4 UNIT 1 UNTRODUCTION TO PATHOLOGY Page ) (General ):(Systemic : . : . 4 : 1. 0052 " ) '(, : ) Intrinsic( ) acquired(. ) ( . ' ) (. " " . 2. . , . ' CF , . , ' , , , . 3. . " . " DNA Micro , arrays . 4. ) (Clinical manifestations , . , , 91 ) (. ).(cell injury - - cell matrix / . 4 OVERVIEW: Cellular Responses to Stress and Noxious Stimuli Page , homeostasis . , ,cellular adaptation " . : Hyperplasia Hypertrophy Atrophy

1

, injurious agent .cell injury , ' - point of no return . : ) ( . Necrosis ' . Apoptosis .DNA , .subcellular alterations intracellular accumulations , . ) (. .TABLE 1-1 -- Cellular Responses to Injury Nature and Severity of Injurious Stimulus :Altered physiologic stimuli .Increased demand, increased trophic stimulation (e.g (growth factors, hormones Decreased nutrients, stimulation (Chronic irritation (chemical or physical Reduced oxygen supply; chemical injury; microbial infection Acute and self-limited (Progessive and severe (including DNA damage Cellular Response :Cellular adaptations Hyperplasia, hypertrophy Atrophy Metaplasia :Cell injury Acute reversible injury Irreversible injury cell death Necrosis Apoptosis Mild chronic injury Metabolic alterations, genetic or acquired Prolonged life span with cumulative sublethal injury Subcellular alterations in various organelles Intracellular accumulations; calcifications Cellular aging

5 Cellular Adaptations of Growth and Differentiation Page , , . , .Metaplasia . " . " . ' ECM .

2

6 Hyperplasia Page

Figure 1-2 The relationships between normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation depicted here is hypertrophy, and the type of cell death is ischemic necrosis. In reversibly injured myocardium, generally effects are only functional, without any readily apparent gross or even microscopic changes. In the example of myocardial hypertrophy, the left ventricular wall is more than 2 cm in thickness (normal is 1 to 1.5 cm). In the specimen showing necrosis, the transmural light area in the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections have been stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme .leakage after cell death

Physiologic Hyperplasia , " . ' ' . DNA . : Hormonal Hyperplasia . ' 1. , . Compensatory Hyperplasia . 2. ' , . ' ,lateral nephrectomy . " , . . GF ) (compensatory . " . ' ' . chronic hepatitis . Pathologic Hyperplasia GF . ' " , " 41-01 . . , . 3

, . , , . . , . . viral infections' papilloamviurses .

Hypertrophy . , . . ,DNA . ) ( . , " . ' ,bodybuilders workload . ' " . chronic hemodynamic overload , . ' , . " ) (. .

Figure 1-3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid )uterus (removed for postpartum bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus (left .(compared with large plump cells in gravid uterus (right

, . ) ( " . , , , . )(. Mecahnisms of Hypertrophy . ),(signal transduction pathways . 4

.Figure 1-4 Changes in the expression of selected genes and proteins during myocardial hypertrophy

: c-fos, c-jun - TGF, insulin-like growth factor 1 IFG1, fibroblast growth factor Vasoactive agents 2(adrenergic agonists, endotelin1, angitensin ) (switch ' , ,ATPase . , ' ' (ANF (atrial natriuretic factor , , . , ) ANF (. ANF , ) (, .hemodynamic load : mechanical triggers 1. 1 ,trophic triggers IGF 2, adrenergic 2. (agonists(Vasoactive agent GF Vasoactive agents " nonmuscle cells " , . " . , . . . . , , .

Atrophy . . , ) (. : . notochord thrygossal duct . . 5

. . : Decreased workload 1. , . . , . . ) (denervation atrophy 2. . )( 3. . , , .atheroclerosis

Figure 1-5 A, Atrophy of the brain in an 82-year-old male with atherosclerotic disease. Atrophy of the brain is due to aging and reduced blood supply. The meninges have been stripped. B, Normal brain of a 36-year-old male. Note that loss of brain substance narrows the gyri and widens the sulci

, ) .(marasmus ).(cachexia ) ) TNF .cachexia , ' . , . )(senile atrophy . . . " .

4.

5. 6. 7.

. , ,ER " . , . , . . Mechanism of Atrophy

6

. . . ' : )' ,(cathepsin . Ubiquitin-proteosome pathway . " ' ubiquitin . - , ) (. TNF ) (. .autophagic vacules ), .(ER " . autophagic vacules " residual body , sarcophagus. - Lipofuscin granules ' .residual body ).(brown atrophy

Metaplasia , ) ( " . . ) ,(squamous .Figure 1-6 Metaplasia. A, Schematic diagram of columnar to squamous metaplasia. B, Metaplastic transformation of esophageal stratified squamous epithelium (left) to mature .(columnar epithelium (so-called Barrett metaplasia

, cilia " . ' , . (A (retinoic acid . A . , . . , . , ) (. .barrett esophagus . )" glandular .(carcinomas . ' . . 7

Mechanisms of Metaplasia . . " , GF ECM . . ' TGF ,superfamiliy . GF . . ,A . cytostatic drugs DNA . Overview if cell injury and cell death . , .

.Figure 1-7 Stages in the evolution of cell injury and death

' :injury cell8-1 Figure Schematic representation of a normal cell and the changes in reversible and irreversible cell injury. Depicted are morphologic changes, which are described in the following pages and shown in electron micrographs in . 71-1 Figure Reversible injury is characterized by generalized swelling of the cell ;and its organelles blebbing of the ;plasma membrane detachment of

8

ribosomes from the endoplasmic reticulum; and clumping of nuclear chromatin. Transition to irreversible injury is characterized by increasing swelling of the cell; swelling and disruption of lysosomes; presence of large amorphous densities in swollen mitochondria; disruption of cellular membranes; and profound nuclear changes. The latter include nuclear codensation (pyknosis), followed by fragmentation (karyorrhexis) and dissolution of the nucleus (karyolysis). Laminated structures (myelin figures) derived from damaged membranes of organelles and the plasma membrane first appear during the reversible stage and become more .pronounced in irreversibly damaged cells. The mechanisms underlying these changes are discussed in the text that follows

: ' . / reversible cell injury.1 : ATP , irreversibly injury and cell death.2 -" lethal hit" , . . , , ' .( ) irreversibly injured cells invariably undergo morphologic changes .3 . : that are recognize as cell death

Figure 1-9 The sequential ultrastructural changes seen in necrosis (left) and apoptosis (right). In apoptosis, the initial changes consist of nuclear chromatin condensation and fragmentation, followed by cytoplasmic budding and phagocytosis of the extruded apoptotic bodies. Signs of cytoplasmic blebs, and digestion and leakage of cellular components

TABLE 1-2 -- Features of Necrosis and Apoptosis Feature Cell size Necrosis (Enlarged (swelling Apoptosis (Reduced (shrinkage Fragmentation into nucleosome size fragments Intact; altered structure, especially orientation of lipids Intact; may be released in apoptotic bodies

Nucelus Pyknosis karyorrhexis karyolysis Plasma membrane Cellular contents Disrupted Enzymatic digestion; may leak out of cell

9

TABLE 1-2 -- Features of Necrosis and Apoptosis Feature Adjacent inflammation Physiologic or pathologic role Necrosis Frequent Invariably pathologic (culmination of (irreversible cell injury Apoptosis No Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage

, , . DNA . . . ' , .

Causes of Cell Injury . : 1. Oxygen Deprivation . . . . , . : ' . ) CO ( . , . ' , , " ) ( ) (. 2. Physical agents , ' , , . Chemical Agents and Drugs 3. . , , . , , . : , , '. Infectious Agents 4. . , , . . Immunologic Reactions' . ' 5. , ) (. 01

Genetic Reactions 6. )' ( ) S' (. . Nutritional Imbalances 7. . , . ) ( . . , . .

Mechanism of Cell Injury . , ' : , . , 1. , , . , . 2. , . , . . 3. .

.Figure 1-10 Cellular and biochemical sites of damage in cell injury

: o ATP o o Figure 1-11 Functional and morphologic consequences of decreased intracellular o .ATP during cell injury o

11

Depletion of ATP ATP ATP" . ATP , , .phospholipids turnover ATP : o oxidative phosphorylation ADP " . Glycolytic pathway o ATP . , , ATP . ATP %5-%01 ' ' : 1. -Na+K. ' , . , , .ER 2. . , , , oxidative .phosphorylation ATP AMP . " . - . pH . 3. ++Ca ,++Ca . 4. ATP , ,RER . . , . ) 8-1, (. 5. , . unfolded protein response . , " .

Mitochondrial Damage . " . " : Oxidative stress " 2A

21

" ) ,(high conductance channels . , - , . oxidative ,phosphorilation - , . C. C , . Influx of intracellular calcium and Loss of Calcium Homeostasis . Figure 1-12 Mitochondrial ) 1.0 ( .dysfunction in cell injury )3.1 .(mmol .ER " .Ca2+,Mg2+ ATPase ' , .ER . ' . : ) ATPase o (ATP o o DNA o . " ) (, . Accumulation of oxygen-derived free radicals ((oxidative stress " . Figure 1-13 Sources and consequences of increased . cytosolic calcium in cell injury. ATP, adenosine , . .reactive oxygen species ' . ' .oxidative stress , , , " .

31

. ' ): , , , , ' (. , ' , . ' :Figure 1-14 The role of reactive oxygen species in cell injury. O2 is converted to superoxide (O2 -) by oxidative enzymes in the endoplasmic reticulum (ER), mitochondria, plasma .membrane, peroxisomes, and cytosol O2 - is converted to H2 O2 by dismutation and thence to OH by the .Cu2+ /Fe2+ -catalyzed Fenton reaction H2 O2 is also derived directly from oxidases in peroxisomes. Not shown is ,another potentially injurious radical singlet oxygen. Resultant free radical ,)damage to lipid (peroxidation proteins, and DNA leads to various forms of cell injury. Note that superoxide catalyzes the reduction of Fe3+ to Fe2+ , thus enhancing OH generation by the Fenton reaction. The major antioxidant enzymes are ,superoxide dismutase (SOD), catalase and glutathione peroxidase

) .(UV, X-ray' 1. ) (. . ' 4 CCL(carbon 2. .(tetrachloride - . 3. , ' " . " ,ER, , . : - 2O Hydrogen peroxide - 2O2H Hydroxyl ions OH PMN . " .NADPH oxidase , - )' (xanthine oxidase . ' , 4. )(Fenton 2+Fe3+ + OH + OH- 2O2 H+Fe - 3 ,(+ferric (Fe 2 (+ferrous (Fe . ) " (. ,(Nitric Oxide (NO " , , 5. , (highly reactive peroxynitrite anion (-ONOO 2NO -.3NO , : ) 41-1( Lipid peroxidation of membrane 1. . OH 41

. ) ,(propagation . Termination ,scavenger ,E . Oxidative modification of proteins 2. , )' (, . . " . Lesions in DNA " 3. . ) 7(. . . , ', . ' - "" ) 41-1(. ' : Antioxidants "" ) (scavenge 1. . : A Eascorbic acid . 2. , .OH : ) (hydrogen proxide. 3. : (2O2H (2H2O2 O2 + 2H2O Superoxide dismutase 22O2H (2O + 2O2H H (+ -2O ' manganese superoxide dismutase , copper-zink-superoxide dismutase glutathione peroxidase " : GSH GSSG (glutathione homodimer)+2 H2O2 2 + 2O2H 2OH + 2GSH GSSG + 2H2O GSSG GSH , "" . , . , .

Defects in Membrane Permeability . , . , ATP " ) (. 51

" , , . ' : Mitochondrial 1. dysfunction , . , . .ATP , . . : Loss of membrane phospholipids , : ) -( -ATP dependent reacylation 2.

Figure 1-15 Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of ischemic tissues, also .(cause membrane damage (not shown

Cytoskeleton abnormalities . -, . , , . -Reactive oxygen species . Lipid breakdown products : unesterified )(acyl carnitine , : - , , . : , , , . ribonucleic acid .ATP , . : ,RNases, DNases .protease, phosphotases, glucoidases, cathepsins , .

3. 4. 5.

Reversible and Irreversible Cell Injury : ATP 61

DNA , , , . , , ' . ) 8-1(. , , ) ( .ATP - - . , , , , ribonucleic acids ATP .hyperpermeable : 1. , , 2. , ) (ripple effect ' - 3. 4. , . -: ) , oxidative phosphorylation 1. (ATP ) , " 2. pH ( -, . , - . / : , . temperature-resistant -. , " . Morphology of Cell Injury and Necrosis . , . time lag . . ) 61-1(. , , .

71

, . ' . 21-4 , - 06-02 .Figure 1-16 Timing of biochemical and morphologic changes in cell .injury

Reversible Injury : - 1. . fatty change 2. , . : .

Morphology . ) (. , . , , .ER ) (hydropic change .vacular degeneration . - ) (ultrastructural changes ) 71-1(:

81

Figure 1-17 Morphologic changes in reversible and irreversible cell injury. A, Electron micrograph of a normal epithelial cell of the proximal kidney tubule. Note abundant microvilli (mv), lining the lumen (L). N, nucleus; V, apical vacuoles (which are normal structures in this cell type). B, Epithelial cell of the proximal tubule showing reversible ischemic changes. The microvilli (mv) are lost and have been incorporated in apical cytoplasm; blebs have formed and are extruded in the lumen (L). Mitochondria are slightly dilated. (Compare with A.) C, Proximal tubular cell showing irreversible ischemic injury. Note the markedly swollen mitochondria containing amorphous densities, disrupted cell membranes, and dense pyknotic nucleus

' Plasma membrane alterations . )( blunting ,( ) blebbing ( ) myelin figures - small phospholipid- Mitochondrial changes , Dilation of ER

.1 .2 rich amorphous densities .3 . .4

. Nuclear alterations

Necrosois -. . , , . : .autolysis , o , o 19

, . . 21-4 , .

Morphology eosinophilia: basophilia " RNA o eosin . ) 81-1( o

Figure 1-18 Ischemic necrosis of the myocardium. A, Normal myocardium. B, Myocardium with coagulation necrosis (upper two thirds of figure), showing strongly eosinophilic anucleate myocardial fibers. Leukocytes in the interstitium are an early reaction to necrotic muscle. Compare with A and with .normal fibers in the lower part of the figure

, . , . , . .myelin figures " . .calcium soaps , : o o myelin figures o osmiophilic debris o ) ,(fluffy ) o (1-17C , ) DNA 8-1 (1-17C - Karyolysis , 1. .DNase Pyknosis ) (. 2. DNA . karyorrhexis . . 3. , . Coagulative necrosis - . ' ) .(1-19A . , - , . 02

, , , . , " " . Coagulative necrosis . Liquefactive necrosis . Liquefactive necrosis , ) .(1-19B , CNS . , , . " , .PUS

Figure 1-19 Coagulative and liquefactive necrosis. A, Kidney infarct exhibiting coagulative necrosis, with loss of ,nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture. B A focus of liquefactive necrosis in the kidney caused by fungal infection. The focus is filled with white cells and .cellular debris, creating a renal abscess that obliterates the normal architecture

Gangrenous necrosis ", . , , . , " ) wet (gangrene Caseous necrosis . caseous ) 02-1(. , ) granulomatous reaction 2(. , , . Fat necrosis . Figure 1-20 A tuberculous lung with a large area of caseous necrosis. The caseous debris is . .acute pancreatities .yellow-white and cheesy , triglyceride esters . ) ,(fat saponification ) 12-1(. , , .inflammatory reaction

Figure 1-21 Foci of fat necrosis with saponification in the mesentery. The areas of white chalky deposits represent calcium soap .formation at sites of lipid breakdown

12

, , " " . , . .dystrophic calcification 32 .(Examples of cell injury and necrosis (p , , , . . Ischemic and hypoxic injury , , . . Hypoxia . . . , Ischemia , , , . " " . . : . end artery . . , , . , . ) ( ) (reperfusion . , . . ) (reperfusion . . ischemia-reperfusion .injury ) (. : 22-1. : . - oxidative phosphorilation - ATP . ATP , . ) ( ) (. : 06 . . : - :ATP , , blebs . " -"myelin figures . , . - RER, , . 22

. . : amorphous densities . . 04-03 . ) (reperfusion . " ) " - (. . " " "myelin figures calcification .calcium soaps

Ischemia- reperfusion injury , , . . . - reperfusion injury ? " , . " " - oxidase . . ).(scavengers -) mitochondrial permeability transition ( - ATP . " . PMN reperfusion ) 2(. ) ( . " , - Ischemia- reperfusion injury . IgM reperfusion . . Chemical injury 32

, 9. 2 : " . : 1. mercuric chloride poisoning - sulfhydryl ATP. , , . ' . - -cytochrome oxidase , .-oxidative phosphorilation . 2. . " 054 P - SER . " , " . " : 1. 4 -(carbon tetrachloride (CCl . " 054 P ) 3 (CCl )054 P (. - SER - autooxidation . lipid peroxides . , - lipid peroxides . : CCl4-induced liver cell injury : , SER - .RER . -fatty ) liver of CCl4 poisoning 42-1(. . " - SER . ) -1 32(. 2. -(Acetaminophen (Tylenol . - " ,sulfation & glucoronidation " " 054 . P - .GSH GSH , - . GSH 42

, 5-3 . " , " . 62.(Apoptosis (p " - DNA . . . , ) 9-1 2-1(. . Causes of apoptosis 2791 " "". , , . , - DNA . , . : . : - , , . " "programmed cell death . . - : , , . - - crypt epithelia, . - -acute .inflammatory response . .GF - . " T- . : : - : - DNA . - DNA . , . -ER . - . - . - . " . . : 52

: ) - ( EM : : , , . : . , . -2 . cytoplasmic blebs- :apoptotic bodies blebing . " : , . " . . . . . H&E . ) 62-1(. " , . , , . Biochemical features of apoptosis )(, .

62

- " . -. , . DNases - DNA. . -DNA -DNA 003-05 .kb 002-081 " - DNA ladder- agarose gel ) electrophoresis 72-1(. . , , smear DNA , DNA . - . " . annexin V , ,thrombospondin , " . " . " . Mechanisms of apoptosis " . . .elegance C " , (ced (cell death abnormal . : - " - . 72

: )" ( ) ( : ) " (- TNF-R death domain - . , death domain . : 1 , TNFR fas 59 .((CD " " :fas cross linking" ) ( 3 fas .)death domain FADD (fas associated death domain FADD " death domain- 8. - 8 82

) 01 ( . " FLIP - 8 . " " fas . . )(- - . GF -,2-bcl-2: bcl ) bcl-x B - c. elegance 9 .(ced -02 . . - : ,bak, bax ,bim . C . apaf-1 (apoptosis 1 activating factor -4 (ced - 9 )2- bcl-bcl-x , (. - , : AIF (apoptosis inducing (factor ) ( . . . - : fas - - bcl bid , .

: " , ) -3- .(ced ) ( -01 : 6+ 3 (initiator (caspase 8 +9) & executioner (caspase . , -, , " , " , . - execution caspases : ) (, ,TF .DNA 3 DNase" . : , . " . . 92

) 13 (CD " . . Examples of apoptosis : , . : - :GF , 1. " , " - -. - :DNA " 2. .genotoxic stress -35 tumor suppressor - P ) , (. 35 P TF : 1- bak, bax, apaf . " TNFR: fas ,fas-L 3. . TNF ) " (. TNF ) ? (: (TRADD (TNF receptor associated death domain FADD. . (TRAF's (TNF receptor associated factors (nuclear factor kappa-B (NF-kappa-B" . . " T: TCL 4. graenzyme B . ) .(execution caspases CTL " fas- fasL . ) ( : 1- - . : )( -35 P : , , . )( - -. 2- - . : )( neurodegradative diseases , : . )( - . )( . 23.(Subcellular responses to injury (p . , . : -Lysosomal catabolism : ,acid phosphatases .glucoronidases, sulfatases, ribonucleases ,collagenases - ,RER 03

', . ) / ( : 1. -hetrophagy " ) , - ( . . ) ( . 2. -Autophagy . autophagyic vacuole " .RER ' . , , . , . - residual bodies . . . . . . oquine chlor . -pH " rheumatoid .is arthrit - .myopathy toxic

13

(Induction (hyperthrophy) of smoth endoplasmic reticulum (SER SER . SER " " -054 .P : , , ,anoids, , eicos , . - . ) ( . " . " .SER Mitochondrial alterations . , : )( . ) (egamitochondria-alchoholic m isease of the liver d . , )mitochondrial (yopathies m

23

, .crystalloids , )( . -Cytoskeletal abnormalities . ): ( 20-25nm ): 8-6 (nm ): 51 (nm ) 01 (nm . , . : - , . " : ) cytocalasin B ( " ) phalloidin -amanita phalloides ( . - )( ) (bronchiectasis )=immotile cilia .(syndrome colchicine ) ( gout .urate ) (vinca alkaloids . - . : )(, )(, )(, ) ( )(. . : Mallory (body (alcoholic hyalin alcoholic liver disease . ' . Neurofibrillary tungle . : ,myopathies . : , . -signal .transduction Wiskott Aldrich ) ( , , , .

43.(Intracellular accumulations (p . -3 : )1( ), , ( . )2( - ) ( ) (. 33

)3( - . . ) ( . ) ( . -3 : 1. . : tty change of the liver fa , . 2. , , , . . - pha1-antitrypsin al - ER . 3. . . . . , , . s : , . myelin figures . 43 Lipid

-

. . :(Steatosis (fatty change . , , . : , , , , ) (anoxia . . , , . " . . : . 4 CCl . . . fatty change . . ) 4 .(CCl . hepatitis-fatty liver disease steato )( .

: fatty change . . ) ( . H&E ) ( 4 Sudan 53

Oil red O - . - (periodic acid Schiff (PAS . . : fatty change , 6-3 " , . )( - .ER , , . . : - :gross ) ( )( ) ( .triggered effect ) - (- . :Cholesterol and cholesterol esters ) 5( . : .atherosclerosis 1. ) ( . ) .(foam cells ) .(atheromas 11. . .xanthomas ) 2. ( , , xantomas - . -inflammation and necrosis 3. . ) , , (. myelin figures. . .cholesterosis 4. -lamina propria . . ) 73-1). Niemann-Pick disease, type 5. .C . -ins Prote

, , . - EM , . , amyloidosis . :

63

1. - proximal tubule ) .(proteinuria , - .proximal tubule ) (. ) 83-1). , - proteinuria . 2. ) (. -ER , , .Russell bodies 3. . " alpha helix ,beta sheet ) ( . . ' , - ,ER' ) 93-1). ' , " , ) heat shock proteins 09/07 (hsp " . ' ) (hsp " . . . : - alpha1-antitrypsin deficiency - ER . - CF ' . - familial hypercholesterolemia - LDL . - ER " . - ER .unfolded protein response " - ER . " ' . " 21 - ER . , -. , : , , , 2. - unfolded protein response . . . . . 73

amyloidosis . : proteinopaphies .protein-aggregation disease Hyali ne chan :ge

hyaline , .H&E . " . ) - , Russell bodies , Mallory alcoholic hyaline). Hyaline , . - hyalinized . :Glycogen . . . , - Best carmine ,(periodic acid Schiff (PAS . -) diastase ( . Diabetes mellitus . proximal convoluted tubules Henle's loop , . " " .glicogenoses . :Pigments , )( . ) ( ) (. : . 83

. ) (anthracosis . .coal worker's pneumoconiosis . " . . : - ) : lipochrome, wear and tear pigment, ageing .(pigment . . . . =Focus, . ) 04-1(. cachexia . - EM . .

): =melas( - . " -) dihydroxyphenylalanine 52(. -, homogentisic acid -alkaptonuria . , .ochronosis ) (hemosiderin , , . 31. " , . , , . , ) 14-1(. . , ) (. , . " ) (, , , . " ) ( " . . " ) - (, " ) ( . hemosiderosis : )1( . )2( )3( )4( ) (. 93

: , , , . . , , , , . ) , , ( . - Prussian blue " - ferricferrocyanide ) .(1-41B . hemochromatosis , , . - . . . . ) 81(. 14.(Pathologic calcification (p , , . : - dystrophic calcification . metastatic calcification . Dystrophic calcification Dystrophic ication ), ( . , ) , , . . : H&E 04 calcif 24-1(.

. , , . . , ) psammoma bodies ( ) ( . ) ( asbestos . :Pathogenesis - Dystrophic calcification apatite - hydroxyapatite . : (initiation (=nucleation- ,propagation . . initiators Dystrophic calcification 002 nm , matrix vesicles . " : )1( . )2( . )3( . )4( - . )4 (PO , .connective tissue matrix proteins - Dystrophic calcification . .

Metastatic calcification Metastatic calcification . 4 : )( PTH PTH related protein . )( : ) ,multiple myeloma(, ) (, turnover ) Paget( . )( :D, ) sacroidosis ,(D ) ( .D )( . : ) ( -milk-alkali syndrome . Metastatic calcification , , , . .Metastatic calcification , -. . ) (nephrocalcinosis . 24.(Cellular aging (p 7 , , , . 14

. , , . " . - . ) -1 34(. :

: : - oxidative phosphorilation" , , , , .TF . : ER ' . -Advanced glycation end products cross linking , diabetes mellitus , senile .cataracts ) (. :cative senescence Repli . . ) 44-1(. , ) er syndrome Wern ( . )cellular .(cence senes , . 24

) 12 cycline dependent kinase inhibitor genes P( . . ) ( . DNA ) (TTAGGG , . , . - DNA . " " " . - RNA - RNA ) 54-1(. " , . " . , , . , . ) ( . , .

: - C. elegance . /1- IGF. 1- IGF , -.C .elegance -1- IGF . " , . 34

: , " . " " . reactive . oxygen species - oxidative phosphorilation . . . : 1. " . : SOD 2. . , " . , ) (E, glutation peroxidase . , -.DNA - DNA " , . - DNA . , -DNA helicase , DNA, - .DNA . . : ataxia telangiectasia - .DNA - budding yeast-.C elegance - DNA. , . " . DNA . , . , : , , , " , , : . .

2 Inflammation , / . , = : - - ,

44

, , " - " , " . , . = . . , . . =, . , ), ( ) (. , , . , : : ) Rheumatoid arthritis ( ) Atherosclerosis ( Lung Fibrosis , . : . . -2: 1. 2. 54

" " , . , , . / .MI

Figure 2-1 The components of acute and chronic inflammatory responses: circulating cells and proteins, cells of blood vessels, and cells .and proteins of the extracellular matrix

1-2: : circulating 64 -

: : ,, ,nonfibrillar tenascin. Basement Membrane

-

-

. : ) (, , . ) (EDEMA , . - , , . , . - . ,Celsus Rubor, Tumor, Calor, Dolor. Virchow . 74 , :

3971, , ' , 0881 ,s , ' ,

. Edema . . , , , , .

. 3 : 1. . 2. - ) (microvasculature . 3. , . 2-2.

84

Figure 2-2 The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth), (2) extravasation and deposition of plasma fluid and proteins (edema), and (3) leukocyte emigration and .accumulation in the site of injury

: = Exudation , . = Exudate , , , gravity 020.1, . = Transduate ) ( gravity 210.1. . = Edema Transduate .Exudate Pus = exudate ) (, . 94

), , ( . ) ( )': , ,frosebites ), , ( )(hypersensitivity

, .

, . , . . : 1. Vasodilation . , . Vasodilation . . " .NO 2. , .= .Vascular Leakage 3. Stasis , . stasis 51 03 , , .

05

, , Stasis 4. . . Vascular Leakage . exudates , , , . , .Edema = :2-3

Figure 2-3 Blood pressure and plasma colloid osmotic forces in normal and inflamed microcirculation. A, Normal hydrostatic pressure (red 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. Although fluid tends to leave the precapillary arteriole, it is returned in equal amounts via the postcapillary venule, so that the net flow (black arrows) in or out is zero. B, Acute inflammation. Arteriole pressure is increased to 50 mm Hg, the mean capillary pressure is increased because of arteriolar dilation, and the venous pressure increases to approximately 30 mm Hg. At the same time, osmotic pressure is reduced (averaging 20 .mm Hg) because of protein leakage across the venule. The net result is an excess of extravasated fluid

51

= 23 " , = 21 " . = 52 " . . = 0. , 05 " , , 03 " . 02 " . , . "": : , , , , ,P. )51 03 (. .Immediate transient response , 02 06 , . , . -< . 5-2:

Figure 2-5 Vascular leakage induced by chemical mediators. A, This is a fixed and cleared preparation of a rat cremaster muscle examined unstained by transillumination. One hour before sacrifice, bradykinin was injected over this muscle, and colloidal carbon was given intravenously. Plasma, loaded with carbon, escaped, but most of the carbon particles were retained by the basement membrane of the leaking vessels, with the result that these became "labeled" black. Note that not all the vessels leakonly the venules. In B, a higher power, the capillary network is faintly visible in the background. (Courtesy of Dr. Guido Majno, University of Massachusetts Medical (.School, Worcester, MA

25

,IL-1, TNF, IF-Gama " . , 6-4 , , 42 .

: , . . , , . ..Immediate sustained response : , , . . : 2 21 ,

. . " , X UV . . " , . " :

, . , , .

35

Transcytosis:

, ,Vesiculovacuolar organelle . VEGF " . . : ,

= .angiogenesis "" . , VEGF . , ,Subtance P, VEGF .

45

4-2 ":.(Figure 2-4 Diagrammatic representation of five mechanisms of increased vascular permeability in inflammation (see text

, . , , " , , " , . . , , : 1. immediate transient response 03 , " .

55

2. delayed response 8 , " , ' . 3. , . : Cellular Events . , . . :EXTRAVASATION, ,, , : ,margination 1. . :Margination , . , , ) ,(wall shear stress . = .margination : . : . " = .pavamenting Transmigration ) (diapedesis 2.

- basement membrane , . " . 3.

65

Figure 2-6 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 processselectins in rolling; chemokines in activating the neutrophils to increase avidity of integrins (in green); integrins in firm .adhesion; and CD31 (PECAM-1) in transmigration

transmigration " . ) (chemoattractants . , , . 3 ,

. domain N .C-type lectins ) C (. , , - . " .Sialylated Olligosaccharides 43.(mucin-like glycoproteins (GlyCAM-1,PSGL-1,ESL-1,CD (E Selectin (CD62E " .

75

. = Lewis X Lewis A : , , T . T , . " . " .E-selectin (P Selectin (CD62P . .Weibel-palade bodies , P-Selectin . , T. " .E-Selectin (L Selectin (CD62L . " .HEV " . . : 1- GlyCAM HEV1- MadCAM MALT. 43 CD . . : L-Selectin .T E-Selectin : P-Selectin . P : E . P .E 85

2 Immunoglobulin family : 1-.ICAM-1, VCAM

. 03

- -. , , . . ,, . : , , . (Arg-Gly-Asp (RGD. ),,, -, (. 3 . 5 . 1 VLA (Very Late Activation (. 92.CD49a-hCD 8 1 8. 1 . 4-) VLA 4(: " 1- .VCAM . 2 81.CD11a-cCD 2 3 81 LFA1 CD11aCD , ,APC .

1 "

95

( CD11cCD18 (CR4 ( CD11bCD18 (Mac-1,CR3 CD11bCD18 . . iC3b , . .CD44 heparin sulfate Mucin-like glycoproteins

. .2-1

TABLE 2-1 -- Endothelial/Leukocyte Adhesion Molecules Endothelial Molecule Leukocyte Receptor P-selectin Sialyl-Lewis X PSGL-1 E-selectin Sialyl-Lewis X Rolling, adhesion to activated endothelium (neutrophils, (monocytes, T cells ICAM-1 (CD11/CD18 (integrins (LFA-1, Mac-1) VCAM-1 41 (VLA4) ((integrins (47 (LPAM-1 GlyCam-1 (CD31 (PECAM L-selection CD31 Lymphocyte homing to high endothelial venules Leukocyte migration through endothelium (Adhesion (eosinophils, monocytes, lymphocytes (Adhesion, arrest, transmigration (all leukocytes Major Role (Rolling (neutrophils, monocytes, lymphocytes

ICAM-1, VCAM-1, and CD31 belong to the immunoglobulin family of proteins; PSGL-1, P-selectin* .glycoprotein ligand 1

60

Figure 2-7 Regulation of endothelial and leukocyte adhesion molecules. A, Redistribution of P-selectin. B, Cytokine activation of endothelium. C, Increased binding avidity of integrins

: 7-2. .A , PAF P-Selectin ) (weibel palade bodies . .B , , " IL-1 TNF. TNF 1- IL : 2-1 .E-Selectin , , , , . " . TNF 1- IL : 1- VCAM -VLA 4, 1- ICAM 1- LFA 1- .Mac .

16

.C, , heparin sulfate glycosaminoglycans . . , , . , , . , .

:Diapedesis/Transmigration , /. ) (, . ) ( . 1- PECAM 13.CD , ,basement membrane , " . . , " 1 44 CD . . :: 1 (LAD1 (Leuukocyte adhesion deficiency type 2 LAD ,.LEWIS X -E Selectin ) Fucosyl transferase (. . 2, 1- LFA 1-.Mac

: : 42-6 : . 26

84-42 : . : , , 42 84 . 1. 2. ) P .(E

Figure 2-8 Schematic and histologic sequence of events following acute injury. The photomicrographs are representative of the early (neutrophilic) (left) and later (mononuclear) cellular infiltrates (right) of infarcted myocardium. The kinetics of edema and cellular infiltration are approximations. For sake of simplicity, edema is shown as an acute transient response, although secondary waves of .delayed edema and neutrophil infiltration can also occur

: , - Pseudomonas , . ,hypersensitivity . , = . , . endogenous exogenous . 36 2 4 .

. -N .formyl-methionine . : . , .C5a . , 4.B . , , 8-.IL ) G-protein 7 ( . PLC, ,PI3K ) 3(. PLC PI3K ) (IP GTPases 24 Rac/Rho/cdc . GTPases . " .

.Figure 2-9 Scanning electron micrograph of a moving leukocyte in culture showing a filopodium (upper left) and a trailing tail

. , cross-linking . , ,gelsolin, .

46

, , , , = . " , PKC 2.A " : " 2A - .Oxidative Burst . .

, . , , , . : (Toll-Like Receptors (TLR ,TOLL . 01, . TLR LPS, CpG , RNA " . microbicidal substances . GPCR . 7 - . , . : ,N-formyl-methionine , ,C5a : ,PAF .E, LTB

56

, ,N-Formyl-Methionine . , G-Protein .GDP ,G-Protein GDP ,GTP , PLC ,IP .PKC microbicidial substances .respiratory burst .

, " NK ,INNATE" T .ADAPTIVE .

. , , . : 1. IgG . " RI Fc . 2. 3 C , ) ( ) (. . 1 CR 3.C 66

3. ,Mannose Binding Lectin (MBL), fibrinectin fibrinogen, C-Reactive protein " . C1q .MBL .fibrinogen

Figure 2-10 Leukocyte activation. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors .(initiate responses that mediate the functions of the leukocytes. Only some receptors are depicted (see text for details

" . -3 : 1. " ) ( , " 2 : Mannose Receptors , . , -N-acetyl .galactosamine . Scavenger Receptors LDL .LDL .LDL 76

* 81 (Mac-1 (Cd11b/Cd . " , .MBL 2. - Engulfment . ,engulfment ) (pseudopods " . , . -. , . , . Receptor-mediated-endocytosis . 3. . . , , " hexose-monophosphate shunt ) ROIs (. ROI " ,NADPH Oxidase NADPH - 2.-O NADPH Oxidase 7 . , . , , ) 11-2 .)B ROI , . NO . 2 H2O" . " , , HOCL MPO. MPO . 86

, halogenation ) . ( . H2O2-MPO-Halide MPO ) (. , .OH " Catalse/ .Glutathione Oxidase ) 1!(.

, " . ,Bactericidal Permeability Increasing protein = BPI , . muramic-acid-N-acetyl-glucoamine , . ,Major Basic Protein ,Defensins , ,Arg , , , . .

. ) (.

, pH 5-4 , .

96

Figure 2-11 A, Phagocytosis of a particle (e.g., bacterium) involves attachment and binding of Fc and C3b to receptors on the leukocyte membrane, engulfment, and fusion of lysosomes with phagocytic vacuoles, followed by destruction of ingested particles within the phagolysosomes. Note that during phagocytosis, granule contents may be released into extracellular tissues. B, Production of .microbicidal reactive oxygen intermediates within phagocytic vesicles

, microbicial : ROI . -

! . : 07

TABLE 2-2 -- Clinical Examples of Leukocyte-Induced Injury Acute Acute respiratory distress syndrome Acute transplant rejection Asthma Glomerulonephritis Reperfusion injury Septic shock Vasculitis Chronic Arthritis Asthma Atherosclerosis Chronic lung disease Chronic rejection

. " : = Regurgitation During Feeding . = Frustrated Phagocytosis , , , . = Cytotoxic Release , Urate Crystals . )( . , " . , , : : 1 LAD . 17

, .

2LAD

: Chediak-Higashi Syndrome , ) (, , . " .Blood Smears T. microbicidal: Chronic Granulomatous Disease

.

. .NADPH Oxidase X-Linked ).(gp91phox 2 ) p47phox .(p67phox : , . , .

TABLE 2-3 -- Defects in Leukocyte Functions Disease Genetic 1 Leukocyte adhesion deficiency 2 Leukocyte adhesion deficiency chain of CD11/CD18 integrins Fucosyl transferase required for synthesis of (sialylated oligosaccharide (receptor for selectin Chronic granulomatous disease Decreased oxidative burst Defect

27

TABLE 2-3 -- Defects in Leukocyte Functions Disease X-linked Autosomal recessive Myeloperoxidase deficiency Chdiak-Higashi syndrome Acquired ,Thermal injury, diabetes, malignancy, sepsis immunodeficiencies Hemodialysis, diabetes mellitus ,Leukemia, anemia, sepsis, diabetes, neonates malnutrition Adhesion Phagocytosis and microbicidal activity Chemotaxis Defect (NADPH oxidase (membrane component (NADPH oxidase (cytoplasmic components Absent MPO-H2 O2 system Protein involved in organelle membrane docking and fusion

: , ' , , . , , ) 1- TNF, IL( . . . , , . , , . : -, - . TGF-Beta " . )" ( TNF. " ) , (. 37

: 1. ) , (kinins " . ) ( - ), ( . : , , /, . ), , ( . 2. " , ,Kinins . 3. . ) ( ) ROI .(NO 4. " . . . 5. , . 6. , -. ) ( " ) kininase (bradykinin "" ) "" ( ) (. 7. .

47

.Figure 2-12 Chemical mediators of inflammation. EC, endothelial cells

Vasoactive amines . . . . : , , . ) 6(. Anaphylatoxins C3a .C5a . ).(Subtance P 8-.IL-1,IL 1. 2. 3. 4. 5. 6.

. ! Immediate transient phase . " 1.H 57

Figure 2-13 A flat spread of omentum showing mast cells around blood vessels and in the interstitial tissue. Stained with metachromatic .stain to identify the mast cell granules (dark blue or purple). The red structures are fat globules stained with fat stain. (Courtesy of Dr. G (.Majno, University of Massachusetts Medical School, Worcester, MA

. )5-(hydroxytryptamine . , ,enterochromaffin . ,, ,ADP -. " PAF .IgE , . PAF .

. 02 . INNATE ADAPTIVE . , , . 9 .C1-C . 3 C 3 : 67

1 C ) IgM (IgG , 2 C 4 C C4b2b .C3 Convertase " )' , ,(LPS , . 3C " C3b .B Bb C3bBb .C3 Convertase ) ( 1 .C . 3 C3 Convertase 3 C : C3a C3b /. : C3b ) (C3 Convertase C5 Convertase 5 C C5a, C5b 9 .C6-C 9 C ,MAC .

" ,MAC :

77

Vacular Phenomena: C3a C5a C4a . ) Anaphylatoxins anaphylaxis). C5a . : C5a , , . : C3b )iC3b (,

1.

2.

3.

, . 3 C 5 C " Exudate. . : , ...

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 2-2 . membrane attack complex (MAC). The steps in the activation and regulation of complement are described in Box

87

" , , . : C3 Convertase :C5 Convertase DAF C3b .I " : , " (C1 Inhibitor (C1INH 1.C MAC 95 CD Membrane Inhibitor of .Reactive lysis : 3 C . 2 C 4 C , Systemic Lupus MAC

. ,Erythematosus -. , .Neisseria , : Paroxysmal Nocturnal Hemoglobinuria - . IP, DAF 95 CD . . 97

C1INH Hereditary Angioneurotic Edema

, " . , 1 C 4 C 2 .C C2 = C2 Kinin . , C1NH ,kallikrein 21 .

3.

Vasoactive ,Kininogens " .Kallikreins ,Bradykinin , . . : ) Hageman 21 ( " 21 ).(prekallikrein activator / factor 12a prekallikrein 1. 2. 3.

.basement membrane

.kallikrein . ) Hageman 1( . . . 5 C .C5a kallikrein kininogen 4.

/ 21 ) 1( - .bradykinin bradykinin " .kininase " .(angiotensin converting enzyme (ACE 08

" Hageman ) 21( basement membrane ) (. 21 .12a . 2 : , , 1.

. ) (2a ) 2( " 4. . ) (Protease Activated Receptors (PAR , (. GPCR , , . , , 1- PAR : P Selectin . 2 PAF NO .

/ fibrolytic system 12a " , . Vascular Phenomena : Plasminogen Activator " , , , . Fibrin Split Products . 3 C 3.C 18

Hageman . , : , C3a, C5a C5a . . C3a C5a : 1. 2. . 3. Plasmin, Kallikrein . Hageman Factor = 12a, 4 : 1. Kinin .vasoactive kinins , kallikrein" Hageman factor . 2. , , X . 3. Fibrinolytic system . 4. . " . , " .

) (.

Extracellular matrix and cell- matrix interactions , ) (induced signaling . , . . - ECM , . 28

) 41-3(. . . . , , . ECM , . , , : 1. . 2. . 3. . ) (intercellular junctions : interstitial matrix- basement . membrane - interstitial matrix , , . , , , , ) (hyaluronate . - BM . ) 4(, , ) (heparan sulfate .

Figure 3-14 Major components of the extracellular matrix (ECM), including collagens, proteoglycans, and .adhesive glycoproteins. Both epithelial and mesenchymal cells (e.g., fibroblasts) interact with ECM via integrins

38

.To simplify the diagram, many ECM components (e.g., elastin, fibrillin, hyaluronan, syndecan) are not included

, . , . - , .gly-x-y 72 14 41 ) 2-3(. 5,3,2,1 - 11 . 4 - BM . meshworks , . -, -- . , - ) 3-51(. - . . ) (cross linking , " . . C -, ) ) (scurvy 9(. ) 3-2( ehlers-danlos syndrom- osteogenesis ) imperfecta 5 -62(.

48

.(Figure 3-15 Steps in collagen synthesis (see text

, , , . , recoil . . , , . , , . - 053 . scaffold . marfan syndrom - ) (aortic dissection.

Cell adhesion proteins

58

, ,CAMs-cell adhesion molecules - 4 : , , . , , . , CAMs ) ( ) (. , - CAMs . . , ) 1-2 box 2(. , , . . - mRNA

TABLE 3-2 -- Main Types of Collagens, Tissue Distribution, and Genetic Disorders Collagen Type I Tissue Distribution Ubiquitous in hard and soft tissues Ehlers-Danlos syndromearthrochalasias type II III V IX IV ,Cartilage, intervertebral disk vitreous Hollow organs, soft tissues Soft tissues, blood vessels Cartilage, vitreous Basement membranes Achondrogenesis type II, spondyloepiphyseal dysplasia syndrome Vascular Ehlers-Danlos syndrome Classical Ehlers-Danlos syndrome Stickler syndrome Alport syndrome Genetic Disorders Osteogenesis Imperfecta Fibrillar Collagens

Basement Membrane Collagens Other Collagens 68

TABLE 3-2 -- Main Types of Collagens, Tissue Distribution, and Genetic Disorders Collagen Type VI VII IX XVII XV and XVIII WA . . - .ECM - BM - ECM . - BM 4 . . ) (. , , , signal transduction . .focal adhesion focal adhesion complexe , . - - MAP, PKC- 3- .IP , )cross (talk , , ) 3-61(. - 1-2 box 2. cadherin . calciumdependent adherence protein 09 , 78 Tissue Distribution Ubiquitous in microfibrils Anchoring fibrils at dermalepidermal junctions Cartilage, intervertebral disks Transmembrane collagen in epidermal cells ,Endostatin-forming collagens endothelial cells Multiple epiphyseal dysplasias Benign atrophic generalized epidermolysis bullosa (Knobloch syndrome (type XVIII collagen Genetic Disorders Bethlem myopathy Dystrophic epidermolysis bullosa

,Courtesy of Dr. Peter H. Byers, Department of Pathology, University of Washington, Seattle

)(. - : 1. -zonula adherence . 2. -desmosoms . . - -, . , , - contact .inhibition , nuclear transcription factor- Wnt signaling pathway 7. - , ) 7(. -4 , : 1. SPARC-secreted protein acidic and rich in cestein - . . 2. -thrombospondins , , - SPARC . 3. 44-.CD 4. :tenacin .

88

Figure 3-16 Mechanisms by which ECM (e.g., fibronectin and laminin) and growth factors can influence cell growth, motility, differentiation, and protein synthesis. Integrins bind ECM components and interact with the cytoskeleton at focal adhesion complexes (protein aggregates that include vinculin, -actin, and talin). This can initiate the production of intracellular messengers or can directly mediate nuclear signals. Cell-surface receptors for growth factors may activate signal transduction pathways that overlap with those activated by integrins. Collectively, these are integrated by the cell to yield various responses, including changes in cell growth, .locomotion, and differentiation

( HA, hyaluronan, hyaluronate) . ECM - (. GAGs) ECM . . 89

, GAGs . ) ( . , heparan sulfate , - .dermatan sulfate . , . HA - GAG - ECM . . , ' )compression .(forces HA . HA , . 44 CD , .HA T . , , , . , ) (healing - "" . : , . - .granulation tissue ECM Tissue remodeling Wound contraction Acquisition of wound strength .

" . :

09

) ( ,

. . , . , . . ,(stimulus ECM . , . , " . , , . , , . . , ) (deposition of connecting tissue . . 42 ) ( , - granulation . tissue , , : )( ) 71-3(. . )(edematous , . 19 , )damaging

, vasculogenesis . -, ) 81-3(. EPC's- endothelial progenitor cells ) 81-3(. , . , - -.

Figure 3-17 A, Granulation tissue showing numerous blood vessels, edema, and a loose ECM containing occasional inflammatory cells. This is a trichrome stain that stains collagen blue; minimal mature collagen can be seen at this point. B, Trichrome stain of mature scar, showing dense collagen, with only scattered .vascular channels

29

Figure 3-18 Angiogenesis by mobilization of endothelial precursor cells (EPCs) from the bone marrow and from pre-existing vessels (capillary growth). EPCs are mobilized from the bone marrow and may migrate to a site of injury or tumor growth (upper panel). The homing mechanisms have not yet been defined. At these sites, EPCs differentiate and form a mature network by linking with existing vessels. In angiogenesis from pre-existing vessels, endothelial cells from these vessels become motile and proliferate to form capillary sprouts (lower panel). Regardless of the initiating mechanism, vessel maturation (stabilization) involves the recruitment of pericytes and smooth muscle cells to form the periendothelial layer. (Modified from Conway (.EM, Collen D, Carmeliet P: Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507, 2001

. , , . , , , . ) -(. EPC's ) 81-3(. . , EPCs Tie2 - E , 93

. EPC's - - , . , - EPC's -. , - ECM . : - NO .VEGF - BM )

( - . . , - - )

. ( . , - ) VEGF 3-3( - ) (angiopoietins . , VEGF , 2-,VEGFR , . 81-3. , ,VEGF 2- ,VEGFR . , . , VEGF .

49

, -FGF 2. , " ."stabilization .ECM 1 - 2 ) ,Ang1,Ang2), PDGF- TGF . 1 Ang 2 Tie -. PDGF , - TGF - .ECM 2 Ang1/Tie , ) 2 endothelial quiescence). Ang 2 Tie , ,VEGF, ,VEGF . - 2 Tie . ),VEGF: TGF -) PDGF )) (hypoxia 3-3(. , VEGF ) (, , - .diabetic retinopathy

ECM , . : , 3 v . ) (matricellular 1, ,SPARC (C (tenascin C - . , 3. , " . 59 1. 2.

, , . FGF-2 - VEGF v3 . )(. : (, MMP-2 ) , ECM-, VEGFR-2 .

(TABLE 3-3 -- Vascular Endothelial Growth Factor (VEGF Proteins Family members: VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D Dimeric glycoprotein with multiple isoforms Targeted mutations in VEGF result in defective vasculogenesis and angiogenesis Production Inducing Agents TGF- PDGF TGF- Receptors VEGFR-1 (VEGFR-2 (restricted to endothelial cells (VEGFR-3 (lymphatic endothelial cells Targeted mutations in the receptors result in lack of vasculogenesis Functions Promotes angiogenesis Increases vascular permeability Stimulates endothelial cell migration Stimulates endothelial cell proliferation VEGF-C selectively induces hyperplasia of lymphatic vasculature Up-regulates endothelial expression of plasminogen activator, plasminogen activator inhibitor-1, tissue factor, and interstitial collagenase Expressed at low levels in a variety of adult tissues and at higher levels in a few sites, such as podocytes in the glomerulus and cardiac myocytes Hypoxia

96

- ECM . : )1( . )2( ECM (deposition of 3(.) (ECM .

) (granulation tissue , , VEGF . - ECM . ,PDGF, EGF,FGF , TGF 1- IL- ) TNF 5-3(. , ) ( . , . )(elaborate PDGF , TGF - ,FGF . , , . . TGF . TGF , , ECM ) (. TGF ,in vivo . TGF .

ECM deposition and scar formation

79

, . . ECM . 5-3 , . - ) ECM 4-3(. , ), ) TGF ,PDGF,FGF 1- IL- 3- IL . . , , ECM. - .

Tissue remodeling - .ECM , -ECM . - ECM - remodeling . ECM , MMPs-matrix metalloproteinases )(ZINC ) 3-91(

89

Figure 3-19 Matrix metalloproteinase regulation. Four mechanisms are shown: (1) regulation of synthesis by growth factors or cytokines, (2) inhibition of synthesis by corticosteroids or TGF-, (3) regulation of the activation of the secreted but inactive precursors, and (4) blockage of the enzymes by specific tissue inhibitors of metalloproteinase (TIMPs). (Modified from Matrisian LM: Metalloproteinases and their inhibitors in matrix (.remodeling. Trends Genet 6:122, 1990, with permission from Elsevier Science

zinc protease , - 02 " , ,'-, MMPs 081 . - ECM ) MMPs. MMPs - (MMP 2,9) ( 2,1 - 3. 'MMP1,2,3 (MMP 3,10,11) . , , ECM - -. 99

Membrane bound MMPs . MMPs - . ), , , (. ) ,(FGF,PDGF ) ,(IL-1,TNF -TGF . , ., . -, . , - TIMPs- tissue inhibitors of , metalloproteinases , ) 91 -3(. . . - MMPs ADAM-disintegrin and metalloproteinase-domain family) . ADAMs TNF- -TGF. 71- ) ADAM - TACE-TNF (converting enzyme . -71- ADAM . ADAM ) 51( - thrombotic ) microangiopethies 31(.

. , . Epidermal appenages , - meshwork . , . , , 001

. , -TGF - 1. TGF " : )1( ) (. )2( -. )3( - ECM ) 3-02(. . , . , - . 3-1. 3-4 . - primary intention - .secindary intention , . 3-4: :,TGF PDFG,FGF 1-PDGF,FGF,EGF, TGF ,TNF,IL

PDGF,EGF,FGF,TNF VEGF,Ang,FGF PDGF, TGF , inhibitirs TGF PDGF,FGF,EGF,TNF

(Healing by first intention ( wounds with opposed edges ) 3-12(. - .healing by first intention - . BM . . :

101

42 , ,

. 42-84 ) (spurs ) ( , BM . . , . . , . . , , - . . . , . , , . , . , , . . . 3-12 ...

201

Figure 3-21 Steps in wound healing by first intention (left) and second intention (right). Note large amounts of .granulation tissue and wound contraction in healing by second intention

(Healing by second intention (wounds with separated edges , , . . .second intention first intention :

301

,

. . .

wound contraction . 6 %5-%01 , . . - - . . .

Wound strength , ? , " , %01 , 4 . %08-%07 , . , ) - (cross linking .

401

Figure 3-22 Healing of skin ulcers. A, Pressure ulcer of the skin, commonly found in diabetic patients. The histology slides show B, a skin ulcer with a large gap between the edges of the lesion; C, a thin layer of epidermal reepithelialization and extensive granulation tissue formation in the dermis; and D, continuing reepithelialization of the epidermis and wound contraction. (Courtesy of Z. Argenyi, M.D., University of (.Washington

, . ) 3-5(. : . . ,Diabatae mellitus, C . - microangiopathy ) 42(.

501

. ,

) - (varicose veins , . , , - . . : , , , , , . . . . , , . , ) (.

Summary of cutaneous wound healing 3-22. , , . , . . first intention ,second intention . , - .ECM . , - ECM .

601

TABLE 3-5 -- Factors That Retard Wound Healing Local Factors Blood supply Denervation Local infection Foreign body Hematoma Systemic Factors Age Anemia (antibiotic therapy Temperature Trauma, hypovolemia, and hypoxia Genetic disorders (osteogenesis imperfecta, (Ehlers-Danlos syndromes, Marfan syndrome Uremia (Vitamin deficiency (vitamin C Hormones Diabetes Malignant disease .Adapted from Schwartz SI: Principles of Surgery. New York, McGraw Hill, 1999 (Trace metal deficiency (zinc, copper Malnutrition Obesity Mechanical stress Necrotic tissue (Protection (dressings Surgical techniques Type of tissue

Drugs (steroids, cytotoxic medications, intensive Systemic infection

. : )1( . . contractures )2( . )3( wound : , ulceration. Dehiscence - dehiscence . . 107

) (ulcerate . , ) 11(. . ) 42 - 72(. . . . keloid ) 3-32(. keloid .african-americans . , -. exuberant granulation . proud flash . , , . desmoids aggressive ,fibromatoses . ) 7(. . - contracture . Contractures , . . 3 ,(stromekysin1 (MMP , .

801

Figure 3-23 A, Keloid. Excess collagen deposition in the skin forming a raised scar known as keloid. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, Saunders, W.B. 1996, p. 219.) B, Note the thick connective tissue deposition in the dermis. (Slide courtesy of Z. Argenyi, M.D., University of (.Washington, Seattle, WA

, , - - - ECM ,rheumatoid arthritis . , ) -42 3(. , - , . , , - ) rheumatoid arthritis 62(. B ,C . ) 81(. - ,pneumoconiosis ) 51(. , , . . 901

. , , ) 9(. , ) 91(.

Figure 3-24 Development of fibrosis in chronic inflammation. The persistent stimulus of chronic inflammation activates macrophages and lymphocytes, leading to the production of growth factors and cytokines, which increase the synthesis of collagen. Deposition of collagen is enhanced by decreased .activity of metalloproteinases

Overview of repair responses after injury and inflammation 1, , , , . , ) 3-52(. ; . , . .lobar , ) ( . , . 011

. . , , , . .

,Figure 3-25 Repair responses after injury and inflammation. Repair after acute injury has several outcomes including normal tissue restitution and healing with scar formation. Healing in chronic injury involves scar .(formation and fibrosis (see text

111

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

112

,Robbins 68-86 ) (: Arachidonic acid metabolites: prostaglandins, leukotrienes and lipoxins " , " , - -, . - autocoids , " . ) - (AA. -, 02 , . . , : , , ).(C5a - ) 2 +Ca - - 1( 2( 3( 4( o

(. . - AA : G-proteins " eicosanoids ) (.

. , - ) NSAID 2- (COX . ) lipoxygenases (. o

- cyclooxygenase pathway 1-) COX ( -2-COX

) ( - .AA : 2 - PGE : ,hyperalgesic o , . -. 2 - PGD ,mast -. - PGF2 -. o o

311

- (PGI2 (prostacyclin prostacyclin synthetase 2 ,PGI 2 PGF1 . PGI -

o

, . o

- (TxA2 (thromboxane thromboxane ,synthetase 2 - TxA: -. - 2TxB .

. , 2- COX "", -1-COX , ) , (. - lipoxygenase pathway -3

. : 5- - (lipoxygenase (5-LO 5- - HETE . . " - 1) CysLT- 1( -2 .CysLT . 4 - LTB 4 LTC4, LTD-4) LTE ( - - , -, (. - lipoxins - AA - ) , , (: , o o o . , - )

. . 4) LXA4, LXB 4 A-4 - (B " 21- lipoxygenase 4 LTA . : ) ( . , . 411

- resolvins - .AA:

" . , , -resolvin.

511

:

TABLE 2-4 - Inflammatory Actions of Eicosanoids Action Vasoconstriction Vasodilation Increased vascular permeability Chemotaxis, leukocyte adhesion Metabolite Thromboxane A2 , leukotrienes C4 , D4 , E4 PGI2 , PGE1 , PGE2 , PGD2 Leukotrienes C4 , D4 , E4 Leukotriene B4 , HETE, lipoxins

:eicosanoid pathways- - 116

- . )(acetylating o o . - COX-2 inhibitors , --COX 2 . - 1-COX .inhibitors - ) ,(NSAIDs .indomethacin o

- 5- LO - ,NSAIDs . . )1 CysLT-2.(CysLT - Broad-spectrum inhibitors :glucocorticoids , down-regulation o -2- ,COX 2 ,A - )(IL-1, TNF -.(iNOS (NO synthase up-regulation - 1 ,lipocortin o - AA " . - . o o

" " . (platelet-activating factor (PAF PAF -. , " IgE . . : - . . ,A. B -. PAF .G-protein " ' inactivating PAF .acetylhydrolases - PAF : , )- ,(mast, / . - : . -. -. : -, ) -001 711

0001 (.

)" . -. .oxidative burst eicosanoids" .

(.

: PAF ) (. cytokines and chemokines " , " , . . . . TNF-1- :IL . " . lymphotoxin " T ): TNF TNF- TNF 1- lymphotoxin). IL " . " -, , , . : ) endothelial (activation , , , GF, eicosanoids- ,NO , , priming . . . ) acute-phase reactions 6- (IL ,

, , ,slow-wave , corticotropin ) septic shock :)TNF ,hypotension , - pH . TNF " . TNF - ,cachexia - anorexia .

811

chemokines )01-8 -( . 04 -02 . -cys : ) CXC : - ( chemokines ) (, : 8- ,IL " , -1- IL-.TNF ) CC : - ( chemokines - cys . (protein 1-RANTES (regulated and normal T cell expressed and monocyte chemoattractant protein (MCP-1), eotaxin, macrophase inflammatory (MIP-1 .(secreted , , , . , eotaxin . ) C : - ( chemokines - cys , - CX3C ,fractalkine : : .lymphotactin . - " 911

;T - , " . : .G-protein , . 4- CXCR-5- CCR - co-receptors- -1- ,HIV . : . . " -.ECM

NO ), , -(. , - " ) : .(endothelial-derived relaxing factor . - ) , ( " ,GMP - , .

021

NO - L-arginine" .(NOS (nitric oxide synthase 3 : ) eNOS(, ) nNOS( - , , .NO - (iNOS (inducible "

) (TNF, IFN-. NO : NO - , , mast . - NO -" "rolling -.postcapillary venules NO . NO - ,atherosclerosis - .hypertension NO , . : - NO -. NO NO . iNOS ) 1( 2( 3( 4(

-.

(. , NO , . lysosomal constituents of leukocytes . . : ) - (secondary , , , ) - (primary , , (, ), ', , -, -.

), ,G , 3(.

121

-. ) ( -, . : - -, - - : , - pH. ,basement membrane, , . 3 C-5 C , anaphylatoxins - . - . , , , - o o

- . , , . " antiprotease , : - 1-antitrypsin . 2-macroglobulin ) - 1-antitrypsin .(deficiency

oxygen-derived free radicals - , . .NADPH 221

- ) ,(SO )2 (H2O ) (OH . NO . - ) 8- ,(IL " . . , . - . : - . . ,xanthine oxidation -. - antiprotease .a1-antitrypsin ), (. : - ceruloplasmin . - transferring . - superoxide dismutase . - catalase - -. - glutathione peroxidase - -. -.ECM - o o :

" . neuropeptides -,eicosanoids -vasoactive amines , . substance P-neurokinin A - ,tachykinin neuropeptides - CNS-.PNS substance P ' . substance P , , " . -, . 321

other mediators , , , . : - , 1( . " ,hypoxia-induced factor 1 ,VEGF . - 2( . : - uric acid ", -. . ) - (gout ) (. summary of chemical mediators of acute inflammation ) (. , . , .in vivo -, , , , anaphylatoxins C5a, )4(LTB -, , . 1- IL- TNF - . NO - . : -.NO (C3a- ,(C5a, C, D- E, PAF-.substance P .

.acute phase reactants

421

TABLE 2-5 - Summary of Mediators of Acute Inflammation Action Mediator Histamine and serotonin Bradykinin C3a C5a Prostaglandins Source Mast cells, platelets Plasma substrate Plasma protein via liver Macrophages Mast cells, from membrane phospholipids Leukocytes Vascular Leakage + + + + Potentiate other mediators + + + + Chemotaxis + Pain Opsonic fragment (C3b) Leukocyte adhesion, activation Vasodilation, pain, fever Other

Leukotriene B4

+ + + + +

Leukocyte adhesion, activation Bronchoconstriction, vasoconstriction Endothelial damage, tissue damage Bronchoconstriction, leukocyte priming Acute-phase reactions, endothelial activation Leukocyte activation Vasodilation, cytotoxicity

Leukotriene C4 , Leukocytes, mast D4 , E4 cells Oxygen metabolites PAF IL-1 and TNF Chemokines Nitric oxide Leukocytes Leukocytes, mast cells Macrophages, other Leukocytes, others Macrophages, endothelium

TABLE 2-6 - Role of Mediators in Different Reactions of Inflammation Vasodilation Prostaglandins Nitric oxide Histamine Increased vascular permeability Vasoactive amines C3a and C5a (through liberating amines) Bradykinin Leukotrienes C4 , D4 , E4 PAF Substance P 125

Chemotaxis, leukocyte recruitment and activation

C5a Leukotriene B4 Chemokines IL-1, TNF Bacterial products

Fever Pain Tissue damage

IL-1, TNF Prostaglandins Prostaglandins Bradykinin Neutrophil and macrophage lysosomal enzymes Oxygen metabolites Nitric oxide

outcomes of acute inflammation . , , . , , , . : 3 126

) - (complete resolution

1(

. , , . , , , ) ( , , . lymphatics )(. ) - (healing by connective tissue replacement 2( , . ) (pleura, peritoneum , , .organization . . - o , . : )*( ) ,(pneumonia , . )*( . )(. ) (. o 3(

721

morphologic patterns of acute inflammation , , . serous inflammation , ) .(effusion .

821

fibrinous inflammation , , , -. ) ( ) (exudate . : ,meninges . " " . - . , ) (resolution , . ) (organization strands ) ( .

suppurative or purulent inflammation , , . ) (staphylococci ) pyogenic (. .acute appendicitis

921

, , . pyogenic . : . . o o o

, . " ): (.

ulcers , , . ulceration . : , , -, o o . . . PMN - . , . ,

031

summary of acute inflammation : , , , " . , lipid messangers ) (. . " " . , - . , . " ) (: - " , . - , ).(exudate - junctions . ) ,(rubor )(calor ) (tumor . - ) ( " , . " " , . , ).(dolor

131

chronic inflammation . ) (, . -, " . , rheumatoid arthritis, atherosclerosis, tuberculosis . causes of chronic inflammation : - tubercle ) bacilli, treponema pallidum ( , . .delayed type hypersensitivity granulomatous reaction )(. ) - particulate silica - - - atherosclerosis o o ( - .silicosis " . - - . : rheumatoid arthritis-.lupus erythematosus morphologic features , , , : - , . - " . " -

" )( . mononuclear cell infiltration .

231

)

:

.(reticuloendothelial system , - .tissue macrophages ) (, , ) (sinus histiocytes )alveolar .(macrophages . , tissue macrophage . - tissue macrophage " , , . . 84 . " ) , (. - . ": ) (IFN- T-.NK - . .

, , .

, . - ) / ( . " : - . ) ( . : 331

, ) 1- .(MCP .delayed-hypersensitivity .C5a ) GF PDGF - platelet derived- .(TGF- . -.

o o o o o

- . - "

.atheromatous plaques .

431

: )(. . . ) , ), ,

: ( -) ECM(. (. ).(GF , , . . : " , , - ,fibrinolytic uric acid . T . , , . 531

: ) (A : , ) - (, )(. )(B : , (.

other cells in chronic inflammation - , ( ) o o -. . )1- (TNF, IL . -, : T co-stimulators )21- IL(, .T T ,(IFN- . B ) , . , APC .germinal centers ,lymphoid organogenesis , .rheumatoid arthritis

631

- IgE .

. .eotaxin major ,basic protein - , .

- mast .

- Fc .(IgE (Fc RI - - IgE -mast , / . . , . - - mast . - , ) .(osteomyelitis : 731 o o - .AA

" .T . granulomatous inflammation , , ) .(epithelioid -, ) (. : ),tuberculosis), sarcoidosis, cat-scratch disease, lymphogranuloma inguinale ,leprosy, brucellosis, syphilis mycotic, berylliosis . : - , , (.

, . , , -, , , . - - epithelioid , "" . , , . . epithelioid giant cells ) 05-04 ,( m , 02 ) ( ) .(foreign body-type . : - foreign-body granuloma " -, : , , " . epithelioid-giant

831

) , cells .( - , immune granuloma . . , . T IFN- - T IL-2 , . . giant cells- epithelioid -. tubercle , . : . acid-fast " ) .( ) .( ) o o o .(

.sarcoidosis-

TABLE 2-7 -- Examples of Diseases with Granulomatous Inflammations Disease Cause Tissue Reaction Noncaseating tubercle (granuloma prototype): a focus of epithelioid cells, rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cell; caseating tubercle: central amorphous granular debris, loss of all cellular detail; acid-fast bacilli Acid-fast bacilli in macrophages; non-caseating granulomas Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells are necrotic without loss of cellular outline Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon Tuberculosis Mycobacterium tuberculosis

Leprosy Syphilis

Mycobacterium leprae Treponema pallidum Gram-negative bacillus

Cat-scratch disease

lymphatics in inflammation

139

-. , . ) (lymphatics , . junctions , basement membrane ) (. -. - junctions " -. , . , . , . ) (lymphangitis ) .(lymphadenitis , - . - hyperplasia ) (follicles- hyperplasia . ,reactive .lymphadenitis , - .bacteremia , . , , , ,meninges . ,endocarditis, meningitis -.septic arthritis systemic effects of inflammation acute phase response systemic .(inflammatory response (SIRS " LPS . -:acute phase response - 4 , . - . pyrogen, " : (LPS (exogenous pyrogens 1- IL- ,(TNF (endogenous pyrogens AA. , 2 ,PGE ,cAMP 041

- set-point . ,NSAIDs , " - . . , - heat shock . - acute-phase proteins , , . : ,(CRP (C-reactive protein - .(serum amyloid A protein (SAA " " , 6-) IL ( -1- IL-) TNF (. CRP- SAA . , . acute-phase response, SAA ,apolipoprotein A , . o o

, . ) ,(rouleaux (sedimentation rate .LPS - acute-phase proteins , ) (SAA: - amyloidosis . - CRP - myocardial infarction . atherosclerosis - infarction (CRP , (. , - - .myocardial infarction - , . " - 000,02-000,51 , - 000,001-000,04 )=(. ) leukemoid reactions (. : o o o . ESR (erythrocyte

141

- postmitotic reserve pool ) 1- IL- .(TNF -

o

) (. , .CSF . - neutrophilia . . ) infectious mononucleosis, mumps-German (measles ) .(lymphocytosis ) bronchial asthma, hay fever, parasitic , (infestations .eosinophilia ) ,typhoid fever , ,rickettsiae protozoa, ( ).(leucopenia . , , ).(rigors ) (chills . . . ) (malaise . o o o o o o o o

.

- sepsis ) (sepsis -LPS

, TNF-1- .IL . TNF - ) .(DIC : LPS- TNF (tissue factor (TF" , . - " (tissue factor (TFPI- thrombomodulin . , - gluconeogenesis . 241 o o

, NO " , . -DIC- .setptic chock - . LPS , ) ( . - adult respiratory distress sybdrome o ((ARDS " , . . . o

consequences of defective or excessive inflammation : - / o . - .innate immunity , . - - - o - . : , ,atherosclerosis - . , , , "silent ."killer , . , .ECM 88 . . ) : , , ( 1. regenaration . 2. healing .

341

,Figure 3-1 Tissue response to injury. Repair after injury can occur by regeneration, which restores normal tissue .or by healing, which leads to scar formation and fibrosis

DEFINITIONS -Regeneration . ) ( . . - hepatectomy .unilateral nephrectomy )( . , , stem cells /. Healing : 1. ) ( 2. 3. . . . . . -scarring MI 441

) 21(. , " F . MI ) constrictive pericarditis 21(. . ) Helicobacter Pylori 71(. . . . / ECM . : . . . . %05 , - . hepatic lobules , ECM . ECM . , ECM ), ( . . . , , . . GF , , . , ECM . , .

541

Figure 3-2 Mechanisms regulating cell populations. Cell numbers can be altered by increased or decreased rates .of stem cell input, by cell death due to apoptosis, or by changes in the rates of proliferation or differentiation (Modified from McCarthy NJ et al: Apoptosis in the development of the immune system: growth factors, clonal 2991 ,751:11 (.selection and bcl-2. Cancer Metastasis Rev

2-3 . . : . . ' , . , " - . . . , , . nodular prostatic heperplasia ) DHT(. TSH. ) (. . , . . Tissue proliferating activitiy 2 G1, S , G .M

641

Figure 3-3 Cell-cycle landmarks. The figure shows the cell-cycle phases (G0 , G1 , G2 , S, and M), the location of the G1 restriction point, and the G1 /S and G2 /M cell-cycle checkpoints. Cells from labile tissues such as the epidermis and the gastrointestinal tract may cycle continuously; stable cells such as hepatocytes are quiescent but can enter the cell cycle; permanent cells such as neurons and cardiac myocytes have lost the capacity to 2002 ,(.proliferate. (Modified from Pollard TD and Earnshaw WC: Cell Biology. Philadelphia, Saunders

Continuously dividing-labile tissues . : , , , . . . " . Quiescent-stable tissues . . 0 G 1G . , , , . ) ( hepatectomy - . , ; , , . ) (. Nondividind-permanent tissues . . - CNS, . . , ) ( . - , . ) ( , . .regenerative medicine , . 741

. . ,