病理学英文课件：Inflammation

1、 Inflammation is Most common pathological change, involving all tissues and organs Basic pathological changes of most disease, infection, allergy, autoimmune disease Participating in almost all pathological conditions, wound healing, ischemic, tumor Important functions overviewoverview Furuncle（疖）（疖

2、） normalSARS Etiology：SARS冠状病毒（冠状病毒（SARS CoV） Allergy - Edema Acute proliferative glomerulonephritisEM Subepithelial “hump” deposit Crescentic glomerulonephritissilver stain Skin blister result from burning Serous effusion accumulated within and underneath the epidermis of skin Outlines of Inflammat

3、ion Part 1：General Considerations of inflammation - Definition - Inflammatory agents（致炎因子）（致炎因子） - Basic pathological changes （基本病变）（基本病变） Part 2：Acute inflammation - vascular and cellular events - Inflammatory mediator (炎症介质）炎症介质）difficult part - Classification and outcomes practical and useful par

4、t Part 3：Chronic inflammation Part 4：Local and systemic manifestations Inflammation is Medieval concepts： imbalance of various humors, including blood, mucus and bile. Rudolf Virchow: reaction to prior tissue injury Julius Cohnheim (Virchows student) : emigration of leukocytes through the walls of t

5、he microvasculature. Russian zoologist Eli Metchnikoff: role of phagocytosis in the inflammatory process. Thomas Lewis (1927): the importance of chemical mediators in the inflammatory response, histamine produced an increase in vascular permeability and elicited the migration of leukocytes into the

6、extravascular spaces. John Hunter (1793) : noted dilation of blood vessels and appreciated that pus represented an accumulation of material derived from the blood. 1.1 Definition 具有具有血管系统血管系统的的活体活体组织对组织对损伤因子损伤因子发生的发生的防御防御反应。反应。 Inflammation is a protective response intended to eliminate the initial

7、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) 本质：损伤本质：损伤 - 抗损伤（包括修复）抗损伤（包括修复） 炎症作用的双面性炎症作用的双面性 致炎因子 损伤损伤 抗损伤抗损伤 炎症 不利：不利： - - 抗损伤的

8、同时，纤维化，瘢抗损伤的同时，纤维化，瘢 痕，过敏反应痕，过敏反应, ,炎症对组织也造炎症对组织也造 成一定程度的损伤。成一定程度的损伤。 有利：防御及抗损伤有利：防御及抗损伤 任何能够引起组织损伤的因素：任何能够引起组织损伤的因素： 生物性生物性 ( Infectious ) :最常见最常见，=感染感染 创伤和物理性创伤和物理性 免疫反应：免疫反应：4 种类型变态反应种类型变态反应 化学性化学性 ( Chemical )：外源性、内源性：外源性、内源性 缺血缺血 ( Ischemic ) 坏死坏死 ( necrosis ) 异物异物 ( Foreign particle ) Herpes s

9、implex 单纯疱疹单纯疱疹 Tinea 癣癣 Differentiate the following 3 conditions： Inflammatory diseases 炎症性疾病炎症性疾病 Infectious diseases 感染性疾病感染性疾病 Communicable diseases 传染病传染病 Inflammation Infection Communicable disease Perniosis 冻疮冻疮 多形性日光疹多形性日光疹 Contact dermatitis 接触性皮炎接触性皮炎 隆乳后异物反应隆乳后异物反应 同时存在，某一具体炎症常以某一病变为主。同时存

10、在，某一具体炎症常以某一病变为主。 急性炎症或炎症早期一般变质和渗出较显著；慢性急性炎症或炎症早期一般变质和渗出较显著；慢性 炎症或炎症后期，增生较显著。炎症或炎症后期，增生较显著。 Alteration（变质）（变质） Exudation（渗出）（渗出） Proliferation（增生）（增生） Alteration Mechanism of the alteration Direct injury from inflammatory agents Inflammatory results - vascular circulation problem - inflammatory medi

11、ators， O-radicals Hallmark of inflammation Definition: extravasation of blood components in inflammation Components: 1）plasma fluid and proteins； 2）leukocytes Occurring in the early stage of inflammation and sustaining during inflammation Mechanism：vascular change Transudate: passive an ultrafiltrat

12、e of plasma, little protein and cells Exudate: active protein-rich and cell-rich fluid，extravagate due to high vascular permeability mm3 mm3 Exudation of leukocytes （inflammatory cells） neutrophils (acute and purulent ) lymphocytes ( chronic ) monocytes ( macrophages, chronic ) eosinophils (allergic

13、 and parasitic ) basophils and mast cell Mononuclear cells ( monocytes + lymphocytes ) Neutrophils Neutrophil (polymorphonuclear cell) Hallmark for purulent and acute inflammation Quick response (extravasation in 15min) Short life span (24h) Pus cell: degenerative and necrotic neutrophils Function：

14、- microphage, strong phagocytosis and killing ability - Azurophilic granule (acid protease, neutal protease, myeloperoxidase, phospholipase) - Specific granule (enzyme) Lymphocytes B lymphocytes transform into plasma cells producing antibodies T lymphocytes have reciprocal relationship to macrophage

15、s Plasma Cells Macrophages The heart of chronic inflammation Extravasation within 24h Long life span: half-life in circulation is 1d, in tissue could be 1m-1yr. Strong ability of phagocytosis and killing after activation. reciprocal activation of T cell and macrophages Macrophages: Antigens processe

16、d by macrophages activate T cells Release 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 cell , foamy cell, multinuclear giant cell epithelioid cell in tubercu

17、losis Eosinophils Characteristic of parasitic infections and IgE mediated immune responses Specific chemotaxin for eosinophils (eotatin) derived from leukocytes or epithelial cells Major basic protein (MBP), a cation protein, is toxic to both parasites and epithelial cells 血吸虫感染血吸虫感染 Basophil and Ma

18、st Cell Widely distributed in connective tissues Sentinel cells in both acute and chronic inflammation Release histamine and arachidonic acid (AA) metabolites that elicit the early vascular changes armed by IgE to certain antigens play central role in anaphylatic shock 静止肥大细胞静止肥大细胞 活化肥大细胞活化肥大细胞 Prot

19、ective function: 1) Limit lfirm adhesion（黏附）; ltransmigration（游出）; 炎症灶炎症灶 血管内皮血管内皮 1) Margination: Leukocyte are pushed out of the central axial column and accumulation at the periphery of vessels. 2) Rolling: Leukocytes tumble on the endothelial surface and transiently sticking along endothelial ce

20、lls. mediated by binding between selectin and selected sialyl-Lewis-X-modified glycoprotein. up-regulated or redistributed after stimulation loose and transient adhesion Mechanisms mediating increased leukocyte-endothelial adhesion L、P和E分别表示 leukocyte,platelet和endothelium 3) Adhesion the leukocytes

21、firmly stick to endothelial surfaces. binding of integrin on leukocyte with ICAM and VCAM on endothelial cells. integrin undergo conformational change to higher affinity Heterodimers :, 20+ type Integrin INSIDE INSIDE OUTSIDE 2 integrin actin ezrin ICAM-1 ICAM (intercellular -) VCAM (vascular -) - I

22、g superfamily - Heterophilic / homophilic adhesion - squeezing between cells at intercellular junctions Leukocytes diapedesis （阿米巴运动（阿米巴运动 ） - occurs in venules of systemic circulation and in capillaries of pulmonary circulation - Mediated by CD31 (PECAM-1) , belong to Ig superfamily Endothelial-neu

23、trophil interaction 炎症时内皮细胞和白细炎症时内皮细胞和白细 胞粘附分子的表达增加，胞粘附分子的表达增加， 亲和性增强，表达新的粘亲和性增强，表达新的粘 附分子附分子 lChemotaxis（趋化作用）（趋化作用）: after extravasating from the blood, leukocytes migrate toward sites of injury along a chemical gradient. lChemotactic agents （趋化因子）（趋化因子） : include bacterial products, chemokines, C

24、5a, leukotriene B4 lspecific binding of the chemotactic agents with their receptors on the specific leukocytes 血吸虫病 1) Recognition and Attachment to microbe lby opsonins binding with opsonin receptors on leukocytes lOpsonin (调理素调理素) ：血清中的促进细胞吞噬功能的蛋白质。血清中的促进细胞吞噬功能的蛋白质。 Fc portion of IgG C3b and C3bi

25、carbohydrate-binding lectins：collectins (集结素集结素) 2) Engulfment : pseudopods are extended around microbes, subsequently forming a phagocytic vacuole phagosome lysosome phagolysosome 酸性水解酶 中性蛋白酶 髓过氧化物酶 阳离子蛋白 溶菌酶 磷脂酶A2 3) Killing and Degradation loxygen dependent mechanism - oxidative burst：Rapid activ

26、ation of leukocyte NADPH oxidase, 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 perm

27、eability-increasing protein (BPI), lysozyme Phagocytosis Defects in Leukocytes Function Genetic or acquired Increased vulnerability of infection Recurrent and life-threatening infection Although rare, highlighting the complex series of molecular events in vivo Defects in Leukocytes Function Leukocyt

28、e adhesion deficiency 1(LAD-1): Defect in chain of CD11/CD18 integrin, impaired adhesion and spreading Leukocyte adhesion deficiency 2(LAD-2):Defect in fucose metabolism resulting in the absence of sialyl-Lewis X(墨角藻糖基转移酶突变使唾液酸墨角藻糖基转移酶突变使唾液酸 化化Lewis X缺乏缺乏 ), impaired rolling and loose adhesion to en

29、dothelial cells Defects in Leukocytes Function Chronic granulomatous disease (CGD): Defects in several components of NADPH oxidase, impaired killing of engulfed microbes Chediak-Higashi syndrome: autosomal recessive disease, defects in phagolysome formation resulting from intracellular trafficking o

30、f organelles, impairing lysomal degranulation into phagosomes, secretion of cytotoxic T cell is also damaged, severe immunodeficiency occurs. chemical mediators) uFunction: mediate the vascular and cellular events in inflammation 参与炎症反应（血管扩张、通透性增加、白参与炎症反应（血管扩张、通透性增加、白 细胞渗出等）的内源性化学因子称为炎症介质细胞渗出等）的内源性化

31、学因子称为炎症介质 uInduce effects by binding specific receptors on target cells（配体（配体-受体特异性结合）受体特异性结合） uStimulate target cells to release secondary effecter molecules (级联反应级联反应) uAct on only one or few targets, or having widespread activity uBeing potential to cause harmful effects, so mediator function is

32、tightly regulated in vivo. Vasoactive amines Arachidonic acid metabolites Platelet-activating factor Cytokines Lysosomal constituents NO and oxygen-derived free radicals Neuropeptides 细胞释放细胞释放血浆成分血浆成分 Kinins Complements Clotting system Fibrinolytic system Various Chemical Mediators Plasma derived Ch

33、emical mediators circulate as inactive precursors that must undergo proteolytic cleavage to acquire activity. 凝血系统凝血系统 纤溶系统纤溶系统 补体系统补体系统 激肽系统激肽系统 activation of factor XII by contacting with collagens, basement membrane, or activated platelets. Clotting and fibrinolytic system Increase permeability a

34、nd leukocyte emigration Enhance leukocyte adhesion Increase permeability chemotaxis Increase permeability Increase permeability Complement system anaphylatoxin（过敏毒素）（过敏毒素） inducing mast cells release histamine activating AA metabolism strong chemotaxin for leucocytes except eosinophils anaphylatoxin

35、（过敏毒（过敏毒 素）素） inducing mast cells release histamine opsonin Bradykinin is the ultimate product - Vessel dilation - Increase vascular permeability - Bronchial smooth muscle contraction - Pain Kininogen Bradykinin 缓激肽缓激肽 Released from secretory granules: Vasoactive amines, lysosomal enzymes newly synt

36、hesized: Arachidonic acid metabolites, Platelet-activating factor (PAF), NO, cytokines Cell derived Chemical Mediators Function: arteriole dilation, increased permeability 类型类型释放细胞释放细胞刺激因素刺激因素 lHistaminel mast cells l basophils l platelets lPhysical limmune (IgE) lC3a and C5a, lleukocyte-derived his

37、tamine released proteins lNeuropeptide lIL-1 and IL-8 l5-droxytryptamine (5-HT)/Serotonin) l platelets Vasoactive Amines Cyclooxygenase pathway Arachidonic acid 花生四烯酸花生四烯酸 Lipoxygenase pathway ,LTC4, LTE4,PGE2, PGG2 Arachidonic Acid Metabolism (AA) activated by physical and chemical stimuli, or by i

38、nflammatory mediators such as C5a A 22-carbon polyunsaturated fatty acid Released via phospholipases which activated by physical and chemical stimuli, or by inflammatory mediators such as C5a Lipoxins（脂毒素）（脂毒素） Negative regulator of leukotriene actions Transcellular biosynthetic mechanism LXA4: inhi

39、bit LTA4 stimulated vasoconstriction inhibit neutrophil adhesion and chemotaxis Functions of Arachidonic Acid Metabolites Vasocontriction: thromboxane A2 , and leukotriene A4 , D4 , E4 Vasodilation: prostaglandin E2 (PGE2 ), PGD2 , PGD2a, prostacyclin (PGI2 ) Increase vascular permeability: leukotri

40、ene C4 , D4 , E4 Chemotaxis and leukocyte adhesion: leukotriene B4 , lipoxins Anti-inflammatory Targets to AA Aspirin and non-steroid anti-inflammatory drugs - inhibit cyclooxygenase Glucocorticoids: - inhibit - down-regulate the expression of specific target genes (COX2, IL-1, TNF), - up-regulate a

41、nti-inflammatory genes (lipoxin-1) Modify the content of dietary lipids: fish oil: leukotrienes from fatty acid in fish oil are less potential than those from animal or vegetable fat Platelet-activating Factor (PAF) Function: (Elicit most of the features of inflammation) Able to aggregate platelets

42、and cause degranulation Cause vasoconstrition and bronchoconstriction 100- 1000 times more potent than histamine in inducing vasodilation and increasing vascular permeability Source: Generated from the phospholipids of neutrophils, monocytes, basophils, endothelial cells, platelet and other cells Cy

43、tokines Polypeptide products of activated lymphocytes and macrophages (mainly), as well as other cells Secretion is transient and tightly regulated Modulating functions of other cells, each cytokine is pleiotrophic (different cells are affected differently), or same effect can be induced by differen

44、t cytokines TNF and IL-1 Produced by activated macrophages and other cells (NK, T, mast, endothelial cells, neutrophils, keratocytes) Secretion is stimulated by endotoxin, immune complexes, toxins, physical injuries, inflammatory mediators Wide-range of effects: acute-phase reaction, endothelial eff

45、ects, fibroblast effects, and leukocyte effects Major effects of IL-1 and TNF Anti-inflammatory Cytokine: IL-10 Secreted by monocytes, B cells, T cells, epithelia, keratocytes, and cells in bone marrow Inhibiting the release of IL-1,IL-6, and TNF Inhibiting specific antigen-activated T cells Inhibit

46、ing MHCII expression in monocytes Inhibiting NO production in monocytes and macrophages Arginine（精氨酸）（精氨酸）NO + Citrulline（瓜氨酸）（瓜氨酸） NOS Nitric oxide (NO) Vasodilation Antagonism of all stages of platelet activation Reduction of leukocyte recruitment Microbicidal agent Sources of Inflammatory Mediato

47、rs Function of Inflammatory Mediators Vasodilation：Histamine, 5-HT, bradykinin, PG, NO. Increase vascular permeability：Histamine; bradykinin; C3a; C5a; Leukotriene C4,D4, E4; Radical oxygen; P substance. Chemotaxis：C5a, Leukotriene B4, Bacterial products, chemokines (IL-8), TNF, Neutrophils products

48、. Fever：PG, IL-1, IL-6, TNF. Pain：PGE2, bradykinin Tissue injury：Radical oxygen, Lysosome enzymes, NO. 血管活性介质血管活性介质 Histamine Bradykinin C3a C5a LT PG PAF NO 组织损伤组织损伤 Trauma Ischemia Neoplasm Infectious agents Foreign particle 炎症介质产生炎症介质产生 细胞活性介质细胞活性介质 C5a LTB4 IL-8, TNF 急性炎症急性炎症 N P Mast cell 慢性炎症慢性炎症 M L P Pathological classification 1）Alteration Inflammation (acute) 2）Exudation Inflammation (acute) 3）Proliferation Inflammation (acute or chronic) Clinical classification Serous Inflammation Fibrinous Inflammaion Suppurative Inflammation Hemorrhagic Inflammation Serous Inflammati