Outline of Lecture
Cell response to stress & noxious stimuli
Causes of Cell injury
ischemic & hypoxic injury
Life meets change & variation everyday. We make appropriate adjustments .So does the cell “The unit of life”
Homeostasis
Normal steady dynamic cell state “Homeostasis”
Ability to adjust its physiological processes to maintain internal equilibrium
Cells are under continuous exposure to stress
Physiological stress →homeostasis
Pathological stress → injury
Reversible Injury →adaptation
Irreversible injury →cell death
Adaptations.
Adaptations. are reversible , functional & structural changes to pathological stress & noxious stimuli.
It allows cell to live & continue to function.
Adaptation
stages of progression in stress beyond homeostatic range
Normal cell ↓ ← ←
Homeostasis ↓ ↑
Adaptation ↓ ↑
Cell injury ↓ → reversible ↑
Irreversible injury ↓
Cell death ↓
Apoptosis/necrosis
Adaptation
Reversible Cell Responses to stress
Cell changes in their
Size
Number
Shape (phenotype)
Metabolic activity
Function of cell.
Causes of injury/Types of stress
Oxygen deprivation “Hypoxia & ischemia”
Free radicals
Chemical agents
Physical agents
Infections
Immune reactions
Genetic defects
Nutritional defects
Aging
Causes of cell injury
Hypoxia.
Physical agent
trauma, extreme heat / cold , ∆ atmosphere pressure, radiation, electric shock.
Chemical agent & drugs,
glucose, hypertonic saline, ↑O & poisons.
Infections.
Autoimmune reactions.
Genetic derangement
gene mutations & chromosomal abnormality. enzyme defects, damaged DNA , misfolded protein, ↑ cell susceptibility to injury.
Nutritional imbalance
↓protein, ↓enzyme, ↑ cholesterol
Cell response to injury
Homeostasis. Ability of normal cell to maintain steady state.
Adaptations. are reversible , functional & structural changes to stress & noxious stimuli. It allows cell to live & continue to function.
Hypertrophy. ↑ size
Hyperplasia. ↑ number
Atrophy. ↓ size
Metaplasia. ∆ phenotype of cell
Cell injury
Stress beyond the adaptive limit of the cell results in cell injury.
Reversible injury stimulus is mild & transient & cell recover their lost functions.
Irreversible injury stimulus is persistent & severe enough leading to cell death.
Reversible injury
light microscopic
Cellular swelling
Hydropic change / vacuolar degenration.
Failure of ionic pump of membrane
Small clear vacuoles formed by pinched-off ER segments
↑ eosinophilic staining of cytoplasm.
Fatty ∆ in hypoxic & toxic injuries
Lipid vacuole in cytoplasm
Hepatocytes & myocardial cells
Revesible injury
electron microscopy
Plasma membrane ∆ blebbing, blunting loss of microvilli.
Mitochondrial ∆ swelling & small amorphous densities.
ER , dilatation myelin figures
Nuclear ∆ separation of granular & fibillar elements
Cell death
Apoptosis. Normal programmed cell death without inflammation during embryogenesis.
Necrosis. Premature cell death accompanied with inflammation during evolution of disease.
1-oxygen deprivation
Hypoxia & ischemia
Causes
↓ O2 in air
↓ Hb “anemia”
Respiratory disease ↓ Oxygen exchange
↓ blood supply
Results
Adapt,↓ injury, ↓ cell death. ↓
Atrophy, inflammation , infarction.
Mitochondrial damage
↓ ATP
Cell death
ischemia
Blood supply decreased below physiological requirement.
Ischemia leads to hypoxia
Reperfusion leads to
Recovery OR
Reperfusion injury ( myocardial & cerebral infarction).
↑ Ca influx
↑ inflammatory cells ↑ free radicals
Immune response against dead tissue
Adaptation to ischemia/hypoxia
Atrophy
↓ cell size & number
Physiologic atrophy
Notochord & Thyroglossal ducts.
Uterus after parturition.
Pathologic atrophy
Disuse
Denervation
Ischemic
Cachexia
Loss of endocrine stimulation
Pressure
Mechanism of atrophy
↓protein synthesis ↓ metabolic activity
↑ protein degradation by Ubiquitin-proteasome pathway.
Activation of ubiquitin ligases attach peptide ubiquitin to cellular protein & target these proteins for degradation in proteasomes.
↑ autophagy ↑ autophagic vacuoles ↑ residual bodies (lipofuscin).
Metaplasia
Reversible ∆ one differentiated cell type replaced by another type.
Columnar → Squamous (respiratory)
Squamous →Columnar (barrett esophagus).
Necrosis
Denaturation of protein & enzymatic digestion.
Histological evidence of myocardial necrosis after 4-6 hrs.
Cytoplasmic changes.
↑ eosinophilia due to ↓ cytoplasmic RNA & denatured cytoplasmic protein, aggregates of fluffy material.
↑ glassy appearance due ↓ glycogen.
Vacuolated cytoplasm after digestion.
Myelin figures are whorled phospholipid masses derived from cell membrane.
Dystrophic calcification of residual fatty acids.
Necrosis
Nuclear changes patterns
Karyolysis ↓ basophilia of chromatin.
Pyknosis nuclear shrinkage ↑ basophilia.
Karyorrhesis fragmentation of pyknotic nuclei.
Pattern of tissue necrosis-I
COAGULATIVE NECROSIS
architecture of dead tissue preserved for some days. due to denaturation of enzymes.
Ischemia → coagulative necrosis except in brain.
Infarct is localized area of coagulative necrosis.
LIQUEFACTIVE NECROSIS
digestion of dead cells → liquid mass.
(infections & hypoxic death in CNS)
GANGRENOUS NECROSIS.
Clinical term for ischemic necrosis of lower limb involving multiple tissue planes with superadded bacterial infections.
Pattern of tissue necrosis-II
Caseous necrosis
Cheese-like in tuberculosis.
Fat necrosis
focal area of fat destruction. (pancreatic lipase digest cell membrane & form fatty acid+calcium white deposits.)
Fibrinoid necrosis
deposition of immune complexes & fibrin in arterial wall. Artrial wall show amorphous pink circumferential necrosis with inflammation.
Cerebral ischemia
Normal cerebral blood flow (CBF) in man is typically in the range of 45-50 ml/min/100g between a mean arterial pressure (MAP) of 60 and 130 mmHg
When CBF falls below 20 to 30 ml/min/100g, marked disturbances in brain metabolism begin to occur, such as water and electrolyte shifts and regional areas of the cerebral cortex experience failed perfusion
At blood flow rates below 10 ml/min/100g, sudden depolarization of the neurons occurs with rapid loss of intracellular potassium to the extra-cellular space.
minimum MAP of 45 to 50 mm Hg is required to preserve cerebral viability in man
Cerebral ischemia
Mechanisms of Ischemic Injury
loss of high-energy compounds
acidosis due to anaerobic generation of lactate
and no reflow due to swelling of astrocytes with compression of brain capillaries
Biochemical Events
20 seconds of interruption of blood flow to the mammalian brain under conditions of normothermia, the EEG disappears,
Within 5 minutes, (ATP depletion) ,
Potassium efflux out of ICF and sodium and calcium begin to enter the cells
Sodium influx results in a marked increase in cellular water content, particularly in the astrocytes
Calcium
Normally, calcium is present in the ECF at a concentration 10,000 times greater than the ICF.
↑ICF calcium enhances the conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO)
Cerebral ischemia
During ischemia, the hydrolysis of ATP via AMP leads to an accumulation of hypoxanthine “XO”
Upon reperfusion and reintroduction of oxygen, XO may produce superoxide and xanthine from hypoxanthine and oxygen
Haber-Weiss reaction as follows
O2- + H2O —-Fe3 ——> O2 + OH-+ OH-
During reperfusion and re-oxygenation, significantly increased levels of several free-radical species that degrade cell and capillary membranes have been postulated ,
O2-, OH-, and free lipid radicals (FLRs).
O2- may be formed by the previously described actions of XO and/or by release from neutrophils which have been activated by leukotrienes
Re-oxygenation also restores ATP levels, and this may in turn allow active uptake of calcium by the mitochondria, resulting in massive calcium overload and destruction of the mitochondria
lactate levels above a threshold of 18 – 25 micromol/g result in currently irreversible neuronal injury .
Cerebral ischemia
Excitotoxins
excitatory neurotransmitters, which are released during ischemia, play an important role in the etiology of neuronal ischemic injury
Those areas of the brain which show the most “selective vulnerability” to ischemia, such as the neocortex and hippocampus, are richly endowed with excitatory NT.
facilitate calcium entry into neurons & these agents are neurotoxic
AMPA (alpha-amino-hydroxy-5-methyl-4-isoxazole proprionic acid)
& NMDA (N-methyl-d-aspartate receptors)
Cerebral ischemia
Histological Ultrastructural Change
Within seconds of the onset of cerebral ischemia, brain interstitial space almost completely disappears.
After 10 minutes of GCI, a significant number of cells (but not all) show clumping of nuclear chromatin and a modest increase in electron lucency
After 60 minutes of GCI, the above changes have become more pronounced with more conspicuous swelling of the ER cisternae. The mitochondria begin to show slight inner matrix swelling and occasional flocculent densities
fter 120 minutes of GCI, the changes discussed above are more pronounced and a larger number of mitochondria exhibit the presence of flocculent densities evidencing calcium overload which is currently considered irreversible.
End
Causes of Cell injury
ischemic & hypoxic injury
Adaptation
HYPERTROPHY
↑ size of cell by ↑ synthesis of structural component.
↑ functional demand (↑workload for striated muscle )
↑ stimulation by hormones & growth factors. (uterine smooth muscle in pregnancy)
Mechanism of cardiac muscle hypertrophy
Mechanical sensor triggered by ↑ workload.
Growth factors TGF-β, IGF-1,FGF, α adrenergic agonist,Endo-1,Angt-II.
Phosphoinositide 3-kinase/Akt pathway (exercise, physiologic)
G-protein coupled receptor (pathologic)
Switching of adult contractile protein to fetal form. (α isoform myosin to β isoform)
Stress beyond the limit of hypertrophy results in regression with loss of myofibrillar contractile protein or cell death .
Hypertrophy of ER
Subcellular organelle
Barbiturate induce hypertrophy of smooth endoplasmic reticulum in hepatocytes.
↑ enzyme Cytochrome P-450 mixed function oxidase.
Hyperplasia
↑ number of cells in organ / tissue
Physiologic
Hormonal
Compensatory after resection / injury. If one lobe of liver is donated for transplant ,organ grows back to its original size.
Pathologic
Excess hormone in endometrial hyperplasia & prostate hyperplasia
Papilloma virus cause warts
Atrophy
↓ cell size & number
Physiologic atrophy
Notochord & Thyroglossal ducts.
Uterus after parturition.
Pathologic atrophy
Disuse
Denervation
Ischemic
Cachexia
Loss of endocrine stimulation
Pressure
Mechanism of atrophy
↓protein synthesis & ↑ protein degradation.
Ubiquitin-proteasome pathway.
Activation of ubiquitin ligases attach ubiquitin to cellular protein & target these proteins for degradation in proteasomes.
↑ autophagy ↑ autophagic vacuoles ↑ residual bodies (lipofuscin).
Causes of cell injury
Hypoxia.
Physical agent
trauma, extreme heat / cold ,∆ atmosphere pressure, radiation, electric shock.
Chemical agent & drugs,
glucose, hypertonic saline, ↑O & poisons.
Infections.
Autoimmune reactions.
Genetic derangement
gene mutations & chromosomal abnormality. enzyme defects, damaged DNA , misfolded protein, ↑ cell susceptibility to injury.
Nutritional imbalance
↓protein, ↓enzyme, ↑ cholesterol
Causes of injury/Types of stress
Oxygen deprivation “Hypoxia & ischemia”
Free radicals
Chemical agents
Physical agents
Infections
Immune reactions
Genetic defects
Nutritional defects
Aging
Reversible injury
light microscopic
Cellular swelling
Hydropic change / vacuolar degeration
Failure of ionic pump of membrane
Small clear vacuoles formed by pinched-off ER segments
↑ eosinophilic staining.
Fatty ∆ in hypoxic & toxic injuries
Lipid vacuole in cytoplasm
Hepatocytes & myocardial cells
Revesible injury
electron microscopy
Plasma membrane ∆ blebbing, blunting loss of microvilli.
Mitochondrial ∆ swelling & small amorphous densities.
ER , dilatation myelin figures
Nuclear ∆ separation of granular & fibillar elements
Necrosis
Denaturation of protein & enzymatic digestion.
Histological evidence of myocardial necrosis after 4-6 hrs.
↑ eosinophilia due to ↓ cytoplasmic RNA & denatured cytoplasmic protein.aggregates of fluffy mateial.
↑ glassy appearance due ↓ glycogen.
Vacuolated cytoplasm after digestion.
Myelin figures are whorled phospholipid masses derived from cell membrane.
Dystrophic calcification of residual fatty acids.
Necrosis
Nuclear changes patterns
Karyolysis ↓ basophilia of chromatin.
Pyknosis nuclear shrinkage ↑ basophilia.
Karyorrhesis fragmentation of pyknotic nuclei.
Pattern of tissue necrosis
COAGULATIVE NECROSIS
architecture of dead tissue preserved for some days. due to denaturation of enzymes.
Ischemia → coagulative necrosis except in brain.
Infarct is localized area of coagulative necrosis.
LIQUEFACTIVE NECROSIS
digestion of dead cells → liquid mass.(infections & hypoxic death in CNS)
GANGRENOUS NECROSIS.
Clinical term for ischemic necrosis of lower limb involving multiple tissue planes with superadded bacterial infections.
Pattern of tissue necrosis
Caseous necrosis
Cheese-like in tuberculosis.
Fat necrosis
focal area of fat destruction. (pancreatic lipase digest cell membrane & form fatty acid+calcium white deposits.)
Fibrinoid necrosis
deposition of immune complexes & fibrin in arterial wall. Artrial wall show amorphous pink circumferential necrosis with inflammation.
Mechanism of cell injury
Dose of injury
State of target cell
Susptable cell components mitochondria, cell membrane, RER, DNA.
ATP Depletion
Hypoxic & chemical injury
ATP generated by
Oxidative phosphorylation in mitochondria
Anaerobic Glycolytic pathway (liver).
ATP depletion 5% -10% of normal affects
Cell membrane Na pump
↑ c-AMP ↑ glycolysis
↑lactic acid &↑ iPO4 ↓pH ↓activity of enzymes.
Ca pump fail → Ca influx.
Unfolded protein response.
Irreversible damage to mitochondria & lysosomal membrane → cell necrosis
Mitochondrial damage
Damaged by ↑ cytoplasmic Ca, free oxygen radicals, oxygen depletion, mitochondrial gene mutation.
Consequence
Mitochondrial permeability transition pore.
Stops oxidative phosphorylation
Cyclosporine → ║ Cyclophilin-D
Squestered Cytochrome c & Caspases proteins enter cytoplasm & trigger apoptosis.
Finding
Depleting Ca protects cell from injury by variety of harmful stimuli.
Ca mediator of inflammation.
Calcium influx
ICF free Ca 0.1µmol
(sequestered in mitochondria & ER)
ECF Ca 1300µmole.
Ischemia & toxin ↑ ICF Ca
Initially by release of sequestered Ca
Later by Ca influx.
Rise in ICF Ca = injury
Opens mitochondrial permeability transition pore → stops ATP generation.
Activates enzymes
phospholipase,
protease,
endonuclease ,
& ATPase.
Triggers apoptosis by
Activating caspases & ↑MP
↑oxygen derived free radicals
Single unpaired electron in outer orbit.
Reacts with adjacent molecules
Autocatalytic reactions
Oxidative stress
↑ROS= ↑production or ↓scavenging
2-Free radicals
By mitochondrial respiration ROS
Superoxide
H2O2
OH
By inflammation
NO→ONOO
Generation of free radical
Respiration
H2+O=H2O &
O2-(1e), H2O2-(2e), OH-(3e),
Radiation=Hydrolysis
H2O=H+OH
Inflammation = rapid burst of ROS in leukocytes
Xanthine oxidase=O2-
Enzymatic metabolism of drugs
CCl4→CCl3
acetaminophen
Transition metals iron & Cu
Fentons reaction H2O2+Fe→Fe+OH+OH-
NO by endothelial cell,macrophages & neuron
NO→peroxynitrite (ONOO)
Pathologic effect of free radical
Lipid peroxidation
Of double bonds in unsaturated FA by OH-
→peroxide →autocatalytic CR propagation →membrane damage
Oxidative modification of protein
Enzyme inactivation,
∆structural protein →degradation
Lesion in DNA
Strand breaks & cross linking →mutation → aging ,malignancy
Removal of free radicals
Spontaneous decay
Antioxidants ↓synthesis or ↑inactivation
vitamen A, E,&C & glutathione
Albumin ,transferrin, ferritin, lactoferrin, ceruloplasmin
Enzymes
SOD in mitochondria
O2- →H2O +O2
Glutathione peroxidase
OH→H2O2→H2O+O2
Catalase in peroxisomes
H2O2→H2O+O2
3-Chemical agents
Cyanide –cytochrome oxidase
HgCl ↑ memebrane pemeability
CO→COHb
Ethanol →acetaldehyde →
Fee radicals & fatty ∆ in liver
Pb competitive inhibition of Ca, Fe & Zn
Pb in CNS block glutamate receptor
Pb ↓ Hb synthesis
4-physical agents
Mechanical injury
Ionizing radiation
Extreme temperature
Hyper / Hypothermia
Extreme Air pressure
↑blast, underwater
↓vaccum
5-infectious agents
Bacterial toxins
Viruses
↓ protein synthesis
Immune reaction
6-Nutitional imbalance
↑protein
Hyer/hypoglycemia
Vitamen deficiencies
General consideration
Function lost before morphological ∆
EM ∆
Microscopic ∆
Gross ∆
Results of injury depends on
Type, duration & severity of injury
Type of cell specialization, regenerative ability or adaptability.
Subcellular targets
Mitochondria
(MPTP) loss of Memb∆ ,↓ATP
Cytochrome c →apoptosis
O2↓ →ROS
Membranes
↓ Na+ pump →edema
lysosome →enzyme release in cytoplasm →digestion of cell components.
Subcellular targets
↓Protein synthesis ,↑fluid →separation of ribosomes from swollen ER →glycolysis →metabolic acidosis.
Genetic apparatus DNA mutations
Subcellular response
SER Hypertrophy (liver)
Mitochondrial ∆ in size & number
Cytoskeletal ∆ e.g. microtubule
Lysosomal catabolism
Heterophagy.Autophagy.
Perrsistent debris→residual body (undigestible lipid peroxidation products)→lipofuscin
Morphology of reversible cell injury
EM
Swelling of organelles
Blebbing of plasma membrane
Detachment of rb-ER
Clumping of nuclear chromatin.
Morphology of irreversible cell injury
↑Swelling of organelles
Disruption of lysosome
Calcium deposits in mitochondria
Disruption of membrane by phospholipase
Nuclear changes
Pyknosis(shrinkage ↑ basophilia)
Karyolysis
Karyohexsis
Anucleate cell
After cell death
Leakage of enzymes & protein into ECF useful in diagnosis
CK-NAC, Troponin in MI
ALT in hepatitis
ALK PO4ase in biliary obstruction
Dead cells →myelin figures →FFA →calcifications
Cellular Adaptation
After non lethal injury cells may adapt to protect themselves.
Growth
Hyperplasia; hypoplasia
Hypertrophy; atrophy
Metaplasia; dysplasia.
Degenerations (accumulations).
Hydropic ∆
Fatty ∆
Hyaline ∆
Pigment strorage-wear& tear
Atrophy
↓ cell size by ↓ cell substance by protein degradation, digestion & endocytosis.
↓ Hormone
↓ Function
Atrophy
Physiologic
Uterus after parturation
Pathologic
Disuse
Denervation
↓ Blood supply (cerebral atrophy)
Malnutrition
↓ Hormone
Ageing
Senile atrophy
Hypertrophy
↑ cell size by ↑ cell substance
↑ Organ size
Caused by ↑ workload ↑hormone.
Hypertrophy beyond adaptive capacity →degenerative changes & organ failure .
Skeletal muscle in atheletes
Smooth muscle in gravid uterus
Cardiac muscle in hypertension
Remaining kidney after partial nephrectomy.
Hyperplasia
↑ number of cells by ↑ rate of division
Cells with mitotic ability both hyperplasia & hypertrophy can occur
Predisposes to neoplasia.
Mitotic ability of cells
High
epidermis, intestinal epithelium, hepatocytes, BM ,fibroblast
Low
bone, cartilage ,smooth muscles.
Nil
neuron,cardiac muscle ,skeletal muscle.
Types of hyperplasia
Physiologic
Uterine during pregnancy
Female breast during puberty & lactation.
Compensatory hyperplasia in liver
Pathologic
Endometrium ↑ homone
Wound healing
HPV infection
Metaplasia
Adaptation a reversible change where one adult/mature cell type replaced by another type more suited to new environment.
epithelial→ bronchial, gastric, cervical
mesenchymal →fracture bone
Results in loss of some function.
Persistent stimulation → dysplasia →carcinoma
Dysplasia
Atypical hyperplasia
Disordered arrangement of cells
Caused by persistent injury / irritation
Premalignant condition.
End
FATTY CHANGE
INTRACELLULAR ACCUMULATION
INTRACELLULAR ACCUMULATION
↑ production of normal product.inadequate function
Normal / abnormal substance accumulate but defective mechanism of removal.
↑ Exogenous substance no removal mechanism.
Accumulations
Water
Fatty change
Cholesterol & esters
Protein
Glycogen
Pigments
Calcium
Amyloid
Fatty change
Accumulation of excessive lipid in cells
Liver , heart ,kidney
Fatty acids→ hepatocytes→ triglycerides+ apoprotein→exit liver
Defect in any of the above steps.
Causes of fatty change
Toxins ,alcohol
Protein malnutrition
Diabetes mellius
Hypoxia ,anemia, ischemia
Drugs, pregnancy & obesity
Morphology of Fatty change
Gross in liver depends on severity.
↑ size ,yellow & greasy when severe.
Histology
Microvesicular cytoplasm
Macrovsicular cytoplasm
Cholesterol & esters
Accumulates in macrophages (foam cells) & FB giant cells
Atherosclerosis
Hereditary & aquired hyperlipidemia →xanthoma
Protein accumulation
Kidney in nephrotic syndrome.
Plasma cells immunoglobulin.
Mallory bodies. eosinophilic intracytoplasmic hyaline body
Glycogen accumulation in glycogen strorage disease.
Pathogical calcification
Dystrophic calcification.
CaPO4 in dead or dying tissue.
Atherosclerosis & valvular heart disease.
Caseation ,coaggulative or fat necrosis.
Dead parasite & their ova.
Metastatic calcification
Ca deposition in normal tissue due to hypercalcemia.
↑ PTH bone resorption.
Metastatic bone tumor →bone resorption.
Chronic renal failure.
↑ Vitamin D
Kidney, stomach, lungs
5-pigments
Endogenous
Hb derived iron,bilirubin
Non Hb derived melanin, lipofusion
Exogenous
Anthracosis
Tatooing
Exogenous pigments
Anthracosis
Accumulation of carbon, black pigment
Smoker
Tatooing
Endogenous pigments
Melanin
Brown pigment synthesized in melanocytes.protects nuclei of basal epidermal cells from UV light.
Nevi benign
Melanoma malignant eye, rectum
lipofusion
Brown pigment in cytoplasm is oxidized lipid derived from digested membrane organelle
Part of aging process & atrophy in which lipid peroxidation occurs.
Harmless to cells
↑ amount in brown atrophic organ
Bile pigment (bilirubin)
Derived from heme of Hb from destroyed RBC in RES
Conjugated in hepatocytes with glucuronic acid & excreted as bile.
Hyperbilirubinemia jaundice
Hemolysis, liver disease, obstruction to outflow of bile.
Excess iron accumulaton
Total body iron 2-4gm
Functional pool
Hb, myoglobin,cytochrome,catalase
Storage pool
Macrophages of RES as Fe3+,ferritin,hemosidern
Purssian blue reaction (PEARLs)
Iron overload
Localized ↑ iron in tissue
Hematoma
Chronic venous congestion lung ,heart
Systemic ↑ iron
Hemosiderosis Fe in RES without damage
Hemolytic disease
Multiple blood transfusions
I/V Fe administration
Idiopathic hemochromatosis
Lack of regulation of iron absorbtion & defects in monocyte macrophage system.
Deposited in liver, pancrease & RES.
→ fibrosis, secondary DM. liver cirrhosis & cancer
Amyloidosis
Extracellular deposition of abnormal fibrillar protein.
Amyloid
Types associated with different disease.
H&E stain hyaline acellular eosinophilic material
Congo red stains red in light & green birefingence in polarized light.
Classificaton of amyloid
Localized
Larynx,lung ,bladder
Systemic Amyloidosis
Multiple myeloma associated
Reactive (secondary amyloidosis)
AA amyloid
Rheumatoid arthritis
IBD
Osteomylitis
Hodgkins disease & RCC
Hereditary amyloidosis
Cell death
Ultimate result of irreversible injury
Physiological embryogenesis
Therapeutic cancer radiotherapy/chemotherapy
Types
Necrosis morpholocical changes seen in dead tissue within vialble tissue
Autolysis dissolution of dead cells by own enzymes
Apoptosis programed cell death .Physiological, cell regulation.
Necrosis
Irreversible
Local cell death & cellular dissolution in living tissue.
Self/auto digestion & lysis.
Morphologic changes
↑ eosinophilia of cells
Pyknosis of nuclei
Karyorrhexis nuclear fragmentation into apoptotic bodies.
Karyolysis dissolution of the nucleus by hydrolytic enzymes
Release of catalytic enzymes from lysosome → autolysis/hydrolysis.
Morphological ∆ in necrosis are due to
Enzymatic digestion of cells
Denatuartion of protein
Types of necrosis
Coagulative,liquifactive, caseous ,fat necrosis ,gummatous necrosis & fibrinoid necrosis.
Steps/sequel of necrosis
Autolysis
Phagocytosis
Organization /fibrous repair
Dystrophic calcification.
Coagulative necrosis
Commonest ischemic
Infarction heart ,kidney, adrenalfirm texture
↑ ICF Ca
Denaturation of all protein including enzymes.
Histology
Preservation of tissue architecture & cll outline.
Necrotic area stain ↑ eosinophilic often devoid of nuclei
Liquifactive necrosis
Autolysis predominates resulting in liquified mass.Cerebral infarction,Abscess.
Brain cells ↑ hydrolases. These make neual tissue soft & liquid.
Abscess hyrolase from neutrophil liquefy tissue.
Caseous necrosis
Cheese-like
Histology
Granuloma
Central cheesy material rimmed by epitheloid cells & giant cells (FB/Langhan)
Tuberculosis coagulative necrosis modified by capsule of lippopolysacchiride of TB bacili
Fat necrosis
Types
Truamatic fat necrosis→FB giant cell + foamy histiocytes→calcification →hard lump.
Acute pancreatits released enzymes digest fat
Adipose tissue →TG + FFA →saponification + calcification.
Gangrene
Necrosis + putrifaction by saprophyes
Wet gangrene coagulative necrosis by ischemia + liquifactive necrosis by superimposed infection.
Dry gangrene. Drying of dead tissue associated with P vascular disease.
Necrosis is separated from viable tissue by line of demarcation.
Gass gangrene gass produced in necrotic tissue by anerobic bacteria clostridium perfringes.
Apoptosis
Programmed cell death-suicide
Cell membrane remains intact
No inflammatory reaction
Apoptosis
Require cellular signal →protein cleavage within cell causing cell death.
Programmed & energy dependent process designed to switch off & eliminate cells.
Cell shrinkage.
Chromatin condensation
Formation of cytoplasmic blebs & apoptotic bodies
Phagocytosis of apoptotic bodies.
Pathways
Intrinsic mitochondrial pathway
↑ permeability of mitochondrial membrane→cytochrome c & AIF →activates caspases → death.
Extrinsic death receptor pathway
FAS & TNF1 receptor families with death domain.
Physiologic apoptosis
During growth develpoment & Embryogenesis.
Homeostatic mechenism maintains cel population.
In aging
Shedding of menstrual endometrium
Involution of breast after weaning.
Pathologic apoptosis
Prostatic atrophy after castration.
Death of inflammatory cells after inflammation.
When cells damaged by disease or injurious agents.
DNA damage by radiation ,chemotherapy, cytotoxic drugs.
Viral hepatits
Neoplasia tumor which regress or involute
Deletion of autoreactive T cells in thymus.
Transplant rejection.
Comparison
Aging & cellular death
Cause by accumulation of injurious events
Genetically controlled developmenta programe.
Mechanism
Genetic , enviromental, behavioral.
∆ regulatory mechanism
Degenerative alteration
Cellular aging
Genetic failure of repair mechanism, clock genes overexpression of antioxidative enzymes (Telomerase )
Telomerase activity stops in somatic cells but continues in stem cells & germ cells.
Enviromental generation of FR
Accumulation of multiple defects →aging
Aged cells show lipofuscin pigment,abnormally folded protein & advanced glycogenated end products(AGES)
