CELL INJURYCELL DEATH

CELL ADAPTATIONS

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

M081 HLRI

247-7469

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.

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 of effects.

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.

CAUSES OF CELL INJURY -THE PATIENT’S VIEW

• Hypoxia

• Infectious agents

• Physical injury

• Chemicals/drugs

• Immune response

• Genetic derangement

• Nutritional imbalance

HYPOXIC INJURY

Cerebral infarction Myocardial infarction

Renal atrophy

INFECTIOUS DISEASE

Primary HerpesCandidiasis

Tuberculosis Actinomycosis

PHYSICAL INJURY

Thermal Burn Traumatic ulcer

CHEMICAL/DRUG INJURY

GingivalHyperplasia

Asprin Burn

IMMUNE RESPONSE

Cinnamon ReactionHemodent Reaction

GENETIC DERANGEMENTS

Down's Syndrome

Ehlers-Danlos

Cancer

NUTRITIONAL IMBALANCE

Diabetes

Scurvy

• Cell injury results from a disruption of one or more of the cellular components that maintain cell viability.

CONCEPTS IN CELL INJURY

• Divergent factors can act at the same point on the cell to induce cell injury.

CELL INJURY - THE CELL’S PERSPECTIVE

CONCEPTS IN CELL INJURY

• Injury at one point induces a cascade of effects.

• The clinical signs and symptoms are several steps 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.

MECHANISMS OF CELL INJURY

• Hypoxia / Ischemia Model

• Generation of Reactive Oxygen Species

• Increased Cytoplasmic Ca++

HYPOXIA - ISCHEMIA MODEL

Blood Clot

O2

Oxidative Phosphorylation

ATP

Impaired function of the plasma membrane

ATP-dependentNa+ pump

Glycolysis

Detachment ofribosomes

HYPOXIA - ISCHEMIA MODEL

Impaired function of the plasma membrane

ATP-dependentNa+ pump

Na+ influxCa++ influxK+ efflux

H2O influx

Cellular swellingMembrane blebs and loss of villiER swelling

HYPOXIA - ISCHEMIA MODEL

Detachmentof ribosomes

Glycolysis pH

GlycogenStores

ProteinSynthesis

LipidDeposition

ChromatinClumping

REACTIVE OXYGEN SPECIESO2

SOD

H20

CATALASE

CELL INJURY

O2ER-P450Oxidases

CytoplasmicNADPHoxidases

H2O2

PeroxisomesOxidases

REACTIVE OXYGEN SPECIES

02

Fe+2 Fe+3SODO2 H2O2 OH + OH

2GSHGlutathione GlutathionePeroxidase Reductase GSSH

H20

CELL INJURY

ROS - CELL INJURY

• Lipid Peroxidation

• Protein Fragmentation

• Single Strand Breaks in DNA

SHSH

-S-CH3

Lipid

Phospholipid

Lipid

Membrane proteins

S--S

HOO

HOO

OHOOH

HO

OH

HO

OH

HOHO OH

Lipid peroxidation

Autocatalytic, OH attacks double bonds in unsaturated fatty acids in cell membranes.

Protein strand excisions

Disulfide linkage

Protein changes alters enzyme activity.

ROS CONTROL•Antioxidants - 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

Ca++ INDUCED CELL INJURY

Ca++Ca++ Ca++

Cytoplasmic ionic Ca++

ATPase Phospholipase Protease Endonuclease

ATP Phospholipids Protein DNA

Disruption Damage

OTHER CAUSES OF CELL MEMBRANE INJURY

• Complement - C5-C9 MAC

• Cytotoxic T Cells - perforin

• Virus

• Bacterial Endotoxins and Exotoxins

• Drugs

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 of effects.

OUTCOMES OF CELL INJURY

REVERSIBLE CELL DEATH CELLADAPTATIONS

NORMAL CELL

CELL INJURY / CELL STRESS

ACUTE CHRONIC

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 increased intracellular Na+ that leads to an isosmotic gain in water and cell swelling.

REVERSIBLE CELL INJURYIschemic injury to the kidney.

Pale kidney Hydropic change

CONCEPTS - CELL DEATH

• There is no signal biochemical event that equates with cell death.

• Necrosis = “cell murder”

• Apoptosis = “programmed cell death or cell suicide”

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

12 24 36 48 60 72Hours After Acute MI

Myoglobin

CK/CK-MB

LD/LD1

cTnI

cTnT

168

Mu

ltip

les

of

UR

L

5

10

15

20

RELEASE OF CELL PROTEINS FOLLOWING CELL DEATH

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.

COAGULATIVE NECROSIS

• Cell outline

• Pink cytoplasm

• Anucleated cells

COAGULATIVE NECROSIS

COAGULATIVE NECROSIS

NOT ALL CELLS DIE

LIQUIFACTIVE NECROSISAbscess

CASEOUS NECROSIS

Tuberculosis

FAT NECROSIS

DEATH IS GOOD FOR YOU

2230 CELLS

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

APOPTOSIS AND DISEASE

• Too Much Apoptosis

toxin induced liver injury

AIDS

ischemia

neurodegenrative diseases

myelodysplasia

APOPTOSIS AND DISEASE

• Inhibition of Apoptosis

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

cancer - e.g. follicular lymphoma, andcarcinomas of the breast, prostate and ovaries

autoimmune diseases - SLE

MORPHOLOGY OF APOPTOSIS

Progressive cell shrinkageChromatin condensation

Plasma membrane blebbingApoptotic bodiesPhagocytosis - no inflammation

MECHANISMS OF APOPTOSIS

NECROSIS VS. APOPTOSIS

NECROSIS APOPTOSIS

Stimuli Pathologic PhysiologicPathologic

Morphology Multiple cellsCell swellingCell lysis

Single cellCell shrinkageChromatinCondensationApoptotic bodies

Host response Inflammation No inflammation

CONCEPTS IN CHRONIC CELL INJURY

• Cells undergo adaptive changes due to persistent (chronic) stress.

• Morphologic changes seldom reflect the type of persistent (chronic) stress.

• Similar responses at the cell level can produce different morphologic changes in different organs.

CAUSES OF CHRONIC CELL INJURY

•Ischemia, hormones, infections, chemicals/drugs, trauma, etc.

•Strength of the insult may be minimal.

•Duration of stress is prolonged as compared to acute cell injury.

CELLULAR ADAPTATIONS

• Alterations in cell size

• Alterations in cell number

• Alterations in cell differentiation

• Abnormal intracellular accumulations

Decrease in cell size and function with concurrent

decrease in organ size and/or function.

ATROPHY

ATROPHY & ISCHEMIA

Renal atrophy Testicular atrophy

ATROPHY & DECREASED FUNCTIONAL DEMAND

ATROPHY & MALNUTRITION

ATROPHY & DECREASED TROPHIC SIGNALS

Normal Endometrium Atrophic Endometrium

ATROPHY & CHRONIC INFLAMMATION

Celiac SprueNormal Jejunum

ATROPHY & AGING

Normal Brain Atrophic Brain

Increase in cell size and function with concurrent

increase in organ size and/or function.

HYPERTROPHY

HYPERTROPHY & TROPHIC SIGNALS

Normal lactationNormal TDLU

HYPERTROPHY & TROPHIC SIGNALS

Cushing syndromeDiffuse goiter

HYPERTROPHY INCREASED FUNCTIONAL DEMAND

HYPERTROPHY & INCREASED FUNCTIONAL DEMAND

A

A

A = Normal heart

B

B

B = Hypertensive heart

C

C

C = Dilated heart

Increase in cell number with concurrent increase in organ

size and/or function.

HYPERPLASIA

Proliferative endometrium

HYPERPLASIA &TROPHIC SIGNALS

Secretory endometrium

Simple hyperplasia

HYPERPLASIA & PERSISTENT STRESS

Traumatic Keratosis

Alteration in cell differentiation with concurrent alteration of

tissue/organ function.

METAPLASIA

METAPLASIA

Barrett's Esophagus

Squamous metaplasia

METAPLASIA

Respiratory mucosa

METAPLASIA

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

CELLULAR ACCUMULATIONS

• Normal constituents - H20, lipids,

proteins, carbohydrate

• Calcium

• Abnormal substances- endogenous or exogenous

• Pigments

MECHANISMS OF INTRACELULAR ACCUMULATIONS

TRIGLYCERIDE ACCUMULATIONSTEATOSIS (FATTY LIVER)

Normal Liver

Fatty Liver Oil Red O Stain

CHOLESTEROL ACCUMULATIONS

CholesterolosisXanthoma

CHOLESTEROL IN VESSELS

Atherosclerosis Cholesterol thrombus

PROTEIN ACCUMULATION

1- Anti-trypsin deficiency

Mallory bodies

Alzheimer's disease

CARBOHYDRATES

Glycogen StorageDisease

Diabetes andGlycosylation

Neiman-Pick's Disease

Gaucher Disease

LYSOSOMAL STOREAGE DISEASE

EXOGENOUS CARBON PIGMENT

Anthracosis

Pneumoconiosis

EXOGENOUS PIGMENTS

Tattooing

ENDOGENOUS PIGMENTS

Lipofuscin

Melanotic-macule

ENDOGENOUS PIGMENTSHemosiderin

Hemosiderosis

Ictericsclera

Hyperbilirubinemia

Liver- bile plugs