Cell Degeneration & Necrosis

Function of normal cells: - Environtment - Supply: O2, Glucose, Amino Acid - Removal of met product: CO2

Cellular Injury
Lethal (Necrosis): - Biochem, structure changes Irreversible - Function (-) clinical disease Differ from Death of individual - Complete & Irreversible cessation of brain function - In legally death many cells and tissue remain viable for transplantation Nonlethal (Degeneration): - Biochem, str abn reversible - Injury persists necrosis

Apoptosis responsible for

Programmed destruction of cells during embryogenesis Hormone-dependent involution in adult Cell deletion in proliferating cell population: int crypt epit Cell death in tumors Death of neutrophils during an acute infl response Death of immune cells: - B & T after cytokine depletion - Deletion of autoreac T in thymus Cell death induced by cytotoxic T cells Path atrophy in parenchym organs after duct obstruction Cell injury in certain viral dis: Councilman bodies Cell death produced by a variety of injurious stimuli: - low doses - large doses necrosis

Morphology

Cell shrinkage Chromatin condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or bodies

Apoptosis
Higher grade High level of Apoptosis, High level of proliferation

Chemotherapy Apo within 24 hrs, prol

End of chemotherapy: - Apo & Pro : residual tissue - Antiapoptotic BCl2

Apoptosis
= Programmed cell death

Apoptosis
- Health: - Metamorphosis of tadpole to frog - Loss of autoreactive response of T cell in thymus

- Atrophy & Involution: menstruation

Disease: - Irradiation, Virus, Action CTL rejection - Tumor Apo & Prol control growth

Programmed Cell Death (Apoptosis)

Deg-Cell Death & renewal: balanced Effete cells are removed from normal tissue: Apoptosis Apoptosis
Removal Inflammation Nucleus Cytoplasm Cell Memb Rapid (-) Fragmentation (pyknosis) Condensation Early: intact, shrunken cell Cytopl or nucl debris: Apo bodies (+)

Necrosis

Cell Damage
-

Reduced oxygen supply Physical agents Chemical agents Toxins Virus Abnormal immunological reaction Genetic abnormalities Downs syndrome

Injury: - mild Repair - severe Necrosis Apoptosis

Morphology of Necrosis
A. Early : - normal - 1-3 hrs: EM, - 6-8 hrs: LM

MI, dies within minutes: no structural evidence of nec 2 days: changes are obvious

B. Nucleus: - Pyknosis (deeply basophilic mass) - Karyrrhexis (small basophilic particles) - Karyolysis Rapid: lysis without pyknosis
C. Cytoplasm: - 6 hrs acidophilic - own lysosomes autolysis D. Biockemical: Ca ion influx

Necrosis
= Death of a cell or group of cells severe hypoxia, phy, chem

Death rapid depletion of intracel. energy system.

Initially: morp. Changes (-), hrs memb, organelle: disrupted

Necrosis: - Denaturation & Coagulation of protein - digestion o/t cell by released enzymes

Naked eye: - Coagulative - Colliquative: soft enzymatic digestion

Coagulative
Retains cellular outline for several days Nuc (-), Cyto: coagulated, pink, homogen lack of blood supply : Solid: Heart, Spleen, Kidney Virus, toxic chem liver Burn: skin

Coagulative Necrosis

Colliquative Necrosis
Brain & tissue ischemia large amount of fluid: enzyme (lysosomal) autolysis softening: pigmented & turbid fluid. Abscess enzym of pmnl Gangrene: complication of necrosis. Putrefactive org saccharolytic & proteolytic foul, green, black breakdown of Hb. Heterolysis source of enzyme: other than cell itself

Caseous Necrosis (Caseation) & Gummatous

Tuberculosis cheese like Syphilis Gum, rubber like

Fat Necrosis
Enzymatic Pancreatitis lipase triglycerides glycerol &fatty acid + Ca ions calcium soap chalky white plaques Lipase blood throughout body (cutan fat & bone marrow) Nonenzymatic: - breast & subcutan, abd Trauma ? - Foamy mphage, neut, lcyte - DD. cancer

Fibrinoid Mecrosis Autoimm dis: rheum fever, polyarteritis nodosa, SLE Collagen, smooth muscle of blood vessels Arteriole in malignant hypertension Eosinophilic Hyaline like fibrin Contain : - Ig, compl, albumin, breakdown product of coll & fibrin Gangrene: extensive tiss necrosis 1. Dry gangrene

Extremities isch coag necr arterial obs

Mac: black, dry, shriveld, sharply demarcated The: removal of dead tiss (debridement)

2. Wet gangrene Severe bac inf superimpose on necrosis Extremities, internal organ Mac: swollen, reddish-black, liquefaction not clearly demarcated difficult to treat surgically Bact fermentation foul odor Mortality > 3. Gas gangrene

Clostridium perfringens Fermentative action gas crepitus X-rays

Sequels of Necrosis
- Phagocytosis: small numbers of cells - Organisation: large number infl, organisation, fibrous - Deposition of calcium: Tbc caseous nec dystrophic

Clinical Effect of Necrosis

A. Abnormal function: - Myocard Heart failure arrhytmia - Kidney renal failure (1 -) - Motor cortex: small muscle paralysis - Intestine obstruction - lung hemiptysis B. Bac. Infection: gangrene removal Disseminate lymohatics, blood C. Release of Content of Necritic Cells diagnostic - Creatine kinase myocardial necrosis -Aspartate amino-transferase (GOT): - myocard - liver D. Systemic: - pyrogen fever - Neut leukocytosis

Free Radicals
- = Mol: single unpaired electron - React & modify lipid (memb), DNAm & protein - OH* = Hydroxyl Radical, O2* = Superoxide Radical

Defence >< Radicals

Decay spontaneously Antioxidants: - Vit E

- Superoxide Mutase & Catalase

Atrophy
= size or number shrinkage (exp. Old) Causes Gradual ddiminution in blood supply Reduced fuctional activity Interupted nerve supply Endocrine deficiency Pressure

Ageing
? Distinction: True Ageing & Disease complicated Ageing True ageing: ideal invirontment (minimal strress) Main controlling factors = intrinsic, ie genetic - ageing genes in mitochondria - loss of cells ability to divide telomeric shortening) (ends of chromosome)

Hereditary, Genes and Disease

Nucleus contains Chromosomes Chromosome: - Transmit hereditary traits - Control synthesis proteins Normal Chr. Map: 22 pairs autosomes: - Paternal - Maternal 2 sex chr : - 2 large X - 1 large X & 1 small Y
Each chr = very long single mol of DNA, condensed during mitosis Function: initiate & control syntesis of protein from amino-acids

Protein (structural protein, hormones, receptors, intracellular messengers etc) are encoded along the molecule Gene: - = unit chromosome responsible fo synt of a single specific protein - vary in length: 20,000 base pairs - 50,000 in all the human chr - coding regions (exons), non-coding (introns)

Amyloid Deposition
Waxy: extra cell: around blood ves, basement membrane

Detection
Post mortem: Lugols Iodine: - Amyloid Deep brown - Normal Yellow B I o p s y : - Light mic: - Congo Red: - Amyloid: Red: Apple green birefringence (Polarized light) - Normal: Pale pink: Biref (-) - Immunostaining: P protein

Effects
Kidney
pale, firm, waxy Glo permebility gross proteinuria Nephrotic renal failure

G I Tract
diarrhoe, protein loss Malabsorption, nutritional deficiency

Heart
enlarged cardiac failure

Calcification
1. Dystrophic - Necrotic, not absorbed: - old caseous tbc - dead parasite - old infarct - fat necr pancratitis - old pus - Tissue (slow deg): - fibroid - atheromatous deg - old thrombi - diseased or abn heart valve 2. Metastatic: Ca X phosphate product in blood (hypercalceami)

Endogenous Pigmentation
Iron-Containing Pigment breakdown of Ecyte - Haemosiderin - Bilirubin Iron (spl, liv, BM) + Apoferritin. In plasma, transported by transferrin. Iron within cell excessive deposited brown gran hemosiderin: 2 situations:

1. Local breakdown of red celss in tissues 2. Visceral siderosis

- Haemosiderosis Haemolytic anaemia, repeated blood transfusion - Haemochromatosis intestine - Pancrease: fibrosis, destroy islet DM - Liver: Kupffer, hepatocyte Cirrhosis - Skin: sweat gl, melanin Bronzed diabetes - Heart muscle - Mesenteric lymph nodes

Haemoglobin
Intravasc hemolysis urine dull red Acute: eg incomp blo trans) acute renal tubular necrosis Chr : paroxysmal haemoglobinuria Hb reabs
brokendown iron (haemosiderin) tubular epithelium

Haematin (Haemazoin)
Malaria: Hb brown pigment monocyte liv, spl Lipofuscin Yellowish brown lipid: atrophied cells of old age (Wear & tear), heart brown atrophy

Exogenous Pigmentation
Introduced: - Inhalation, ingestion, injection Inhalation: - Coal dust (carbon) black - Stone dust (silica) grey

Pneumoconiosis

Ingestion: silver, lead metalic hue lead blue line: gum (lead+ hydrogen sulphide) carrot: caotene yellowish skin Injection: tattoing

Degenerations Hyaline
Glossy, refractile (HE) Dense collagen: leiomyoma, arteriosclerosis Mallorys hyaline: intracellular: cytoskletal proteins: alc liver

Mucoid
Epit Tumor: secrete mucin degenerate epithel Conn tissue: mucin: mucopolisach (hyaluronic acid) Myxomatous

Cellular Aging : - intrinsic

- extrinsic (wear and tear) Intrinsic Normal human fibroblast: stop dividing senescent 50 doubling

Fibroblast - neonatus: 65 doubling before cease dividing

- progeria: only 35 ? Finite number of replication ignorant

? How cells know the number of division theyve undergone

Cellular Aging
Intrinsic Normal human fibroblast: stop dividing senescent 50 doubling ? Finite number o replication ignorant ? How cells know the number of division theyve undergone

Incompl replication of chr ends (telomere shortening) DNA repl truncated copy of each chr

To overcome this telomeres (ends of chr: TTAGGG)

- short multiple repeated sequences of non transcribed DNA

1. Incompl replication of chr ends (telomere shortening)

- DNA replication truncated copy of each chr

- To overcome this telomeres (ends of chr: TTAGGG)

- short multiple repeated sequences of non transcribed DNA - Telomerase stabilizes telomere length by + to its ends - Regulatory protein: represses telomerase - Immortal cancer cells telomerase is reactivated, not shortened

Clock genes
Genetic timers control the tempo of aging clk1 in Caenorhabditis elegans nematode growth rate Mutated clk-1 rate of development 50% longer life spans

Theory of Aging

Smaller animal: shorter life span & faster metabolic rates

life spans is limited by fixed total metabolic consumption

1 . Longevity >< rates of mitochondrial generation of superoxide anion radicals 2. Overexp of antioxidative enzymes superoxide dismutase & catalase extends life span 3. Restriction of calori intake lowers steady-state levels of oxidative damage, slows age related changes, and extends the maximal life span.

Oxidative phosphorylation, nucleic acid, enzymatic protein, cell receptor, & transcription factor.

Morphology Irr & abn lobed nuclei Pleomorphic vacuolated mitochondria Endoplasmic reticulum Distorted Golgi apparatus

Werners syndrome
Defective gene product: DNA helicase

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