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CELL INJURY

CELL DEATH

CELL ADAPTATIONS

Charles L. Hitchcock M.D.,Ph.D.

M081 HLRI247-7469

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CONCEPTS IN CELL INJURY

Cell injury results from a disruption of one

or more of the cellular components that

maintain cell viability.

The clinical signs and symptoms are several

steps removed from the biochemical changes

associated with cell injury.

Cell injury is common to all pathologic

processes.

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CONCEPTS IN CELL INJURY

Cell injury may be reversible, result in cell

adaptation, or lead to cell death. Biochemical alterations occur prior to morphologic changes.

The result of cell injury is determined, in part, by the intensity,

duration and/or the number of exposures to an etiologic agent.

The result of cell injury is determined, in part, by the cell

type and its physiologic state.

Injury at one point induces a cascade ofeffects.

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CONCEPTS IN CELL INJURY

The clinical signs and symptoms are several

steps removed from the biochemical changes

associated with cell injury.

Cell injury is common to all pathologic

processes.

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CAUSES OF CELL INJURY -

THE PATIENTS VIEW

Hypoxia Infectious agents

Physical injury Chemicals/drugs

Immune response

Genetic derangement

Nutritional imbalance

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HYPOXIC INJURY

Cerebral infarction Myocardial infarction

Renal atrophy

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INFECTIOUS DISEASE

Primary Herpes

Candidiasis

Tuberculosis Actinomycosis

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PHYSICAL INJURY

Thermal Burn Traumatic ulcer

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CHEMICAL/DRUG INJURY

Gingival

HyperplasiaAsprin Burn

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IMMUNE RESPONSE

Cinnamon ReactionHemodent Reaction

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GENETIC DERANGEMENTS

Down's SyndromeEhlers-Danlos

Cancer

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NUTRITIONAL IMBALANCE

Diabetes

Scurvy

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Cell injury results from a disruption

of one or more of the cellular

components that maintain cellviability.

CONCEPTS IN CELL INJURY

Divergent factors can act at the same

point on the cell to induce cell injury.

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CELL INJURY - THE CELLS

PERSPECTIVE

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CONCEPTS IN CELL INJURY

Injury at one point induces a cascade

of effects.

The clinical signs and symptoms are severalsteps removed from the biochemical changes

associated with cell injury.

Cell injury results from a disruption of one

or more of the cellular components that

maintain cell viability.

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MECHANISMS OF CELL

INJURY

Hypoxia / Ischemia Model

Generation of Reactive Oxygen

Species

Increased Cytoplasmic Ca++

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HYPOXIA - ISCHEMIA MODELBlood Clot

O2

Oxidative

Phosphorylation ATP

Impaired function of the

plasma membrane

ATP-dependent

Na+ pump Glycolysis

Detachment of

ribosomes

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HYPOXIA - ISCHEMIA MODELImpaired function of the

plasma membrane

ATP-dependent

Na+ pumpNa+ influxCa++ influxK+ efflux H2O influx

Cellular swelling

Membrane blebs

and loss of villi

ER swelling

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HYPOXIA - ISCHEMIA MODELDetachment

of ribosomes Glycolysis pH

GlycogenStores

ProteinSynthesis

Lipid

Deposition

ChromatinClumping

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REACTIVE OXYGEN

SPECIESO2

SOD

H20CATALASE

CELL INJURY

O2ER-P450

OxidasesCytoplasmic

NADPH

oxidases

H2O2

Peroxisomes

Oxidases

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REACTIVE OXYGEN

SPECIES02Fe+2 Fe+3

SOD

O2 H2O2 OH + OH

2GSH

Glutathione Glutathione

Peroxidase Reductase

GSSH

H20CELL INJURY

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ROS - CELL INJURY Lipid Peroxidation

Protein Fragmentation

Single Strand Breaks in DNA

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SHSH

-S-CH3

LipidPhospholipid

Lipid

Membrane proteinsS--S

HOOHOO

OHOOH HO

OHHO

OHHO HO

OH

Lipid peroxidationAutocatalytic, OH attacks double bonds inunsaturated fatty acids in cell membranes.

Protein strandexcisionsDisulfide linkage

Protein changes alters enzyme activity.

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ROS CONTROLAntioxidants - Vitamins E, C and A,glutathione, cysteine

Serum proteins that reduce the iron

(transferrin, ferritin) and copper

(ceruloplasmin) needed to catalyze

the formation of ROS.

Enzymes catalase, SOD and

glutathione peroxidase

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Ca++ INDUCED CELL INJURYCa++

Ca++ Ca++Cytoplasmic ionic Ca++

ATPase Phospholipase Protease Endonuclease

ATP Phospholipids Protein DNADisruption Damage

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OTHER CAUSES OF CELL

MEMBRANE INJURY Complement - C5-C9 MAC

Cytotoxic T Cells - perforin Virus

Bacterial Endotoxins and Exotoxins

Drugs

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CONCEPTS IN CELL INJURY

Cell injury may be reversible, result in a cell

adaptation, or lead to cell death. Biochemical alterations occur prior to morphologic changes.

The result of cell injury is determined, in part, by the intensity,

duration and/or the number of exposures to an etiologic agent.

The result of cell injury is determined, in part, by the cell

type and its physiologic state.

Injury at one point induces a cascade ofeffects.

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OUTCOMES OF CELL INJURY

REVERSIBLE CELL DEATH CELLADAPTATIONS

NORMAL CELL

CELL INJURY / CELL STRESSACUTE CHRONIC

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REVERSIBLE CELL INJURY Oftentimes is an acute process.

Cell injury of short duration and minimal

intensity.

Causes include: ischemia, exposure to

toxins, infectious agents, and thermal injury.

Plasma membrane injury leads to increasedintracellular Na+ that leads to an isosmotic

gain in water and cell swelling.

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REVERSIBLE CELL INJURYIschemic injury to the kidney.

Pale kidney Hydropic change

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CONCEPTS - CELL DEATH

There is no signal biochemical event that

equates with cell death. Necrosis = cell murderApoptosis = programmed cell death orcell suicide

Cell death occurs when the strength ofthe insult cannot be compensated for.

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12 24 36 48 60 72Hours After Acute MI

MyoglobinCK/CK-MB

LD/LD1

cTnIcTnT

168MultiplesofURL

5101520

RELEASE OF CELL PROTEINS

FOLLOWING CELL DEATH

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NECROSIS Morphologic types of necrosis

Coagulative

Liquifactive

Caseous Enzymatic (fat)

The type of necrosis is dependent upon

patterns of enzymatic degradation of cells

and extracellular matrix, the type of

necrotic debris, and by bacterial products

when present.

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COAGULATIVE NECROSIS Cell outline

Pink cytoplasm

Anucleated cells

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COAGULATIVE NECROSIS

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COAGULATIVE NECROSIS

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NOT ALL CELLS DIE

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LIQUIFACTIVE NECROSISAbscess

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CASEOUS NECROSIS

Tuberculosis

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FAT NECROSIS

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DEATH IS GOOD FOR YOU2230CELLS

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APOPTOSIS

MAINTAINS HOMEOSTASIS

Embryogenesis

Normal cell turnover

cells with short half-life tissue involution due to loss of growth

factor stimulation

Immune function Elimination of autoreactive T cells NK and CTL killing

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APOPTOSIS AND DISEASE Too Much Apoptosis

toxin induced liver injury

AIDS

ischemia

neurodegenrative diseases

myelodysplasia

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APOPTOSIS AND DISEASE Inhibition of Apoptosis

various viral diseases - e.g. Herpes,poxvirus, and adenovirus

cancer - e.g. follicular lymphoma, and

carcinomas of the breast, prostate andovaries

autoimmune diseases - SLE

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MORPHOLOGY OF APOPTOSIS

Progressive cell shrinkage

Chromatin condensation

Plasma membrane blebbing

Apoptotic bodies

Phagocytosis - no inflammation

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MECHANISMS OF APOPTOSIS

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NECROSIS VS. APOPTOSISNECROSIS APOPTOSIS

Stimuli Pathologic PhysiologicPathologic

Morphology Multiple cellsCell swellingCell lysis

Single cellCell shrinkageChromatinCondensationApoptotic bodies

Host response Inflammation No inflammation

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CONCEPTS IN CHRONIC

CELL INJURY Cells undergo adaptive changes due to

persistent (chronic) stress.

Morphologic changes seldom reflect thetype of persistent (chronic) stress.

Similar responses at the cell level can

produce different morphologic changesin different organs.

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CAUSES OF

CHRONIC CELL INJURYIschemia, hormones, infections,

chemicals/drugs, trauma, etc.

Strength of the insult may be minimal.

Duration of stress is prolonged

as compared to acute cell injury.

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CELLULAR ADAPTATIONS Alterations in cell size

Alterations in cell number

Alterations in cell differentiation

Abnormal intracellular accumulations

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Decrease in cell size and

function with concurrent

decrease in organ size and/orfunction.

ATROPHY

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ATROPHY & ISCHEMIA

Renal atrophy Testicular atrophy

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ATROPHY & DECREASED

FUNCTIONAL DEMAND

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ATROPHY & MALNUTRITION

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ATROPHY & DECREASED

TROPHIC SIGNALSNormal Endometrium Atrophic Endometrium

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ATROPHY & CHRONIC

INFLAMMATION

Celiac SprueNormal Jejunum

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ATROPHY & AGINGNormal Brain Atrophic Brain

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Increase in cell size and

function with concurrentincrease in organ size and/or

function.

HYPERTROPHY

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HYPERTROPHY & TROPHIC

SIGNALSNormal lactationNormal TDLU

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HYPERTROPHY & TROPHIC

SIGNALS

Cushing syndromeDiffuse goiter

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HYPERTROPHY INCREASED

FUNCTIONAL DEMAND

HYPERTROPHY & INCREASED

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HYPERTROPHY & INCREASED

FUNCTIONAL DEMANDA

A

A = Normal heart

B

BB = Hypertensive heart

C

C

C = Dilated heart

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Increase in cell number with

concurrent increase in organsize and/or function.

HYPERPLASIA

HYPERPLASIA &TROPHIC

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Proliferative endometrium

HYPERPLASIA &TROPHIC

SIGNALSSecretory endometrium

Simple hyperplasia

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HYPERPLASIA & PERSISTENT

STRESS

Traumatic Keratosis

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Alteration in cell differentiationwith concurrent alteration of

tissue/organ function.

METAPLASIA

METAPLASIA

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METAPLASIA

Barrett's Esophagus

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Squamous metaplasia

METAPLASIA

Respiratory mucosa

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METAPLASIA

Necrotizing sialometaplasiaRef: http://www.uiowa.edu/~oprm/AtlasWIN/AtlasFrame.

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CELLULAR ACCUMULATIONS Normal constituents - H20, lipids,

proteins, carbohydrate

Calcium

Abnormal substances- endogenousor exogenous

Pigments

MECHANISMS OF INTRACE U AR

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MECHANISMS OF INTRACELULAR

ACCUMULATIONS

TRIGLYCERIDE ACCUMULATION

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TRIGLYCERIDE ACCUMULATION

STEATOSIS (FATTY LIVER)

Normal Liver

Fatty Liver Oil Red O Stain

CHOLESTEROL ACCUMULATIONS

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CHOLESTEROL ACCUMULATIONS

CholesterolosisXanthoma

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CHOLESTEROL IN VESSELS

Atherosclerosis Cholesterol thrombus

PROTEIN ACCUMULATION

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PROTEIN ACCUMULATION

1- Anti-trypsindeficiency

Mallory bodies

Alzheimer's disease

CARBOHYDRATES

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CARBOHYDRATES

Glycogen Storage

Disease

Diabetes and

Glycosylation

LYSOSOMAL STOREAGE

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Neiman-Pick's DiseaseGaucher Disease

LYSOSOMAL STOREAGE

DISEASE

EXOGENOUS CARBON PIGMENT

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EXOGENOUS CARBON PIGMENT

AnthracosisPneumoconiosis

EXOGENOUS PIGMENTS

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EXOGENOUS PIGMENTSTattooing

ENDOGENOUS PIGMENTS

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ENDOGENOUS PIGMENTS

Lipofuscin

Melanotic-macule

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ENDOGENOUS PIGMENTSHemosiderin

H id i

Icteric

scleraHyperbilirubinemia