Cell injury Cell injury &&

Adaptation -1Adaptation -1Dr.CSBR.Prasad, M.D.

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Case-1• A 45 yo male with a chronic smoking history

suddenly developed chest pain after a meal.• Pain was retrosternal and radiating to left

arm along the ulnar to the tip of left little finger

• After 6 hours of travelling he reached a cardiac care center where Chest x-ray, ECG and some blood tests were done

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Case-2• 25yo male developed fever associated

with jaundice• He had a tender hepatomegaly• Serum bilirubin was 7.0mg/dl• Liver enzymes are enormously elevated

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Divisions in the study of Pathology

• General pathology• Systemic pathology

Basic reactions of cells and tissues to abnormal stimuli that

underlie all diseases

Specific responses of specialized organs and tissues

to stimuli

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The four aspects of disease process

1. Etiology (cause)2. Pathogenesis

(mechanism of disease)3. Morphological changes

(structural alterations)4. Functional consequences

(clinical significance)

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Rudolf Virchow[Father of Modern Pathology]

““Virtually all forms of Virtually all forms of tissue injury starts with tissue injury starts with molecular or structural molecular or structural alterations in CELLS”alterations in CELLS”

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Subcellular compartments:Subcellular compartments:

1. Nucleus2. Mitochondria3. ER4. Golgi apparatus5. Lysosomes6. Cytosol

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Homeostasis Homeostasis

When the cell is functioning properly it’s said to be in a

“steady statesteady state” i.e. it can handle normal

physiological demands

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TermsTerms

• Cell injuryCell injury• AdaptationsAdaptations

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Cell injuryCell injury• Reversible injuryReversible injury 1-Cell swelling 2-Fatty change 3-Mitochondrial swelling 4-ER disruption 5-Membrane blebs 6-Cytoskeleton disruption• Irreversible injuryIrreversible injury 1-Apoptosis 2-Necrosis

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Causes of injuryCauses of injury1. Ischemia / hypoxia2. Physical agents3. Chemical agents4. Infections5. Immune reactions6. Gene defects7. Nutritional imbalances

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Ischemic & Hypoxic injuryIschemic & Hypoxic injury

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ISCHEMIAISCHEMIA HYPOXIAHYPOXIA

Blood flowBlood flow Decreased due to Decreased due to vascular occlusionvascular occlusion Flow is normalFlow is normal

OO22 tension tension NormalNormal Low Low

Delivery of Delivery of substratessubstrates DecreasedDecreased NormalNormal

Anerobic glycolysisAnerobic glycolysis Ceases faster as there is Ceases faster as there is no substrate deliveryno substrate delivery

Continues for a much Continues for a much more longer timemore longer time

Tissue injury Tissue injury Occurs with in a short Occurs with in a short timetime Takes longer time Takes longer time

Note:Note: Ischemia injures tissues faster than hypoxia.Ischemia injures tissues faster than hypoxia.

Differences between Ischemic and Hypoxic injuryDifferences between Ischemic and Hypoxic injury

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Ischemic & Hypoxic injuryIschemic & Hypoxic injuryDecreased oxidative phosphorylation in Decreased oxidative phosphorylation in

mitochondria [mitochondria [effecteffect: low ATP levels]: low ATP levels]

Effects of Low ATP levels:Effects of Low ATP levels:

1.< activity of Na+ pump [Link]

2.> glycolysis (< intracellular glycogen)

3.Lowered intracellular pH (acidosis)

4.Detachment of ribosomes (< protein synthesis)

DD Ischemia / Hypoxia CSBRP-V3-Dec-2011

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Ischemia Ischemia // Reperfusion injury Reperfusion injury

• It represents exaggerated / accelerated exaggerated / accelerated injuryinjury that occurs when blood flow is restored contrary to the expectation of recovery

• It’s seen especially in myocardium and brain

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Ischemia Ischemia // Reperfusion injury Reperfusion injury

MechanismsMechanisms:• Reperfusion results in high concentration of Ca+

in the environment which cannot be handled by the injured cell

• Reperfusion results in augmented recruitment of inflammatory cells to the injured area with resultant >levels of reactive oxygen species

• Antioxidant defence mechanisms are not well restored

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Free radical – induced cell injuryFree radical – induced cell injury

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Free radical – induced cell injuryFree radical – induced cell injuryWhat are free radicals?What are free radicals?

• They are a chemical species with a single unpaired electron in an outer orbital

• They are extremely unstable• They readily react with organic & inorganic

chemicals• With in the cell they attack

– Nucleic acids– Membrane molecules

• They are autocatalytic

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Free radical – induced cell injuryFree radical – induced cell injury

• Injury by activated oxygen species• Free radical injury underlies

1. Chemical2. Radiation3. Toxicity from oxygen4. Cellular aging5. Microbial killing by phagocytes6. Inflammatory cell damage7. Tumor destruction by MØ

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NOTE:

Production of free radicals in the cell:Production of free radicals in the cell:

1. due to insults (ex: chemical, radiation)2. as a part of normal cellular activities

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Free radical – induced cell injuryFree radical – induced cell injuryHow they are produced with in the cells?How they are produced with in the cells?

They are by products of normal cell They are by products of normal cell metabolismmetabolism

1. Redox reactions [link]2. Nitric oxide3. Ionizing radiation4. Enzymatic metabolism of some

exogenous chemicals (ex: CCl4)

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Free radical – induced cell injuryFree radical – induced cell injury

Important reactions that mediate cell Important reactions that mediate cell injury by free radicals:injury by free radicals:

• Lipid peroxidation of membranesLipid peroxidation of membranes• DNA fragmentationDNA fragmentation• Cross-linking of proteinsCross-linking of proteins

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NOTE:

Production of free radicals in the cell:Production of free radicals in the cell:

1. due to insults (ex: chemical, radiation)2. as a part of normal cellular activities

There are many intracellular mechanisms There are many intracellular mechanisms that neutralize the normally produced free that neutralize the normally produced free radicalsradicals

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Mechanisms to neutralize free radicals Mechanisms to neutralize free radicals produced normally with in the cells:produced normally with in the cells:

• SODs• GSH / GSSH• Catalase• Anti-oxidants (Endogenous or exogenous)

• Sequestration into other proteins

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Free radical – induced cell injuryFree radical – induced cell injuryNatural NeutralizersNatural Neutralizers

Superoxide radical O2

Hydrogen peroxide H2O2

OH

SOD

Catalase

GSH/GSSH

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Chemical injuryChemical injury

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Chemicals induce injury by any one of the two mechanisms:

1. Direct action (unaltered chemical)2. Indirect action (altered chemical)

Chemical injuryChemical injury

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1. Direct action (unaltered chemical):

They combine with a critical molecular component or cellular organelle

Ex: HgCl2 (binding with –SH groups of various cell membrane proteins)

Other examples: anti-neoplastic drugs antibiotics

Chemical injuryChemical injury

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1. Direct action (unaltered chemical):

“The greatest damage occurs to those cells that use, absorb, excrete or

concentrate the compound”

Chemical injuryChemical injury

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2. Indirect action (altered chemical):

They are converted toxic metabolitesConversion occurs in the P450 of SER of liver

Mechanism of injury: a- formation of reactive free radicals b- direct covalent binding to protein & lipids

Ex: CCl4 and Acetaminophen

Chemical injuryChemical injury

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2. Indirect action (altered chemical):

Action of CCl4 It’s converted in to toxic free radical CCl3Cause lipid peroxidation, break down of ERIn <30 min hepatic synthesis of proteins drops

and in 2hrs swelling of SER and dissociation of ribosomes

Fatty liverMitochondrial injury – drop in ATP – cell swellingAt the end Ca+ influx – activation of enzymes –

cell death

Chemical injuryChemical injury

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The answer is “No”“No”Injury of limited severity and short duration

allows the cells to come back to their normal functional levels

Survival of the cell to injury depends on its ability to respond and adapt to injury

Are all injurious stimuli lethal?Are all injurious stimuli lethal?

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Clinical scenariosClinical scenarios

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This is normal liver at medium power with zone 1 in periportal region, zone 2 in the middle of the lobule, and zone 3 in centrilobular region. A central vein and a portal triad define the lobule.CSBRP-V3-Dec-2011

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More examplesMore examples1. Saccharin induced bladder cancer2. Benzidine induced bladder cancer3. Tx hyperthyroidism with radioactive iodine.4. Anemia and DM5. Hypoxic brain damage in severe anemia6. Cystein given before radiation treatment for

cancers7. Antioxidants and longivity

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Which cell in the body that Which cell in the body that runs by anerobic glycolysis runs by anerobic glycolysis

NORMALLY?NORMALLY?

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Response to injuryResponse to injuryDepends on:Depends on:• Type of injury• Duration• Severity / extent• Consequences depend on

1. cell type2. pre-existing state3. adaptive response

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Response to injuryResponse to injury

Can be:Can be:

1. Recovery2. Adaptation3. Apoptosis 4. Necrosis

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Adaptation:Adaptation:Alterations in cellular function /

morphology to survive the insult

Response to injuryResponse to injury

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Adaptation Adaptation

Can be seen in twotwo situations:1.1. PhysiologicalPhysiological adaptation2.2. PathologicalPathological adaptation

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Adaptation Adaptation

PhysiologicalPhysiologicalAdaptation to demand

Ex:Ex: Enlargement of breast during pubertyEnlargement of uterus during

pregnancyEnlargement of biceps in iron

pumpers

PathologicalPathologicalAdaptation to injury in

order to withstand the insult

Ex:Ex:Wasting of muscle due to

ischemia / disuseIncrease in thickness of

LV in HTNOsteopenia in bed ridden

patientsCSBRP-V3-Dec-2011

Cell adaptation to stressCell adaptation to stress

Types of adaptations:Types of adaptations:

1. Hyperplasia2. Hypertrophy3. Atrophy 4. Metaplasia

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Cell adaptation to stressCell adaptation to stressMolecular mechanisms:Molecular mechanisms:

Changes can occur at different levels1. Receptors2. Protein transcription3. Switch of protein synthesis from one

type to other

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Hyperplasia Hyperplasia • Increase in the number of cells in an organ or

tissue• Hence there is increase in volume of the organ

or tissue• There is increased mitotic activity – >DNA

synthesis• Usually it occurs with hypertrophy• Triggered by external stimuli• Hyperplasia can be physiological or pathologicalEx: hormone induced growth of uterus

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Hyperplasia (HP) Hyperplasia (HP) • Physiological hyperplasia divided into 1-Hormonal HP 2-Compensatory HP

1-Hormonal HP: increases the functional capacity of the tissueEx: Proliferation of glandular epithelium in breast at puberty,

pregnancy Proliferation of smooth muscle of gravid uterus 2-Compensatory HP: increases tissue mass after damage /

partial resectionEx: Capacity of the liver to regenerate unilateral nephrectomy with compensatory hyperplasia of

contralateral kidney

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Prometheus chained to a mountain

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Pathological hyperplasiaPathological hyperplasia

• Due to the action of GF or excessive hormonal stimulation on target cells

• This proliferation is controlled – once the stimulus is removed, the proliferation regresses

• This constitutes a fertile soil in which cancerous proliferations may occur

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Pathological hyperplasiaPathological hyperplasia

Examples:Examples:EM hyperplasia – EstrogensProstatic hyperplasia – AndrogensConnective tissue hyperplasia – wound

healingWarts – viral infections (HPV)

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EM HyperplasiaEM Hyperplasia

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Prostatic HyperplasiaProstatic Hyperplasia

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HyperplasiaHyperplasia

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HypertrophyHypertrophy

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Atrophy Atrophy

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Atrophy Atrophy

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AtrophyAtrophy

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MetaplasiaMetaplasia

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Metaplasia in esophagusMetaplasia in esophagus

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E N D

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DysplasiaDysplasia

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Dystrophic calcification

• Any cell death• Tumor necrosis• Atheroma• Tuberculosis

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Intracellular accumulations

• Endogenous a- Lipid (alcohol) b- Protein (alcohol, Alzheimer’s,

Enzyme deficiencies) c- Glycogen (Enzyme deficiencies) d- Pigment (Lipofuchsin / melanin)• Exogenous pigment - hemosiderin

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Mechanisms of injuryMechanisms of injury1.1. Mechanical disruption – TraumaMechanical disruption – Trauma2. Failure of membrane integrity3. Altered metabolic pathways4. DNA damage5. Deficiency of essential metabolites6. Free radical generation

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Mechanisms of injuryMechanisms of injury1. Mechanical disruption – Trauma2.2. Failure of membrane integrityFailure of membrane integrity3. Altered metabolic pathways4. DNA damage5. Deficiency of essential metabolites6. Free radical generation

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Mechanisms of injuryMechanisms of injuryFailure of membrane integrityFailure of membrane integrity• Compliment mediated cell lysis• Altered ion pumps & channels• Altered membrane lipids• Cross-linking membrane proteins• Altered calcium homeostsis• Lysosomal release

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Mechanisms of injuryMechanisms of injury1. Mechanical disruption – Trauma2. Failure of membrane integrity3.3. Altered metabolic pathwaysAltered metabolic pathways4. DNA damage5. Deficiency of essential metabolites6. Free radical generation

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Mechanisms of injuryMechanisms of injuryAltered metabolic pathwaysAltered metabolic pathways• Cell respiration• Decreased protein systhesis• Depletion of ATP & active

transport system

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Mechanisms of injuryMechanisms of injury1. Mechanical disruption – Trauma2. Failure of membrane integrity3. Altered metabolic pathways4.4. DNA damageDNA damage5. Deficiency of essential metabolites6. Free radical generation

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Mechanisms of injuryMechanisms of injuryDNA damage / lossDNA damage / loss• Immediate consequences• Delayed consequences

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Mechanisms of injuryMechanisms of injury1. Mechanical disruption – Trauma2. Failure of membrane integrity3. Altered metabolic pathways4. DNA damage5.5. Deficiency of essential metabolitesDeficiency of essential metabolites6. Free radical generation

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Mechanisms of injuryMechanisms of injuryDeficiency of essential metabolitesDeficiency of essential metabolites• Oxygen depletion (Link)• Glucose depletion• Hormone deficiency

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Mechanisms of injuryMechanisms of injury1. Mechanical disruption – Trauma2. Failure of membrane integrity3. Altered metabolic pathways4. DNA damage5. Deficiency of essential metabolites6.6. Free radical generationFree radical generation

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Mechanisms of injuryMechanisms of injuryFree radical generation Free radical generation [link]Damaged lipids, proteins, DNA et.c.

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Mechanisms of injuryMechanisms of injury1. Mechanical disruption – Trauma2. Failure of membrane integrity3. Altered metabolic pathways4.4. DNA damageDNA damage5. Deficiency of essential metabolites6. Free radical generation

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