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Cell Response to Stress and Noxious Stimuli

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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)

 

 

 

 

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