CELL INJURY CELL DEATH CELL ADAPTATIONS

Charles L. Hitchcock M.D.,Ph.D. M081 HLRI 247-7469

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

CONCEPTS IN CELL INJURY

Injury at one point induces a cascade of effects.

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.

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 PATIENTS VIEW

Hypoxia Infectious agents Physical injury Chemicals/drugs Immune response

Genetic derangement

Nutritional imbalance

HYPOXIC INJURY

Cerebral infarction

Myocardial infarction

Renal atrophy

INFECTIOUS DISEASE

Tuberculosis

Actinomycosis

Candidiasis

Primary Herpes

PHYSICAL INJURY

Thermal Burn

Traumatic ulcer

CHEMICAL/DRUG INJURY

Gingival Hyperplasia

Asprin Burn

IMMUNE RESPONSE

Hemodent Reaction

Cinnamon Reaction

GENETIC DERANGEMENTS

Cancer

Down's Syndrome Ehlers-Danlos

NUTRITIONAL IMBALANCE

Scurvy

Diabetes

CONCEPTS IN CELL INJURY

Cell injury results from a disruption

of one or more of the cellular components that maintain cell viability.

Divergent factors can act at the same

point on the cell to induce cell injury.

CELL INJURY - THE CELLS PERSPECTIVE

CONCEPTS IN CELL INJURY

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.

Injury at one point induces a cascade

of effects.

MECHANISMS OF CELL INJURY

Hypoxia / Ischemia Model Generation of Reactive Oxygen

Species

Increased Cytoplasmic Ca++

HYPOXIA - ISCHEMIA MODEL

Blood Clot

O2
Oxidative ATP Phosphorylation

Impaired function of the plasma membrane ATP-dependent Na+ pump Glycolysis Detachment of ribosomes

HYPOXIA - ISCHEMIA MODEL

Impaired function of the plasma membrane ATP-dependent Na+ pump

Na+ influx Ca++ influx K+ efflux

H2O influx

Cellular swelling Membrane blebs and loss of villi ER swelling

HYPOXIA - ISCHEMIA MODEL

Glycolysis
Detachment of ribosomes Protein Synthesis Lipid Deposition pH Chromatin Clumping Glycogen Stores

O2

REACTIVE OXYGEN SPECIES

Peroxisomes Oxidases

ER-P450 Oxidases Cytoplasmic NADPH oxidases

O2

SOD

H 2 O2
CATALASE

H 20

CELL INJURY

REACTIVE OXYGEN SPECIES

02

O2

SOD

Fe+2

Fe+3

H 2 O2
2GSH Glutathione Peroxidase Glutathione Reductase

OH + OH

GSSH

H 20

CELL INJURY

ROS - CELL INJURY

Lipid Peroxidation Protein Fragmentation Single Strand Breaks in DNA

Protein changes alters enzyme activity. Protein strand Disulfide linkage Membrane proteins excisions
SH SH

S--S
HOO HOO OH OOH OH HO HO

Lipid

Phospholipid
OH

OH
HO

HO

Lipid
-S-CH3

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

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 ATP Phospholipase Protease Endonuclease

Phospholipids Protein Disruption

DNA 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

Injury at one point induces a cascade of effects.

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.

OUTCOMES OF CELL INJURY

CELL INJURY / CELL STRESS
ACUTE CHRONIC

REVERSIBLE

CELL DEATH

CELL ADAPTATIONS

NORMAL CELL

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 INJURY

Ischemic injury to the kidney.

Pale kidney

Hydropic change

CONCEPTS - CELL DEATH

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

There is no signal biochemical event that

equates with cell death.

Necrosis = cell murder Apoptosis = programmed cell death or

cell suicide

RELEASE OF CELL PROTEINS FOLLOWING CELL DEATH

Multiples of URL
cTnT
20

cTnI
15 10 5

CK/CK-MB

LD/LD1
Myoglobin 12 24 36 48 60 72 168

Hours After Acute MI

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 NECROSIS
Abscess

CASEOUS NECROSIS

Tuberculosis

FAT NECROSIS

DEATH IS GOOD FOR YOU

2230 CELLS

APOPTOSIS
Normal cell turnover cells with short half-life

MAINTAINS HOMEOSTASIS
tissue involution due to loss of growth factor stimulation

Embryogenesis Immune function

Elimination of autoreactive T cells NK and CTL killing

APOPTOSIS AND DISEASE

Too Much Apoptosis

AIDS ischemia neurodegenrative diseases myelodysplasia toxin induced liver injury

APOPTOSIS AND DISEASE

Inhibition of Apoptosis
cancer - e.g. follicular lymphoma, and carcinomas of the breast, prostate and ovaries autoimmune diseases - SLE various viral diseases - e.g. Herpes, poxvirus, and adenovirus

MORPHOLOGY OF APOPTOSIS

Chromatin condensation Progressive cell shrinkage Plasma membrane blebbing Apoptotic bodies Phagocytosis - no inflammation

MECHANISMS OF APOPTOSIS

NECROSIS VS. APOPTOSIS

NECROSIS Stimuli Morphology Pathologic Multiple cells Cell swelling Cell lysis APOPTOSIS Physiologic Pathologic Single cell Cell shrinkage Chromatin Condensation Apoptotic bodies No inflammation

Host response 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

ATROPHY
Decrease in cell size and function with concurrent decrease in organ size and/or function.

ATROPHY & ISCHEMIA

Renal atrophy

Testicular atrophy

ATROPHY & DECREASED FUNCTIONAL DEMAND

ATROPHY & MALNUTRITION

ATROPHY & DECREASED TROPHIC SIGNALS

Normal Endometrium Atrophic Endometrium

ATROPHY & CHRONIC INFLAMMATION

Normal Jejunum

Celiac Sprue

ATROPHY & AGING

Normal Brain
Atrophic Brain

HYPERTROPHY
Increase in cell size and function with concurrent increase in organ size and/or function.

HYPERTROPHY & TROPHIC SIGNALS

Normal TDLU
Normal lactation

HYPERTROPHY & TROPHIC SIGNALS

Diffuse goiter

Cushing syndrome

HYPERTROPHY INCREASED FUNCTIONAL DEMAND

HYPERTROPHY & INCREASED FUNCTIONAL DEMAND

B A C

A B A = Normal heart C

B = Hypertensive heart

C = Dilated heart

HYPERPLASIA
Increase in cell number with concurrent increase in organ size and/or function.

HYPERPLASIA &TROPHIC SIGNALS

Proliferative endometrium Secretory endometrium

Simple hyperplasia

HYPERPLASIA & PERSISTENT STRESS

Traumatic Keratosis

METAPLASIA
Alteration in cell differentiation with concurrent alteration of tissue/organ function.

METAPLASIA

Barrett's Esophagus

METAPLASIA

Respiratory mucosa

Squamous metaplasia

METAPLASIA

Necrotizing sialometaplasia

Ref: http://www.uiowa.edu/~oprm/AtlasWIN/AtlasFrame.h

CELLULAR ACCUMULATIONS Normal constituents - H20, lipids,

proteins, carbohydrate

Abnormal substances- endogenous Calcium

or exogenous Pigments

MECHANISMS OF INTRACELULAR ACCUMULATIONS

TRIGLYCERIDE ACCUMULATION STEATOSIS (FATTY LIVER)

Normal Liver

Fatty Liver

Oil Red O Stain

CHOLESTEROL ACCUMULATIONS

Xanthoma

Cholesterolosis

CHOLESTEROL IN VESSELS

Atherosclerosis

Cholesterol thrombus

PROTEIN ACCUMULATION

Mallory bodies
1- Anti-trypsin deficiency

Alzheimer's disease

CARBOHYDRATES

Diabetes and Glycosylation

Glycogen Storage Disease

LYSOSOMAL STOREAGE DISEASE

Neiman-Pick's Disease

Gaucher Disease

EXOGENOUS CARBON PIGMENT

Anthracosis Pneumoconiosis

EXOGENOUS PIGMENTS
Tattooing

ENDOGENOUS PIGMENTS
Lipofuscin

Melanotic-macule

ENDOGENOUS PIGMENTS
Hemosiderin
Hyperbilirubinemia
Icteric sclera

Hemosiderosis

Liver- bile plugs