炎症与组织细胞损伤的修复PPT演示课件

炎症与损伤的修复Inflammation and Repair,学习内容,炎症的概念(Conception of Inflammation)病因(Etiologic Agents)局部表现和全身反应(Local and Systemic Manifestations Signs & Symptoms)炎症的基本病理变化(Morphologic Patterns of Inflammation)急性性炎症类型及特点、发病机制(Acute Inflammation and Pathogenesis)损伤的修复(Repair)慢性炎症及其类型和特点 (Chronic Inflammation)炎症的结局(Prognosis of Inflammation),HISTORICAL HIGHLIGHTS: Big Robbins lists, or might have listed.,Cornelius Celsus (ancient Rome) described rubor (redness), calor (heat - this applies only to the skin), dolor (pain), and tumor (which then simply meant swelling) as the cardinal signs of inflammation. John Hunter (the great early surgeon, * 1793, * parodied by William Blake as Jack Tearguts) first characterized inflammation as a nonspecific body response. Rudolf Virchow added functio laesa (loss of function) as the fifth cardinal sign of inflammation, and his student, Julius Cohnheim, provided the basic studies of the pathologic microanatomy of inflammation. Elie Metchnikoff (* 1892) was the first to observe and study phagocytosis. (* This is the same Metchnikoff who popularized yogurt as a health and longevity food. He died at age 70.) Paul Ehrlich developed the idea of humoral immunity early in this century. (This is the same Ehrlich who developed the magic bullet for syphilis, and most of the stains we still use.) Thomas Lewis demonstrated that inflammation is brought about by chemical mediators, most of which act locally. Someone may still ask you about the triple response of Lewis to a superficial scratch: (1) an immediate red scratch mark; (2) a red flare around the scratch mark; (3) a red swollen area (wheal) around the flare. (Try it!) Dr. Lewis found that he could eliminate the flare, but not the others, by cutting the autonomic nerve supply (i.e., preventing the axon reflex). This experiment led to the discovery of histamine, which mediates events 1 and 3.,Inflammation Definition,各种致炎因子引起机体的组织损伤所诱发的以防御为主的局部组织反应。(第一版）具有血管系统的活体组织对损伤因子所发生的防御反应。（第四版）Inflammation and repair - Defensive reaction. Defensive ? Defective ?,Definition by Big Robbins,“Inflammation is the reaction of living tissues to all form of injury. It involves vascular, neurologic, humoral and cellular response at the site of injury” （Basic Pathology）,Etiologic Agents of Inflammation,“All the factors that can injury the tissues and cells can also cause inflammation of the body. They include the physical, chemical biological, and Immunological agents et al.”,炎症的致病原因,Local and systemic manifestations,Acute Inflammation Cardinal Signs (Celsus, 1 AD),Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor) Loss of function (functio laesa) (the fifth cardinal sign supposedly added by Virchow),Acute Inflammation Cardinal Signs - Redness,Acute Inflammation Cardinal Signs - Swelling,Acute Inflammation Cardinal Signs - Pain,InflammationSystemic Manifestations of Inflammation,Fever - clinical hallmark of inflammationEndogenous pyrogens: IL-1 and TNF-aLeukocytosis - may be neutrophils, eosinophils, or lymphocytesLeukopenia - rareAcute Phase Reactants - non-specific elevation of many serum proteins - will markedly increase the “sed rate”,Leukocytosis,Lines of Defense,InflammationSystemic Manifestations of Inflammation,Shock most common in gram-negative septicemia (bacteria in the bloodstream), although it can occur with gram-positive bacteremiaLipopolysaccharide (endotoxin) of gram-negatives can produce symptoms of shock when injected into animalsTNF-a can produce a similar syndrome,三、炎症的基本病理变化,基本病变,变质：Alteration,渗出：Exudation,增生：Proliferation,变质和渗出出现于早期，而增生出现于晚期,变质（Alteration） 1、概念： 炎症局部组织发生的变性和坏死2、原因： 致病因子直接作用 局部血液循环障碍 免疫介导 炎症反应产物的间接作用,3、变质的细胞的类型和形态变化,实质细胞,变性：细胞水肿、脂肪变性,坏死：凝固性和液化性坏死,间质细胞,变性：黏液变性、玻璃样变性,坏死：纤维素样坏死,渗出 (Exudation)1、概念：炎症局部组织血管内的液体成分、蛋白质和各种白细胞通过血管壁进入 组织、体腔、体表和粘膜表面的过程，称为渗出渗出是炎症最重要特征性变化,增生 (Proliferation )1、实质细胞增生：肝炎时，肝细胞的再生 慢性胆囊炎时粘膜上皮和腺体增生2、间质细胞增生：包括巨噬细胞、血管内 皮细胞和成纤维细胞,炎症的类型 Classification of inflammation,临床类型,急性炎症：病程短，几天1月，以变质渗出为主,慢性炎症：病程长，数月数年，以增生为主,OUTCOMES OF INFLAMMATION,Inciting Stimulus,AcuteInflammation,Chronic-active Inflammation,ChronicInflammation,Resolution,Abscess,Resolution with scarring*,*The longer the stimulus persists, the greater the scarring will be.,A dynamic continuum of change,Spreading,BacteremiaToxemiaSepticemiaPyemia,Story of mice,Acute Inflammation,Pathogenesis of Acute InflammationType of Acute Inflammation,急性炎症,PHASES OF INFLAMMATIONInitiationAmplificationTermination,急性炎症的类型,病理分类,浆液性炎,纤维素性炎,化脓性炎,出血性炎,InflammationPhases of Acute Inflammation,Initiation(开始或启动) 血管反应为中心Stimulation (injury) with changes in microvasculatureStructural changes leading to extravasationEmigration of WBCs to the site of injuryAmplification(扩大或进展)* - 炎症介质和炎细胞的作用Both soluble mediators and cellular inflammatory systems are activated and amplifiedTermination(终止)* - 再生、修复和愈合- accomplished by specific inhibition or dissipation of the mediators,急性炎症的早期反应Phases of Acute Inflammation - Initiation,Initial vasoconstriction (seconds to minutes), followed by a longer period of vasodilationLeakage of fluid and plasma from the intravascular compartment (increased permeability)Stasis, with transmigration of leukocytes and erythrocytes into extravascular tissue,The Triple Response - Sir Thomas Lewis (1927),Normal regulation of fluid transport,Extravascular fluid (little protein or pressure),Hydrostatic pressure,Oncoticpressure,EDEMA -TRANSUDATE (protein content low - specific gravity 1.012),Hydrostatic pressure,Oncoticpressure,Non-Inflammatory Edema,Increased Hydrostatic Pressure,EDEMA -TRANSUDATE (protein content low: specific gravity 1.020),Hydrostatic pressure,Oncoticpressure,Inflammatory Edema Increased Vascular Permeability,Diapedesis血球渗出,Acute InflammationPathogenesis of Edema,Non-inflammatory edema, e.g.:Pulmonary edema due to heart failure (increased hydrostatic pressure)Nephrotic syndrome (decreased oncotic pressure)Inflammatory edema, either:Direct, irreversible injury - all vessels (burns)Transient increase in vascular permeability, i.e., the effect of mediators on post-capillary venules,浆液性炎,Serous exudation Serous inflammation,Serous exudation Serous inflammation,浆液性炎,Fibrinous exudation,白喉,纤维素性炎,Fibrinous exudattion,白喉,Fibrinous exudattion,绒毛心,Pseudomembranous enterocolitis,假膜性炎,Pseudomembranous enterocolitis,假膜性炎,Hemorrhagic Inflammation,Hemorrhagic Fever with Renal Syndrome,出血性炎,炎症灶的血管损伤严重，渗出物中含有大量红细胞。不是独立的类型，常与其他类型合并存在，如纤维素性出血性炎常见于流行性出血热、钩端螺旋体和鼠疫等急性传染病。,急性炎症扩展Phases of Inflammation - Amplification,PMNs and macrophages are recruited to the site of injury from peripheral blood by chemokines, principally IL-8, plus c5a, TGF-b, and Platelet-derived Growth FactorIL-1 and TNF cause the release of post-mitotic reserve granulocytes from the marrow, plus induce the production of Colony Stimulating Factors (CSF),Exudation of blood cells,InflammationNeutrophil,InflammationNeutrophil Granules,Primary - contain serine proteases, lysozyme and phospholipase A2Secondary - similar to primary, but also contain lactoferrin and collagenaseTertiary - present at the leading edge of migrating PMNs, contain gelatinases that are capable of degrading basement membrane,InflammationEosinophil,InflammationMONONUCLEAR PHAGOCYTES,InflammationLymphocyte,InflammationPlasma cell,白细胞游出Leukocyte Extravasation,Margination, rolling, and adhesionTransmigration (diapedesis)Migration toward the site of injury along a chemokine gradient,Sequential involvement of adhesion molecules,Central Axial Stream,Rolling Adhesion Transmigration,SELECTINS (E&P),INTEGRINS & Ig-LIKE MOLECULES (ICAM, VCAM),Qualitative and Quantitative Endothelial and PMN Changes,Inflammation Adhesion Molecule Modulation,P-selectin is redistributed to the cell surface from the Weibel-Palade bodies due to stimulation by thrombin, histamine, and Platelet Activating Factor (PAF)Induction of E-selectin on endothelium by IL-1 and TNFIncreased avidity of binding of integrins (conformational change),InflammationMargination and Pavementing,InflammationTransmigration,趋化作用 Chemotaxis,Exogenous mediators, e.g.:N-formyl methionine terminal amino acids from bacteria Lipids from destroyed or damaged membranes (including LPS)Endogenous mediators, e.g.:Complement proteins (C5a)Chemokines, particularly IL-8Products of lipoxygenase (LTB4),炎细胞的作用 Inflammatory Cell Function,Phagocytosis opsonized by IgG (subtypes 1 or 3) or C3bLocal immune response by monocytes and lumphocytes as well as cytokinesTissue injury by inflammatory cells though the proteinase and inflammatory mediators,吞噬作用、免疫作用、引起组织损伤,InflammationMononuclear Phagocytes,Neutrophil ingestion of bacteria, gram stain,炎症介质Chemical Mediators of Inflammation,Vasoactive aminesComplement systemKinin systemCoagulation pathwayFibrinolytic pathwayArachodonic acid metabolitesPlatelet activating factorCytokinesNitric oxide,-以中性粒细胞渗出为主，并伴有不同程度的组织坏死和脓液形成。脓液：为脓性渗出物，外观呈浑浊的凝乳状液体，灰黄色或灰白色，稀薄或粘稠脓液的成分：脓细胞、细菌、坏死组织、浆液脓细胞：为变性坏死的中性粒细胞。,化脓性炎 中性白细胞渗出 Purulent inflammation - Exudation of Neutrophil,(1).表面化脓和积脓表面化脓- 指发生于粘膜或浆膜的化脓性炎, 黏膜的化脓性炎又呈脓性卡他性炎如化脓性尿道炎，中性白细胞向黏 膜表面渗出，深部组织不明显.积脓 - 当化脓性炎发生于粘膜或浆膜时，脓液积聚于浆膜腔、胆囊和输卵管腔内.(2).脓肿(3).蜂窝织炎（phegmonous inflammation） 疏松结缔组织的弥漫性化脓性炎，常发生于皮肤、肌 肉和阑尾。,溶血性链球菌,透明质酸酶降解结缔组织基质中的透明质酸,链激酶溶解纤维素,Acute meningitis - Purulent exudate,表面化脓,Acute salpingitis - Purulent exudate,积脓,Acute salpingitis - Purulent exudate,Abscesss,脓肿,InflammationTissue Injury by Inflammatory Cells,脓肿,InflammationAcute Inflammatory cell infiltration,弥漫性化脓,Activated oxygen speciesCan migrate through intact plasma membranesInitiate lipid peroxidationReact with DNAOxidize sulfhydryl groups of proteinsDegrade extracellular matrix components,炎症引起组织损伤Tissue Injury by Inflammatory Cells,炎症引起组织损伤Tissue Injury by Inflammatory Cells,Lysosomal enzymesSince these enzymes are used to degrade microorganisms in lysosomes, obviously they could damage tissue in the extracellular environmentUsually protease activity is controlled by a variety of anti-proteases present in plasma (a1-anti-trypsin, a2-macroglobulin, etc.),炎症引起组织损伤Tissue Injury by Inflammatory Cells,Phagocytic cell adherenceAdherence to basement membranes, other components of the extracellular matrix and other cells by phagocytes enhances the damage caused by reactive oxygen species and lysozyme, because normal inhibitors present in plasma cannot gain access to that space by virtue of the phagocytic cell adherence,炎症引起组织损伤Tissue Injury by Inflammatory Cells,The relatively primitive and non-specific immune effects of polymorphonuclear leukocytes and macrophages upon invading microorganisms are also capable of damaging the host by the extracellular release of enzymes and activated oxygen species,InflammationTissue Injury by Inflammatory Cells,Inflammation Typhoidal ulcers,InflammationTissue Injury by Inflammatory Cells,损伤的修复 Tissue Repair,损伤的修复与愈合 Regeneration, Repair and Healing,修复（repair）：损伤造成机体部分细胞和组织丧失后，机体对所形成缺损进行修补恢复的过程，称为修复。,方式,再生性修复, 由周围同种细胞增生修复纤维性修复, 由肉芽组织填补,再生（Regeneration）：是指由同种细胞分裂增生来补充机体老化、消耗或坏死的细胞的过程。可分为：生理性再生：也称为完全性再生。是指生理过程中老化、消耗的细胞由同种细胞分裂增生补充，如表皮角化层经常脱落，由表皮基底细胞增生、分化，予以补充。 病理性再生：也称不完全再生。是指病理状态下，组织细胞损伤后发生的再生，一般由纤维组织增生代替。,再生修复Repair by Regeneration,Definition - Regeneration,Regeneration is a type of repair. The best example of healing by regeneration in humans occurs in the liver, which has incredible regenerative properties. It is possible to resect virtually an entire lobe of liver, and the organ will repair itself over a period of months to completely recapitulate its previous structure.,（1）不稳定细胞（Labile cells）再生能力最强，如全身的上皮细胞、淋巴造血细胞等。 （2）稳定细胞（Stable cells）损伤后，有较强再生能力。如肝、胰、内分泌腺等腺上皮，成纤维细胞、血管内皮细胞、骨细胞和原始间叶细胞等，平滑肌细胞也属稳定细胞，但再生能力弱。（3）永久性细胞（Permanent cells）几乎没有再生能力，受损伤后由结缔组织增生修补，如神经细胞、心肌细胞及骨骼肌等。,细胞的再生能力Classification of cells by their proliferative potential,Cell classification,Labile cells: This sub-population of cells is constantly turned over. The best examples are found in the epithelial cell population of the skin or gut, and the hematopoetic cells of the bone marrow. These cells have a short, finite life span, die via apoptosis, and are rapidly replaced.,Cell classification,Stable cells: Stable cells are a sub-population of cells that are normally replaced very slowly, but are capable of rapid renewal after tissue loss. Hepatocytes and the proximal convoluted tubule cells of the kidney are good examples.,Cell classification,Permanent cells: Permanent cells are found in the central nervous system and heart. Once they are destroyed, they cannot regenerate.Peripheral nerve cells are capable of limited regeneration has been demonstrated, but, for all practical purposes, those of the CNS are permanent cells.,损伤的修复 Wound Healing - Chickenpox,REGENERATION再生,ATN, regenerative (polyuric) phase.,Hyperplasia增生,Chronic ulcerative colitis with crypt abscesses,Squamous Metaplasia 化生 Uterine Cervix,Dysplasia, cervix 不典型增生,损伤的纤维性修复Repair by connective tissue,Wound Healing,Repair Granulation tissue is the initial response to an injury, and consists of richly vascular connective tissue which contains capillaries, young fibroblasts, and a variable infiltrate of inflammatory cellsDo not confuse with GRANULOMA,Definition Fibroplasia or Fibrosis,Fibrosis is a also a type of repair. The best example of healing by fibrosis in humans occurs in the heart, which contains post-mitotic myocytes. Necrotic (dead) myocytes are always replaced by collagenous scar laid down by fibroblasts, since they are incapable of regeneration.,Wound Healing by Fibrosis,Induction of an acute inflammatory responseFormation of new blood vessels (angiogenesis)Migration and proliferation of both parenchymal and connective tissue cellsSynthesis of extracellular matrix proteinsRemodeling,Wound Healing by Fibrosis,RepairThe orderly process by which a wound is eventually replaced by a scarDestruction of epithelium only is termed an erosion, and heals exclusively by regenerationIf destruction of the basement membrane occurs (extracellular matrix), then a scar will form,Healing in specific tissues (Skin),Definition - Healing,Healing is a response to tissue injury, and represents an attempt by the organism to maintain normal structure and function. It overlaps the inflammatory process.,愈合（Wound healing）：是指组织遭受创伤进行再生修复的过程。,Wound Healing,Primary intention: the usual case with a surgical wound, in which there is a clean wound with well-apposed edges, and minimal clot formationSecondary intention: when wound edges cannot be apposed, (e.g., following wound infection), then the wound slowly fills with granulation tissue from the bottom up A large scar usually results,Tissue RepairPhases of Wound Healing,Factors that influence wound healing,Type, size, and location of the wound (determines primary or secondary intention)Vascular supply (diabetics heal poorly)Infection - delays wound healing and leads to more granulation tissue and scarringMovement - wounds over joints do not heal well, due to tractionRadiation - ionizing radiation is bad, UV is good,Factors that influence wound healing,Overall nutrition: vitamin and protein deficiencies lead to poor wound healing, especially vitamin C, which is involved in collagen synthesisAge: younger is definitely better!Hormones - corticosteroids impair wound healing, because of their profound effect on inflammatory cells,Complications of Wound Healing,Defective scar formationExcessive scar formation (keloid)Contraction,Complications of Wound Healing,Defective scar formation Dehiscence or ulceration is usually due to:Wound infection (common)Malnutrition (scurvy - rare)Hypoxia with ulceration, usually due to inadequate vascularity in the skin flap (common),Excessive Scar Formation,Excessive scar formation (keloid). Keloids (hypertrophic scars) are the result of over-exuberant production of scar tissue, which is primarily composed of type III collagen. The cause is thought to be due to genetic factors, perhaps due to lack of the proper collagenases to degrade type III collagen.Contraction,Keloid,Keloid (micro),Contraction,Excessive contraction of a wound is known as a contracture. They are a special problem in the treatment of extensive burnsSeveral diseases of unknown cause are characterized by the formation of contracturesPeyronie disease of the penisDupuytren disease of the palms,Healing in specific tissues (heart),Cardiac myocytes are permanent cells. They do not divide, and the heart thus heals by resolution (dead myocytes are phagocytized by macrophages) and collagenous scar formation.,Acute MI (gross),Acute MI (micro),Remote MI (micro),Healing in specific tissues (liver),The liver heals by regeneration. It can regenerate perhaps 75% of its volume. Scarring occurs when the extracellular matrix of the liver is damaged by repeated or severe injury. Bile ducts then proliferate, regenerative nodules form, and collagenous scars become evident. This scarring process is commonly called cirrhosis.,InflammationChronic Inflammation Hepatitis,Cirrhosis, trichrome,Healing in specific tissues (Bone),Chronic Inflammation,慢性炎症,InflammationChronic Inflammation,Chronic inflammation may occur as a sequel to acute inflammation, or as a primary immune response to a foreign antigen (usually viral)Type of chronic inflammation includes: general, granulomatous inflammation, Inflammatory polyp and pseudotumor,ACUTE,CHRONIC,Vascular changes,Cellular infiltra