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1、CELL INJUREY AND ADAPTATION BY DR.SOHEIR SAAD M.D PATHOLOGY AL-AZHAR UNIVERISITY CELL INJURY AND ADAPTATION The basis of all diseases is injury to the smallest living unit of the body, namely the cell. Cell encounters many stresses as a result of changes in their internal and external environments.
2、However, the normal cell is in steady state able to handle physiologic demand according to its adaptive capacity. Causes of cell injury: 1. Hypoxia (deficiency of oxygen) due to: (i) Ischaemia (ii) decrease of oxygen carrying capacity of blood due to anaemia, cardiac or respiratory failure and CO po
3、isoning. 2. Physical agent: burns, deep cold, radiation, mechanical trauma and electric shock. 3. Biological agents e.g. viruses, bacterial toxins, fungi and parasites. 4. Chemical agents and drugs e.g. alkalis, acids, insecticides, alcohol and narcotic drugs & air pollutants et 5. Endogenous toxins
4、 as in case of uremia, jaundice and diabetic ketosis. 6. Immunologic reactions (hypersensitivity). 7. Nutritional imbalance such as protein calorie malnutrition, starvation, obesity, diabetes mellitus and deficiency of other substances and vitamins. 8. Genetic abnormalities as in Down syndrome & sic
5、kle cell anemia. Pathogenesis of cell injury: Hypoxic and ischemic injury to the cells occur through:- a)- ATP depletion b)- over production of oxygen derived free radicals due to imbalance between free radicals generation and radical defense system. Other mechanisms caused by all forms of cell inju
6、ry include:- a) - Defect in membrane selective permeability b)- Increased intracellular ca+ and loss of ca+ homeostasis that result from damage of both cell membrane & mitochondrial membrane and ER.The increased intracellular Ca+ cause activation of degenerative cellular enzymes as protease,ATpase,
7、phospholipase and endonuclease. (that cause damage & mutation of the nucleus) . - Mechanism Of Bacterial And Viral Injury a) By production of cytotoxic lymphokins & activation of lytic complement substance b) Direct effect of bacterial toxins on the cell membrane & mitochondrial damage, through inco
8、rporation of viral genome to cell DNA and their alteration c) Irreversible mitochondrial damage. CAUSES OF CELL INJURYCAUSES OF CELL INJURY CAUSES OF CELL INJURY Cellular Reaction PatternTo Stress Depends On: 1. Type, duration, and severity of stress. 2. Type, state and adaptability of cell. I-Irrev
9、ersible Cell Injury: Severe stimuli leads to necrosis .& Apoptosis II-Reversible Cell Injury: Mild stress for short duration leads to biochemical change or mild form of morphologic change in the affected cells ( hydropic swelling). III-Persistent prelethal stress leads to cellular adaptation. 1-Adap
10、tation of growth. a) Increased growth and cellular activity e. g.Hypertrophy & Hyperplasia b) Decreased growth and cellular activity e.g. Atrophy. 2-Disturbances of cellular differentiation and morphology e.g. Metaplasia,& Dysplasia. 3-Intra and Extra cellular accumulations e. g. a) Lipids as in fat
11、ty change & Cholesterol deposits. b) Proteins as in Hyaline change& Amyloidosis. c) Pigments as in Pathologic pigmentation. d) Calcium as in Pathologic Calcification e) Enzymatic metabolic deficiency as in Gout& lyzosomal storage disease. IRREVERSIBLE CELL INJURY Necrosis Definition: Necrosis is loc
12、al death of cells while the individual is a life followed by morphological changes in the surrounding living tissue, (cell placed immediately in fixative are dead but not necrotic). Causes of cell necrosis: See before, but the most common causes of cell death are viruses, ischaemia, bacterial toxins
13、, hypersensitivity, and ionizing radiation. Morphologic change in necrosis: The changes dont appear in the affected cells by light microscopy before 2-6 hours according to the type of the affected tissue. NECROSIS Changes in the cytoplasm: i. Swelling and granularity of the cytoplasm due to (a) Imbi
14、bition of water (ATP in the cell) (b) Coagulation of the cytoplasm. ii. Loss of cellular membrane and release of intracellular enzymes in the blood e.g. Serum Transaminase(ST )& LDH where their detection is of diagnostic value in liver and heart diseases. iii. Fusion of cells forming homogeneous eos
15、inophilic mass. Nuclear changes: Occur due to hydrolysis of nucleoproteins: i. Pyknosis i.e. the nucleus becomes shrunken condensed and deeply stained. ii. Karyorrhexis: rupture of nuclear membrane with fragmentation of the nucleus. iii. Karyolysis: the nucleus dissolves and disappears. Finally the
16、affected tissue changes to homogeneous eosinophilic mass with nuclear debris. NUCLEAR CHANGES IN NECROSIS Types of necrosis The variable types of necrosis differ as regards causes, gross and microscopic pictures. (1) Coagulative necrosis: It is mainly caused by sudden ischaemia e.g. infarction of he
17、art, kidney and spleen. The protein of the affected tissue becomes denaturated. Grossly, it appears dry pale opaque. It is triangular ? subcapsular with the base towards the capsule of the affected organ. This is due to the fan like distribution of the supplying blood vessels. The infarct area is su
18、rrounded by narrow zone of inflammation and congestion. Microscopically, the structural outline of the affected tissue is preserved but the cellular details are lost. GROSS AND MICROSCOPIC PICTURE OF NECROSIS (2) Liquifactive necrosis The necrosed tissue undergoes rapid softening e.g. infarction of
19、the nervous tissue which has abundant lysosomal enzymes. Also, this type of necrosis occurs in case of suppurative inflammation (Abscess) where liquefaction occurs under the effect of proteolytic enzymes of PNLs liquefaction of the amoebic abscess occurs due to the effect of strong proteolytic enzym
20、es and hyaluronidase secreted by E. Histolytica. Grossly: the affected tissue appears as homogenous amorphous substance. Microscopically: it appears as homogenous eosinophilic structure. . (3) Caseous necrosis: It is characteristic of tuberculosis. The necrotic tissue undergoes slow partial liquefac
21、tion forming yellow cheesy material. Microscopically, it shows amorphous granular eosinophilic material lacking the cell outlines. Unlike coagulative necrosis, the necrotic cells do not retain their cellular outlines, and do not disappear by lysis, as in liquifactive necrosi Grossly, the caseous mat
22、erial resembles clumpy cheese, hence the name caseous necrosis. The cause of necrosis in TB is hypersensitivity reaction caused by the tuberculoprotein content of the cell wall of Mycobacterium Caseous necrosis in LN. Amorphous ,granular ,eosinophilic ,necrotic center is surrounded by granulomatous
23、inflammation. T.B LUNG : (Large Area Of Caseous Necrosis)AREA ,YELLOW-WHITE AND CHESSY (4) Fat necrosis it is necrosis of adipose tissue including two types: a)Traumatic: caused by trauma to adipose tissue e.g. breast and subcutaneous tissue. b) Enzymatic: which occurs in case of acute haemorrhagic
24、pancreatitis. Obstruction of the pancreatic duct leads to release of lipase which splits the fat cells of the omentum into fatty acid (combine with Ca giving chalky white calcification) and to glycerol which is absorbed in the circulation. (5) Fibrinoid necrosis This is characterized by swelling, fr
25、agmentation, increased eosinophilia of collagen fibers and accumulation of mucopolysaccharides and fibrin due to vascular exudation of fibrinogen at the site of lesion, e.g.: a) Collagen diseases (Rheumatic fever, Rheumatoid, Sclerodermia, Lupus erythematosus and Polyarteritis nodosa). b) In the wal
26、l of blood vessels in malignant hypertension FIBRINOID NECROSIS (6) Zenkers necrosis: vOf the rectus abdominus muscle and diaphragm as a complication of : vbacterial infection particularly typhoid fever. vThe striated muscles lose its striation, swell and fuse together in homogeneous structureless m
27、ass. (7) Gangrenous necrosis: The tissue in this case have undergone ischaemic cell death and coagulative necrosis followed by liquifactive action of putrefactive organisms. When coagulative pattern is dominant the process is termed dry gangrene. When the liquifactive action of the bacteria is more
28、pronounced it is called wet gangrene. Obtraction of blood supply to bowel is alrmost followed by Gangrene Fate and local effects OF NECROSIS : 1. A small area undergoes repair: A) The products of the necrotic cells irritate the surrounding tissue forming a zone of inflammation. B) The accumulated ne
29、utrophils in the zone of inflammation soften the necrotic tissue and make its removal by macrophages and blood stream easy and help the process of healing. C) Repair by regeneration or fibrosis depends upon the type of cells affected (labile-stable- permanent). 2. If the necrotic area is wide, its p
30、roducts cant be removed and a fibrous capsule form around it in order to separate it from the living tissue. Areas of necrotic softening in the brain become surrounded by proliferated neuroglia (gliosis). 3. Old unabsorbed caseous lesions and fat necrosis usually becomes heavily calcified (dystrophi
31、c calcification). 4-when the necrotic tissue is infected with putrefactive Organism-Gangrine General effects of necrosis 1. Release of enzymes from the breakdown tissue into the blood forms the basis of clinical tests for diagnosis e.g. detection of transamenase in myocardial infarction and liver ne
32、crosis in hepatitis. 2. Absorption of dead products into the circulation leads to leukocytosis and fever (Not diagnostic). N.B.: I. Necrosis of: 1) Of small groups of cells is called focal necrosis. 2) Of large groups of cells is called confluent necrosis. 3) Of extensive areas of an organ is called
33、 massive necrosis. II. Somatic death means death of the individual. III. Post-mortum autolysis of the tissue occurring after death can be differentiated from necrosis by the absence of inflammatory zone around the affected tissue (inflammation is reaction of living tissue to an injury). Apoptosis De
34、finition: It is programmed death of cells in living tissues. It is an active process differing from necrosis by the following points: Occurs in both physiological and pathological conditions. Starts by nuclear changes in the form of chromatin condensation and fragmentation followed by cytoplasmic bu
35、dding and then phagocytosis of the extruded apoptotic bodies. Plasma membrane are thought to remain intact during apoptosis until the last stage so does not initiate inflammatory reaction around it. Death by Committing Suicide APOPTOSIS While committing suicide cells: Shrink Chromatin Degraded Mitoc
36、hondria Break Down Break into Membrane- bound Fragments Phosphatidylserine Exposed Phagocytic Receptors Inflammation Inhibition Microscopically: In the tissue stained with H & E apoptosis affects single or small clusters of cells and apoptotic cell appears as round mass of intensely eosinophilic cyt
37、oplasm with dense nuclear chromatin fragments. Major criteria of Apoptosis 1- Morphological changes 2- Chromatin condensation 3- DNA fargmentation 4- Cell death Initiation for apoptosisInitiation for apoptosis Factors predisposes to apoptosisFactors predisposes to apoptosis 1- Nontoxic stimuli can l
38、ead to apoptosis . 2- loss of growth factors. 3- Direct action of cytokines (e.g., tumor necrosis factor) 4- Immune system action (e.g., natural killer cells or cytotoxic T lymphocytes). 5- Viral infection. 6- Adult tissue homeostasis . 7- Sublethal damage to the cells (e.g., by ionizing radiation,
39、hyperthermia, toxins.) 8- Loss of cell-cell or cell-matrix attachments. Examples of physiologic and pathologic cases accompanied with apoptosis: 1. Programmed cell death during embryogenesis. 2. Hormone dependent cell involution in case of endometrial cell break down during menstrual cycle. 3. Cell
40、death in tumours during regression induced by cytotoxic drugs or irradiation. 4. In some viral disease e.g. viral hepatitis in which apoptotic cells are known as councilman bodies. ROLE (VALUE)OF APOPTOSIS 1-Defense: Against nonself multicellular organisms (cell commits suicide when infected by a vi
41、rus may protect other cells from further spread of the virus) 2-Digestion: The cellular DNA destroy the genetic information of any external stimulus. 3-Protecting: Protection of the organism from unregulated growth of individual cells Apoptosis Cells shrink and condense Release small membrane bound
42、bodies Small fragments are engulfed by surrounding cells Necrosis Cells swell and burst, releasing their intracellular contents Damaging to surrounding cells Causes inflammation Apoptosis vs. Necrosis REVERSIBLE CELL INJURY Hydropic swelling Hydropic swelling is an acute stress cell injury caused by
43、 a variety of agents leading to swelling in the cells. Pathogenesis: Hydropic swelling results from impairment of the process controlling ionic sodium concentration in the cytoplasm. This regulation is controlled by: (i) Plasma membrane itself, (ii) Plasma membrane sodium pump, (iii) The supply of A
44、TP. Injurious agents may interfere with one of these factors leading to intracellular accumulation of sodium and increase water to maintain isosmotic condition of the cell. The result is swelling and enlargement of the cell. Structural changes: Grossly, the affected organ increases in size becomes p
45、ale, bloodless, having sharp edge which bulge over the capsule on cut section of that organ. Microscopically, the cell becomes large with pale cytoplasm and normally located nucleus. Examples of hydropic swelling:Ballooning of hepatocytes in cases of acute viral hepatitis, epidermal cells in burns,
46、Mickulicz cell(Histiocytes) in Rhinoscleroma . The hepatocytes adjacent to the portal tract (right) are very swollen and hydropic (severe ballooning degeneration) Viral hepatitis CELLULAR ADAPTATION Cellular adaptation is a state that lies intermediate between the normal unstressed cell and the inju
47、red over stressed cells. The major most important adaptive changes in the cells are: Hyperplasia, Hypertrophy, Atrophy, Metaplasia, Dysplasia and intracellular storage. DIFINITION: Hyperplasia: It is an increase in the size of tissue or organ due to increase in the number of its specialized cells. T
48、his can result from: 1. Increased functional demand: Physiological hyperplasia of the breast in pregnancy and lactation. Hyperplasia of the bone marrow in haemolytic anaemia, Fe, B12 or folic acid deficiency anaemias. Hyperplasia of the lining epithelia in the process of regeneration and repair of a
49、n ulcer or skin wounds. Definition: 2. Increased hormonal stimulation A) Hyperplasia of endocrine glands: * Pituitary gland excess growth hormone: Before puberty gigantism. After puberty acromegaly. * Thyroid gland thyrtoxicosis. * Parathyroid gland hypercalcaemia metastatic calcification osteitis fibrosa cystica. * Adrenal cortex Cushings syndrome. THYROID HYPERFUNCTION Exophthalmos B) Hyperplasia of endocrine-target organs: * Breast mammary cystic hyperplasia (Fibrocystic disease). * E