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