CELLULAR RESPONSES TO STRESS AND TOXIC INSULTS (1)

1) Pathology
a) Study of Disease the structural, biochemical and functional changes (cells/tissues/organs
that underlie disease)
2) Four Aspects of disease process
a) Cause (etiology)
i) Two Major Classes
(1) Genetic : Inherited Mutations / Disease Associated Gene Variants
(2) Acquired : Infectious / Nutritional / Chemical / Physical
b) Mechanism of development (pathogenesis)
i) Response of cells/tissues to etiological agent (stimulus expression of disease)
c) Biochemical/Structural Alterations (Molecular/Morphological Changes)
i) Characteristic of a disease, diagnostic of etiological process
d) Function Consequences of the Changes (Clinical Manifestations)
i) Functional abnormalities
(1) End result in changes to cells/tissues
(2) Symptoms and Signs
(3) Lead to the progression of disease (clinical course/outcome)
ii) Disease
(1) Molecular/Structural alteration of disease
(2) Leads to injury to cell/extracellular matrix (determine morphological/clinical patterns
of disease)
3) Normal Cell
a) Narrow range of function/structure (State of
metabolism, differentiation, specialization)
i) Constraints of neighboring cells
ii) Availability of metabolic substrates
b) Maintains homeostasis
4) Cell Injury
a) Due To
i) Injurious agent / Stress
ii) Deprivation of Essential Nutrients
iii) Mutations that affect essential cellular
constituents
b) Reversible to a certain point
c) Irreversible Injury (Stimulus persists) Cell
Death
5) Cell Death
a) End result (progressive cell injury)

b) Crucial event in evolution of

disease
c) Results From
i) Ischemia / Infection / Toxin
d) Normal/Essential
i) Embryogenesis /
Maintenance of Homeostasis
e) Principal Pathways
i) Necrosis / Apoptosis

6) Stress / Injury to the Cell

a) Adaptations (Cell adapts due to the stress or injury inflicted on it, if the cell cant adapt
Injured)
i) Reversible functional/structural responses
ii) Types
(1) Hypertrophy (Increase in SIZE of cells)
(a) General
(i) Results in increased organ size
(ii) NO new cells Just larger
(iii)Due To: Synthesis of structural components of cell (cell proteins)
(b) Cause
(i) Physiological or Pathological
1. Increased functional demand
2. Stimulation by hormones/growth factors
(c) Example: Striated Muscle Cells (Heart/Skeletal)
(i) Limited division
(ii) Response to increased metabolic demand = HYPERTROPHY
(iii)Most common stimulus Increased workload (body builders) increased size of
muscle fibers
(d) Example : Uterus
(i) Image of Uterus which has never given
birth vs. uterus that has given birth
(and the histological differences)
(e) Example: Barbiturates
(i) Hypertrophy USUALLY refers to size
of cells/tissues, can refer to subcellular organells
(ii) Barbiturates
1. Hypertrophy of sER in Hepatocytes
a. Adaptive Response, Increase enzymes available for detoxification of
drugs
b. Patients eventually respond less to drugs
c. May result in increased capacity to metabolize other drugs
(f) Mechanisms
(i) Induced by linked action

1. Mechanical Sensors / Growth Factors /

Vasoactive Agents
(g) Biochemical Pathways
(i) (Physiological) Phosphoinositide 3-kinase/AKt
Pathway
(ii) (Pathological) Signaling downstream of Gprotein coupled receptors
(2) Hyperplasia (Increase in NUMBER of cells)
(a) General
(i) Increased Mass of Organ/Tissue
(ii) May occur along with hypertrophy
(iii)May lead to cancer (doesnt have to)
(b) Physiological Hyperplasia
(i) Hormonal hyperplasia (increases functional capacity of tissue when needed)
1. Ex: Female Breast in Puberty (Proliferation of glandular epilthelium
puberty/pregnancy)
(ii) Compensatory hyperplasia (Increases tissue mass after damage/resection)
1. Ex: Liver Transplant
(c) Pathological Hyperplasia
(i) Caused by excess of hormones/growth factor acting on target cells
(ii) Ex: Endometrial hyperplasia
1. Abnormal hormone induced hyperplasia, common cause of abnormal
menstrual bleeding
2. Nothing to oppose estrogen
(iii)Ex: Benign Prostatic Hyperplasia
1. Induced by androgens (fertile soil for cancer to arise)
(3) Atrophy (Decrease in SIZE/METABOLIC ACTIVITY of cells)
(a) General
(i) Reduced size of organ/tissue
(b) Physiological Atrophy
(i) Common during development
1. Ex: Embryonic structure (Notochord/Thyroglossal Duct)
2. Ex: Uterus (Decreased size shortly after birth)
(ii) Ex: Uterus (decrease after parturition)
(c) Pathological Atrophy
(i) Depends on underlying cause (local or generalized)
(ii) Common Causes
1. Decreased workload (dis-use) Muscle atrophy secondary to immobilization
2. Loss of innervation (de-nervation atrophy)
3. Diminished Blood Supply
4. Inadequate Nutrition (marasmus) Use skeletal muscle as source of energy
after fat stores are depleted
5. Loss of endocrine stimulation (hormone-responsive tissues Breast and
Reproductive Organs)
6. Pressure Tissue compression
(d) Mechanisms
(i) Result of decreased protein synthesis (reduced metabolic activity)
(ii) Result of increased protein degradation in cells (Ubiquitin-proteasome pathway
Responsible for the accelerated proteolysis (catabolic conditions- cancer
cachexia))

(e) Accompanied by: Increased autophagy (self-eating)

(i) Starved cell eats its own components to survive
(ii) Autophagic Vacuoles
1. Vacuoles ultimately fuse with lysosomes
2. Contents digested by lysosomal enzymes
3. Some cell debris (in vacuoles) resist digestion
persist as membrane-bound residual bodies
a. Ex: Lipofuscin granules (brown atrophy)
(4) Metaplasia (CHANGE in type of cells)- Reversible
(a) One cell type replaced by another cell type
(b) Adaptive substitution of cells (to stress) Cells better able withstand environment
(c) Types
(i) Most Common Epithelial Metaplasia - Columnar Squamous (Respiratory Tract)
a. Chronic Irritation (cigarette smoker) Normal PCEE replaced by stratified
squamous, lack of muco-cilliary elevator
b. Persistant ay initiate malignant transformation in meta-plastic
epithelium
(ii) Squamous Columnar (Barrett esophagus)
1. Esophageal squamous epithelium replaced by intestinal-like columnar cells
2. Caused by Influence of refluxed gastric acid
(iii)Connective Tissue Metaplasia
1. Form cartilage, bone or adipose tissue in tissues
that dont contain those elements
2. **Bone Formation in muscle (myositis
ossificans) can occur following
intramuscular hemorrhage
(d) Mechanisms
(i) Phenotype of already differentiated cell DOES NOT
change (not squamouscolumnar)
(ii) Stem Cells / Undifferentiated MEsenchymal cells (in CT) Different cell type
than others in tissue
(iii)Pre-cursor cells differentiate along a new pathway

CELLULAR RESPONSES TO STRESS AND TOXIC INSULT (2)

1) Causes of Cell Injury
a) Oxygen Deprivation
i) Hypoxia (Deficiency of oxygen)
(1) Reduces aerobic oxidative repiration
(2) Causes:
(a) Reduced Blood Flow (Ischemia)
(b) Inadequate Oxygenation of the Blood (Cardio-respiratory failure)
(c) Decreased oxygen-carrying capacity of the blood (Anemia/CO poisoning/Severe
Blood Loss)
(3) Depending on Severity Cells adapt, undergo injury or die
b) Physical Agents
i) Mechanical Trauma / Extremes of Temp (Burns/Cold) / Change in Atmospheric Pressure /
Radiation / Electric Shock
c) Chemical Agents & Drugs
i) Chemicals / Glucose or Salt in hypertonic conc. / Oxygen at High conc. / Poisons /
Environmental & Air Pollutants / Insecticides & Herbicides / Industrial & Occupational
Hazards / Recreational Drugs / Therapeutic Drugs
d) Infectious Agents

i) Viruses Large Tapeworms / Rickettsiae / Bacteria / Fungi / Higher Forms of Parasites

e) Immunological Reactions
i) Injurious reactions to endogenous self-antigens (several autoimmune diseases)
ii) Immune reactions to external agents (Microbes / Environmental Substances)
f) Genetic Derangements
i) Severe Defects
(1) Congenital Malformations associated w. Down Syndrome (Chromosomal anomaly)
ii) Subtle Defects
(1) Decreased lifespan of RBCs (Single AA substitution in hemoglobin in sickle cell
anemia)
iii) Variations in genetic makeup
(1) Influence susceptibility of cells by chemicals / other
environmental insults
g) Nutritional Imbalances
i) Protein-calorie deficiencies (underprivileged)
ii) Deficiencies of specific vitamins
iii) Self-imposed problems (anorexia)
iv) Nutritional Excess (excess of cholesterol / obesity)
2) Morphological Alterations
a) Reversible Injury
i) Swelling of cell & organelles / Blebbing of Plasma Membrane / Detachment of ribosomes
from ER / Clumping of nuclear chromatin
ii) Associated with
(1) Decreased ATP prod / Lose cell mem Integrity / Defects in protein syn. / Cytoskeletal
damage /DNA damage
iii) Features
(1) Cell Swelling
(a) Failure of energy dep. Ion pumps in plasma membrane
(b) 1st manifestation of almost all forms of injury to a cell
(c) Difficult to appreciate at microscopic level (w. light micro.) Apparent at whole
organ level
(i) Small clear cytoplasmic vacuoles (distended/pinched off ER)
(d) Pallor, increased turgor, and increase in
weight of organ
(2) Fatty Change
(a) Hypoxic Injury / Various Forms of Toxic &
Metabolic Injury / Appearance of lipid
vacuoles in cytoplasm
(b) Ex: Hepatocytes and Myocardial Cells
iv) Ultra-structural changes

(1) Plasma Mem. Blebbing, Blunting, Loss of Microvilli

(2) Mitochondrial Changes Swelling, Small amorphous
densities
(3) Dilation of the ER
(a) Detachment of polysomes / Intra-cytoplasmic myelin
figures
(4) Nuclear alterations Disaggregation of
granular/fibrillar elements
b) Irreversible Cell Injury / Death
i) Continuous damage injury becomes irreversible (cell cant
recover
and dies!)
ii) Two Principle Types of Cell Death
(1) Necrosis
(a) Severe Membrane Damage Lysosomal enzymes
enter cytoplasm and digest cell (Cellular Contents
Leak Out)
(b) ALWAYS PATHOLOGICAL process
(c) Morphological Appearance
(i) Result of denaturation of intracellular proteins, and
enzymatic digestion of lethally injured cell
(ii) Necrotic cells unable to maintain membrane, contents leak
Elicits
inflammation in surrounding tissue
(d) Necrotic Cells
(i) Increased Eosinophilia in H&E stain
1. Loss of cytoplasmic RNA Binds H (blue dye)
2. Denatured cytoplasmic proteins Binds E (red dye)
(ii) Glassy homogenous appearance Loss of glycogen particles
(iii)Digestion of cytoplasmic organelles Vacuolated cytoplasm (moth-eaten)
(iv)
Nuclear Changes of Necrotic Cells
1. Kayolysis Fading of Chromatin, DNA loss bc of enzymatic degradation by
endonucleases
2. Pyknosis Nuclear shrinks, increased color, chromatin condenses into solid
shrunken mass
3. Kayorrhexis Nucleus undergoes fragmentation, nucleus totally disappears
(1-2 days)

(e) Dead Cells

(i) Replaced by large phospholipid masses derived from damaged cell
membranes
(ii) Phospholipid precipitates Phagocytosed by other cells, further degraded into
FAs

(2) Apoptosis
(a) Cells DNA or Proteins damaged beyond repair
(i) Cell kills itself: Nuclear dissolution / Fragmentation of cell WITHOUT complete
loss of membrane integrity
(ii) Rapid removal of cellular debris
(b) Serves normal functions NOT necessarily associated with cell injury
PATTERNS OF TISSUE NECROSIS
Types
Coagulative
Necrosis

General
Associate w.
Ischemia
Architecture of dead
tissue preserved for a
few days

Liquefactive
Necrosis

FOCAL BACTERIAL
INFECTION
(occasionally in
fungal)

Identification
Tissue Firm
Dead Cells persist for
days-weeks
Removed by
phagocytosis
(leukocytes), digestion
by lysosomal enzymes
of leukocytes

Example
Infarct Ischemia
(obstruction) coaqulative
necrosis of supplied tissue

Creamy Yellow purulent

matter (dead
leukocytes)

Infarct in Brain (Dissolution

of Tissue)

Applied to limb (usually

lower leg) Loss of
blood supply (Coag.
Nec.) involves
multiple tissue planes

Add bacterial infection

(liquefactive nec.) Wet
Gangrene

Microscopic collection
of fragmented/lysed
cells, amorphous
granular debris w.
distinctive inflamed
border (granuloma)

Tuberculosis

Digestion of dead cell

Transform tissue to
liquid

Gangrenous
Necrosis

Caseous Necrosis

Hypoxic death of
cells (CNS)
No specific pattern of
cell death

Most often seen in TB

infection
Cheese-like
friable white
appearance in area
of necrosis

Fat Necrosis

Doesnt denote a
specific pattern of
necrosis
Release of activated
pancreatic lipases
into substance of
pancreas / peritoneal
cavity

Microscopic Foci of
shadowy outlines of
necrotic fat cells,
basophilic calcium
deposits, inflammatory
reaction Spongiform
Appearance
White chalky deposits

Fibrinoid Necrosis

Immune Reactions
involving blood
vessels
Complexes of Ag-Abs
deposited in walls of
arteries

(foci of fat necrosis)

Microscopic Bright
pink and amorphous
appearance (Deposits
of immune complexes
and fibrin)

Arteries

3) Mechanisms of Cell Injury

a) Principles of Cell injury
i) Cell Response to Injurious Stimulus
(1) Depends on: Nature of Injury, Duration, and Severity
(2) Small doses of toxin or brief period of ischemia may induce reversible change
(3) Large doses of toxin or prolonged ischemia Instantaneous Cell Death / Slow
irreversible injury cell death
ii) Consequences Depend on type, state, and adaptability of injured cell
iii) Cell injury (result of different biochemical mechanisms)
(1) Act on several essential cellular component (mitochondria, cell membrane, DNA in
nuclei)
iv) Any injurious stimulus May simultaneously trigger multiple connected mechanisms that
damage cells (cant attribute injury to a single or dominant biochemical activity)
b) ATP
i) Production (Two Ways)
(1) Major Oxidative phosphorylation of adenosine diphosphate (reduction of oxygen
ETC in mitochondria)
(2) Minor Glycolytic Pathway (ATP in absence of oxygen uses glucose)
ii) ATP Depletion/Decreased synthesis
(1) Associated w. hypoxia and chemical injury
(2) Major Causes
(a) Reduced oxygen supply and nutrients /
Mitochondrial Damage / Action of toxins (ex: CN)
(3) High-Energy phosphate in form of ATP
(a) Required for all processes in the body
(b) Depletion of ATP to 5-10% of normal levels
WIDESPREAD effect on critical cellular systems
(4) Effects on Cellular Systems
(a) Reduced activity of plasma membrane Na-K
pump
(i) Failure Na enters/accumulate inside cells, K
diffuses out
(ii) Gain of Solute Isoosmotic gain of water (cell
swelling/dilation of ER)
(b) Cellular Metabolism altered
(i) Reduced supply of oxygen to cells (ischemia)
(ii) Oxidative phosphorylation ceases (Decrease in cellular ATP / Increase in
adenosine monophosphate / glycogen stores rapidly depleted)
(c) Failure of Ca pump Influx of Ca (damages intracellular organelles)
(d) Prolonged or Worsening depletion of ATP
(i) Structural disruption of protein synthetic apparatus detachment of ribosomes
from rough ER / Dissociation of polysomes (reduction in protein synthesis)
(e) Oxygen/Glucose deprivation
(i) Protein misfoldinng Trigger cellular reaction (Cell Injury or even Death)
(f) Irreversible damage to mitochondrial and lysosomal membranes Cell Necrosis

c) Mitochondrial Damage
i) General
(1) Cells supplier of energy (ATP) Critical Player in cell injury/death
ii) Damaged by:
(1) Increases cytosolic Ca / Reactive oxygen species / Oxygen
deprivation
(2) Mutations in mitochondrial genes (cause of some inherited diseases)
iii) Formation of a high-conductance channel in mito. membrane
(1) Mito. permeability transition pore Loss of mito. mem. Potential
(Failure of oxidative phosphorylation and progressive depletion of
ATP) NECROSIS of the cell
iv) Sequester proteins between inner and outer membrane
(1) Capable of activating apoptatic pathways
(a) Cytochrome C and Caspases indirectly activate apoptosis inducing enzymes
(b) Increased permeability of outer mito. mem. (leakage of
proteins into cytosol) Death by apoptosis
d) Calcium Homeostasis
i) General
(1) Ca Ions (important mediators of cell injury)
(2) Cytosolic free Ca (maintained at low levels)
(3) Intracellular Ca (Sequestered in mitochondria and ER)
ii) Increased cytosolic Ca Activates enzymes
(1) Proteases Break down membrane and cytoskeletal proteins
(2) Endonucleases Responsible for DNA / Chromatin
fragmentation
(3) ATPases hasten ATP depletion
iii) Increased intracellular Ca levels
(1) Induction of apoptosis (direct activation of capases) increases
mitochondrial permeability
e) Free Radicals
i) General
(1) Chemical species with single unpaired electron in outer orbit
(2) Energy created by unstable configuration
(a) Released through reactions with adjacent molecules (inorganic/organic chemicals,
Lipids, Carbs, Nucleic Acids)
(3) Decay spontaneously
(4) Multiple non-enzymatic/enzymatic mechanisms in cells remove free radicals (minimize
injury)
(5) Iron/Copper catalyze formation of ROS (Min. levels by binding ions to storage/transport
proteins : Transferrin, ferritin, lactoferrin Min. formation of ROS)
(6) Reactive Oxygen Species (ROS)
(a) Oxygen-derived free radical
(b) Produced normally in cells (during respiration/energy generation)
(c) Degraded & removed by cellular defense systems
(d) Produced in large amounts by leukocytes (neutrophils / macrophages)
ii) Generation of Free Radicals
(1) Reduction-Oxidation Reactions occur during normal metabolic processes
(2) Absorption of radiant energy (Ultraviolet light, X-rays, ionizing radiation- hydrolyzes
water into OH and H free radicals)
(3) Rapid bursts of ROS (production in activated leukocytes- inflammation)
(4) Enzymatic metabolism of exogenous chemicals or drugs
(5) Metals (Iron/Copper) donate or accept free electrons during intracellular reactions
(6) Nitric Oxide (Important chemical mediator- acts as free radical) generated by
endothelial cell, macrophages, and neurons
iii) Three Reactions of Free Radicals
(1) Lipid Peroxidation in Membranes (Presence of O2)
(a) Cause peroxidation of lipids within plasma and organelle membranes

(b) Oxidative damage (Initiated when double bond in unsaturated FAs of mem. lipids
are attacked by O2 derived free radicals
(2) Oxidative modification of proteins (Free Radicals promote)
(a) Oxidation of AA side chains / Formation of protein-protein cross-links (disulfide
bond) / Oxidation of protein backbone
(3) Lesions in DNA
(a) Single & Dbl strand breaks in DNA / Cross-linking of DNA Strands / Formation of
adducts
f) Membrane Damage
i) Biochemical Mechanisms:
(1) Reactive oxygen species / Dec. phospholipid synthesis & Inc. breakdown /
Cytoskeletal abnormalities
ii) Important Sites of Membrane Damage during Cell Injury
(1) Mito: Opening mitochondrial permeability pore = dec. ATP / Release of proteins
Apoptotic Death
(2) Plasma Mem: Lose Osmotic Balance/Loss of Cellular Contents/Cells may leak
metabolites even lower ATP
(3) Lysosomal Membrane
(a) Leak Enzymes/Activate acid hydrolases/Activate of enzymes Enzymatic
Digestion/Cells Die (Necrosis)
CELLULAR RESPONSES TO STRESS & TOXIC INSULTS (3)
1) Hypoxia Reduced oxygen availability
2) Ischemia
a) General
i) Supply of oxygen/nutrients decreased (reduced blood flow) obstruction in artery or
reduced venous drain
ii) Compromise delivery of glycolysis substrates (no energy!)
iii) More rapid/severe cell & tissue damage than hypoxia w/o ischemia
iv) No reliable way for reducing injurious consequences of ischemia
b) Ischemic Tissues
i) Aerobic metabolism compromised
ii) Anaerobic energy generation stopped glycolytic sub gone, glycolysis inhibited
(accumulation of metabolites)
c) Mechanisms of Ischemic Cell Injury
i) Sequence of Events
(1) Oxygen tension w.i cell decreases
(a) Lose oxidative phosphorylation
(b) Decreased generation of ATP Failure of Na pump (Loss of K / Influx Na & H20 /
Cell Swelling)
(2) Influx of Ca
(3) Progressive loss of glycogen
(4) Decreased Protein Synthesis
ii) Ex: Heart Muscles (stop contracting w.i 60 seconds of coronary occlusion)
(1) Loss of contraction = NOT CELL DEATH
(2) Continued Hypoxia
(a) ATP depletion Deterioration
(i) Cytoskeleton disperses
1. Loss of Ultra-structural features-microvilli/blebbing
2. Myelin figures (degen. cell mem. seen w.i cytoplasm or extracellularly)
3. Mitochondria swollen (loss of volume control in organelle)
4. ER remains dilated
5. Entire cell markedly swollen (Increased water, Na, Cl / Decreased K)
(b) ***OXYGEN RESTORED REVERSIBLE***
(3) Ischemia persists Irreversible Damage
(a) Severe Swell of Mito / Damage to Plasma Mem. / Swelling Lysosomes / Large
densities in mito matrix
iii) Ex: Myocardium
(1) Irreversible injury 30/40 min after ischemia

(a) Massive Influx of Ca (Ischemic zone)

(b) Death mainly necrosis, also apoptosis(activated -release of pro-apoptotic
molecules from leaky mito)
(c) Leakage of cell enzymes into extracellular space
(d) Dead cells replaced by large masses (myelin figures)
(i) Phagocytosed by leukocytes / Degraded into FAs
d) Treatment(?) None reliable for
i) MOST useful (ischemic brain/spinal cord)
(1) Induction of hypothermia (lower body temp to 92degrees)
(a) Reduce metabolic demands / Decreases Cell Swelling / Inhibit host inflammatory
response
ii) Restoration of Blood Supply to Ischemic Tissues
(1) Promote cell recovery (cells MUST be reversibly injured cant have died
(2) Ischemic-Reperfusion Cell Injury
(a) Reperfusion can contribute to tissue damage (heart/brain inf.) Cells might have
otherwise recovered
(i) Mechanism
1. Reoxygenation (Inc. generation of reactive oxygen/nitrogen species)
2. Cellular antioxidant defense mechanism (compromised by
ischemia/accumulate free radicals)
3. Mediator of cell injury (Ca may re-enter reperfused cells) damage
organelles, increase free radical production
4. Associated w. Inflammation production of cytokines/inflamm. causes
additional tissue injury
5. Activation of complement (involved in host defense Immune Injury)
3) Chemical (Toxic) Injury
a) General
i) Can be caused by drugs (limitation of drug therapy) metabolized in Liver
(1) Liver = frequent site of drug toxicity
(2) Toxic Liver Injury (most frequent reason for stopping a drug)
b) Mechanism
i) Chemicals Induce Cell Injury
(1) Direct Injury
(a) Combine with critical molecular components
(b) Ex: Mercuric Chloride Poisoning
(i) Mercury binds to sulfhydryl group (Cell mem. proteins) Inc. Membrane
permeability/inhibition of ion transport
(ii) Damage to cells that use/absorb/excrete or concentration the chemicals (GI
Tract/Kidneys)
(c) Apoptosis
(i) Induced by suicide program (activate enzymes degrade nuclear DNA /
degrade nuclear, cytoplasmic proteins) **Cell Membrane remains INTACT**
4) Apoptosis
a) General
i) Pathway of Cell Death
ii) Cells destined to die Activate enzymes (degrade nuclear DNA, degrade
nuclear/cytoplasmic proteins)
iii) Cell breaks into apoptotic bodies (fragments) Portion of cytoplasm/nucleus
iv) Plasma membrane remains INTACT (structure altered easy target for macrophages)
v) Dead cells / Fragments Rapidly Devoured (Cell Contents NOT leaked)
vi) Does NOT elicit inflammatory reaction in host
b) Death By Apoptosis
i) Normal eliminate cells no longer needed (maintain steady numbers)
NORMAL CAUSES OF CELL APOPTOSIS
CAUSES

Hormone

Cell loss in

Elimination of

Death of

withdrawal of
Hormonedependent Tissue

EXAMP o Endometrial cell

o
LES
breakdown
o
(menstrual cycle)
o Ovarian follicular
atresia in menopause
o Regression of lactating o
breast after weaning
o Prostatic atrophy after o
castration

proliferating
populations to
maintain
homeostasis

potentially
harmful selfreactive
lymphocytes

host cells
that have
served
purpose

Immature
o Before or after
o Neutrophils in
lymphocytes in BM
maturation prevent
acute
Thymus fails to
autoimmune
inflammatory
express useful Ag
reactions
response
o Lymphocytes at
receptor
B-lymphocytes in
end of
germinal centers
Immune
Epithelial cell in
Response
intestinal crypts

ii) Pathological Apoptosis

(1) Elimination of cells beyond repair (w.o eliciting host reaction minimize collateral
tissue damage)
(a) DNA damage radiation, cytotoxic anticancer drugs, hypoxia Prod. Of Free
Radicals
(b) Accumulation of mis-folded proteins
(i) Mutations in genes encoding them, damage caused by free radicals,
accumulation in ER (ER stress)
(c) Certain Infections (Viral)
(i) Apoptosis induced by the virus Adenovirus/HIV infections
(ii) Host Immune Response Viral Hepatitis
(d) Pathological Atrophy in parenchymal organs after duct obstruction
(i) Pancreas, parotid gland, kidney
c) Morphology of Apoptosis
i) Cell shrinkage (Smaller, Dense cytoplasm, Tightly packed
organelles) ALL OTHER CELL INJURY = SWELL
(1) Chromatin Condensation
(a) Most characteristic aggregate peripherally in dense
masses, nucleus may fragment to 2+ pieces
(2) Cytoplasmic blebs/apoptotic bodies
(a) Extensive surface blebbing, Fragmentation into membranebound apoptotic bodies
(3) Phagocytosis of apoptotic cells or cell bodies (by macrophage)
d) Biochemical Features of Apoptosis
i) Specific
(1) Activation of cysteine proteases
(2) Caspases
(a) C=cysteine proteases, aspase=unique ability to cleave after aspartic residues
(b) Divided into two groups: Initiators (Caspase 8 & 9) and Executioners (Caspase 3 &
6)
(c) Exist as zymogens cleaved to activate (cleaved caspases= marker- cell
undergoing apoptosis)
e) Mechanisms
i) Process

(1) Phases
(a) Initiation caspases become active
(b) Execution caspases trigger degradation of
critical cell components
(i) Initiation pathways converge to a cascade of
caspase activation
(ii) Enzymatic Death Program
1. Set in motion by activation of executioner
caspases (caspases 3 & 6 Act on many
cell processes)
(2) Pathways
(a) Intrinsic (mitochondria)
(i) Major mechanism in mammalian cells
(ii) Result of increased mitochondrial
permeability and release of pro-apoptotic
molecules (death inducers) into cytoplasm
(iii)Leads to activation of initiator caspase 9
(b) Extrinsic (death-receptor initiated)
(i) Engagement of plasma membrane death
receptors on variety of cells
(ii) Death receptors (Member of TNF receptor
family)
1. Cytoplasmic domain- protein-protein interactions
2. Delivers apoptatic signals
(iii)Leads to activation of the caspase 8 & 10

(c) Removal of Dead cells

(i) Apoptotic bodies break cells into bite-sized pieces edible by phagocytes
(ii) Healthy cells phophatidylserine present on inner leaflet of plasma membrane
1. Apoptotic cells phospholipid flips out recognized by macrophage
receptors
5) Autophagy
a) General
i) Cell eats its own contents (survival mechanism or nutrient deprivation)
ii) Starved cell cannibalizes itself and recycles digested contents
iii) Eaten: Intracellular Organelles and Portions of Cytosol
(1) Sequestered from cytoplasm in autophagic vacuole fuses with lysosome (cellular
components digested by lysosomal enzymes)

6) Intracellular Accumulations
a) Manifestation of metabolic derangements in cells (intracellular accumulation of abnormal
amounts of substances) f
i) Abnormal accumulation of normal cellular constituent
(1) Water, Lipids, Proteins, Carbs
ii) Abnormal accumulation of abnormal substance
(1) Types
(a) Exogenous (mineral or products of infectious agent)
(b) Endogenous (product of abnormal synthesis or
metabolism)
(2) May be harmless - occasionally severely toxic
(3) Location: Cytoplasm / Nucleus
b) Types
i) Normal Endogenous substance (prod. at norm. or inc. rate)
metabolism not sufficient to remove it
(1) Fatty change in Liver
(2) Reabsorption Protein Droplets (Tubules of Kidneys)
ii) Abnormal Endogenous substance accumulates (defect in
protein folding/transport Inability to degrade abnormal
protein)
(1) Accumulation of mutated -1 antitrypsin in liver
(2) Mutated protein in degenerative CNS disorders
iii) Normal Endogenous substance accumulates (defect
(inherited) in enzymes required for metabolism of
substance)
(1) Storage Disorders of Lipids/Carbs
iv) Abnormal Exogenous substance
deposited/accumulates (cell doesnt have enzymatic
machinery to degrade or ability to transport)
(1) Accumulation of carbon particles and nonmetabolizable chemicals (silica)

c) Materials which Accumulate

i) Lipids
(1) Morphology
(a) Fatty change (often Liver/Heart)
(b) Clear Vacuoles w.i parenchymal cells
(c) Identification of Lipids (Avoid fat solvents used in tissue
prep / Sections stained with Sudan IV or Oil Red-O
Orange-Red color of lipid)
(2) Gross Examination (Liver)
(a) Mild Fatty Change doesnt affect gross appearance
(b) Progressive accumulation: Organ Enlarges, Becomes Yellow
Fatty
(c) Extreme Cases: Organ 2-4 times normal weight, Bright Yellow soft and greasy
Liver
(3) Gross Examination (Heart)

ii)

iii)

iv)

v)

(a) Bands of yellowed myocardium, alternating red-brown uninvolved myocardium

(TIGER)
Cholesterol/Cholesterol Esters
(1) Intracellular Vacuoles Several Pathological Processes
(a) Atherosclerosis
(i) Plaques (Smooth Muscles/Macrophages Intimal
layer of aorta and large arteries, filled with lipid
vacuoles)
(ii) Foamy appearance, yellow cholesterol laden
atheromas
(b) Xanthomas
(i) Intracell. Accum. of cholesterol in macrophages
(acquired and hereditary hyperlipidemia states)
(ii) Clusters of foamy cells in CT of skin and in tendons
(c) Cholesterolosis
(i) Focal accumulations of cholesterol-laden macrophages in lamina proper of
gallbladder
(d) Niemann-Pick Disease (Type C)
(i) Lysosomal storage disorder (mutation defective enzyme involved in
cholesterol trafficking)
(ii) Cholesterol accumulation in multiple organs
Protein
(1) Intracelluar accumulation found in: rounded, eosin-loving droplets in cytoplasm
(2) Reabsorption droplets in proximal renal tubules
(a) Renal disease associated with protein loss in
urine
(b) May be normal secreted proteins- produced in
excessive amounts
(3) Defective intracellular transport/secretion of critical
proteins
(a) 1-antitrypsin deficiency Emphysema
(4) Accumulation of cytoskeleton proteins
(a) Alcoholic Hyaline
(i) Eosin-loving cytoplasmic inclusion in liver
cells, composed predominantly of keratin
intermediate fibers
(b) Neurofibrillary tangle (Alzheimers disease)
(i) Neuro-filaments and other proteins
Hyaline Cartilage
(1) Alteration w.i cell or in extracellular space homogenous, glassy
pink appearance
(2) Produced by a variety of alterations
(3) No specific pattern of accumulation
Glycogen
(1) Stored in cytoplasm of healthy cells
(2) Visualization: Tissues fixed w. absolute alcohol, stained w.
carmine or PAS (rose-violet color) Less grainy than
cholesterol esters
(3) Excessive intracellular deposits
(a) Abnormality in glucose or glycogen metabolism

vi) Pigments
(1) Colored Substances normal in some cells (melanin)
(2) Abnormal Pigments
(a) Exogenous pigments
(i) Carbon (coal dust) pollutants in urban cities

1. Blackens the tissues of lungs (anthracosis), and lymph nodes involved

(ii) Tatoos
1. Localized pigmentation of skin (phagocytosed by dermal macrophages)
(b) Endogenous pigments
(i) Lipofuscin
1. Insoluble pigment (not injurious sign of free radical
injury/lipid peroxidation)
2. Yellow-brown finely granular cytoplasmic, often perinuclear
3. Seen in cells undergoing slow regressive changes
4. Prominent in heart and liver (Aging / Severe
Malnutrition / Caner Cachexia Patients)
(ii) Melanin
1. Non-hemoglobin derived brown-black pigment
2. Formation: Oxidation of tyrosine to
dihydroxyphenyalanine in melanocytes
(iii)Hemosiderin
1. Hemoglobin-derived (major form of iron storage)
2. Aggregates of ferritin micelles
3. Seen in mononuclear phagocytes of BM, spleen and
liver (actively engaged in RBC breakdown)
4. Golden yellow-brown (granular/crystalline pigment)
5. Systemic Hemosiderosis: Mononuclear Phagocytes
Liver, BM, Spleen, Lymph Nodes, scattered throughout
other organs
(iv)
Iron
1. Coarse, Golden, Granular (Cell Cytoplasm)
2. Visualized with Prussian Blue
3. Cause: Localized breakdown of RBCs
(v) Bilirubin
1. Normal pigment found in bile (derived from hemoglobin no Iron)
vii) Calcification
(1) Two types (Pathological Calcification)
(a) Dystrophic Calcification
(i) Local Deposition in dying tissues (normal serum levels) Areas of Necrosis
(ii) Absence of derangements in Ca metabolism
(iii)Ex: Calcification of the aortic valve
(b) Metastatic Calcification
(i) Deposition of Ca salts in otherwise normal tissue
(ii) Hypercalcemia (secondary to some disturbance
in Ca metabolism)
(2) Morpholgy
(a) Basophilic, amorphous granular, clumped
(intracellular, extracellular or both)
(b) Can become heterotopic bone over time
(c) Lamellations (psammoma bodies in benign/malignant conditions)

7) Cell Aging
a) Progressive decline in function/viability (caused by genetic abnormality)
b) Accumulation of cellular/molecular damage (effect of exogenous influences)
c) Aging
i) Regulated process (Influenced by a number of genes)
ii) Associated with definable mechanistic alterations

d) Changes contributing to cellular aging

i) Decreased cellular replication, accumulation of metabolic/genetic damage
e) Cellular Life Span
i) Balance between
(1) Damage from metabolic events w.i cell
(2) Molecular Response to repair the damage