or by inflammatory mediators such as C5a化生四烯酸的代謝產物及其作用。5-HETE：5-羥基二十碳四烯酸； LT：白細胞三烯；LX：脂質素；PG：前列腺素；TX：血栓素Functions of Arachidonic Acid MetabolitesVasocontriction: thromboxane A2 , and leukotr

50、iene A4 , D4 , E4Vasodilation: prostaglandin E2 (PGE2 ), PGD2 , PGD2a, prostacyclin (PGI2 ) Increase vascular permeability: leukotriene C4 , D4 , E4Chemotaxis and leukocyte adhesion: leukotriene B4 , lipoxins Anti-inflammatory Targets to AAAspirin and non-steroid anti-inflammatory drugs - inhibit cy

51、clooxygenaseGlucocorticoids: - inhibit Phospholipase A2 - down-regulate the expression of specific target genes (COX2, IL-1, TNF), - up-regulate anti-inflammatory genes (lipoxin-1)Platelet-activating Factor (PAF)Function: (Elicit most of the features of inflammation)Able to aggregate platelets and c

52、ause degranulationCause vasoconstrition and bronchoconstriction 100-1000 times more potent than histamine in inducing vasodilation and increasing vascular permeabilitySource: Generated from the phospholipids of neutrophils, monocytes, basophils, endothelial cells, platelet and other cellsCytokinesPo

53、lypeptide products of activated lymphocytes and macrophages (mainly), as well as other cellsSecretion is transient and tightly regulatedModulating functions of other cells, each cytokine is pleiotrophic (different cells are affected differently), or same effect can be induced by different cytokines細

54、胞因子IL-1、TNF的作用Arginine（精氨酸）NO + Citrulline（瓜氨酸）NOSNitric oxide (NO)Vasodilation Antagonism of all stages of platelet activationReduction of leukocyte recruitmentMicrobicidal agent Function of Inflammatory MediatorsVasodilation：Histamine, 5-HT, bradykinin, PG, NO.Increase vascular permeability：Histam

55、ine; bradykinin; C3a; C5a; Leukotriene C4,D4, E4; Radical oxygen; P substance.Chemotaxis：C5a, Leukotriene B4, Bacterial products, chemokines (IL-8), TNF, Neutrophils products.Fever：PG, IL-1, IL-6, TNF.Pain：PGE2, bradykininTissue injury：Radical oxygen, Lysosome enzymes, NO.Inflammatory Mediator, adap

56、ted from Robbins Basic Pathology 9E VasodilatationVascular permeabilityEDEMA血管活性介質HistamineBradykininC3a C5aLT PGPAFNO組織損傷TraumaIschemiaNeoplasmInfectious agentsForeign particle炎癥介質產生細胞活性介質 C5a LTB4 IL-8, TNFinflammatory cells急性炎癥 N P Mast cell 慢性炎癥M L P 2.3 The classification of inflammation 1）Pera

57、cute inflammation2）Acute inflammation3）Subacute inflammation4）Chronic inflammationPathologicalclassification 1）Alteration Inflammation (acute)2）Exudation Inflammation (acute)3）Proliferation Inflammation (acute or chronic) Clinical classification Viral hepatitis (hepatocyte necrosis)Epidemic Type B E

58、ncephalitis (neuronal necrosis) Poliomyelitis (neuronal necrosis)Alteration InflammationViral hepatitisEpidemic Type B EncephalitisExudation InflammationBased on main compontent of exudation:Serous InflammationFibrinous InflammaionSuppurative InflammationHemorrhagic InflammationSerous InflammationFe

59、atures: exudation of a watery, relatively protein-poor fluid (with 3%-5% plasma proteins, Albumin) Location: mucosa(Catarrh), body cavities (Hydrops ) , loose connective tissues (edema), skin (blister)Outcome: complete resolutionFibrinous InflammationFeatures：Larger molecules (esp. fibrinogen) come

60、out through the endothelial cells. Pathologic changes: Eosinophilic meshwork of threads or sometimes as an amorphous coagulum.Causes: More severe injuries result in greater vascular permeability. Location: Mucosa: PseudomembraneousSerosa：Pericardium （Shaggy heart，絨毛心）Lung: lobar pneumoniaFibrinous I