CELLULAR

RESPONSE TO STRESS AND TOXIC INSULTS

Francis F. Dematera, MD, DPSP

Reference: Robbins and Cotrans Pathologic Basis of Disease 8th Ed


CELLULAR ADAPTATIONS

1. HYPERTROPHY
INCREASE in the SIZE of cell due to
increased production of cellular proteins
resulting to increase in the size of organ
Selective hypertrophy: Organelle
Physiologic or Pathologic
o Increased functional demand
o Stimulation by hormones or
growth factors

2. HYPERPLASIA
INCREASE in the NUMBER of cells in an organ or tissue resulting to increased
mass of the organ or tissue
PHYSIOLOGIC
HORMONAL
COMPENSATORY
To increase functional capacity
To increase tissue
when needed
mass after damage
or partial resection
Ex. Female breast during puberty
and pregnancy

Ex. Liver
regeneration

PATHOLOGIC
Excess of hormones or
growth factors
Ex. BPH;
Endometrial hyperplasia

3. ATROPHY
DECREASE in cell SIZE and number resulting to decrease in size of an organ
or tissue

PHYSIOLOGIC
PATHOLOGIC
Notochord
Atrophy of disuse
Thyroglossal duct
Denervation atrophy
Uterus after parturition
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation
Pressure
4. METAPLASIA
Differentiated CELL TYPE IS REPLACED by another cell type
MOST COMMON-Columnar to Squamous
Seen in: respiratory tract, salivary excretory duct, pancreatic ducts,
bile duct, cervix

CELL INJURY
CAUSES OF INJURY
Injurious Agents
Oxygen Deprivation
Physical Agents
Chemical Agents /
Drugs
Infectious Agents
Immune Reactions
Genetic Derangements
Nutritional Imbalances

Cases
Hypoxia
Mechanical trauma, Extremes of temperature, Sudden change in
atmospheric pressure, Radiation, Electric shock
Glucose, Salt in hypertonic solution, Oxygen, Poisonous elements,
Drugs, Environmental pollutants, Insecticides/Herbicides
Various biologic agents
Hypersensitivity, Autoimmunity
Functional protein deficiency, Accumulation of damaged DNA
Deficiency, Excess

PRINCIPLES RELEVANT TO MOST FORMS OF CELL INJURY
1. The cellular response to injurious stimuli depends on the nature of the injury,
its duration, and its severity.
2. The consequences of cell injury depend on the type, state, and adaptability of
the injured cell.
3. Cell injury results from different biochemical mechanisms acting on several
essential cellular components.
4. Any injurious stimulus may simultaneously trigger multiple interconnected
mechanisms that damage cells.

MECHANISMS OF CELL INJURY
1. Decrease ATP has multiple downstream effects
2. Mitochondrial damage leads to leakage of pro-apoptotic proteins and has
other multiple downstream effects due to decrease in ATP
3. Entry of calcium activation od cellular enzymes and increase in
mitochondrial permeability
4. Increase in ROS leads to damage to lipids, proteins and DNA
5. Membrane damage leads to loss of cellular components (plasma
membrane) and enzymatic digestion of cellular components (lysosomal
membrane)
6. Protein misfolding, DNA damage activation of pro-apoptotic proteins

REVERSIBLE INJURY
Hallmarks - reduced oxidative phosphorylation ! depletion of ATP, and cellular
swelling caused by changes in ion concentrations and water influx
1. CELLULAR SWELLING
Characterizes and is a hallmark of reversible injury; First manifestation of
almost all forms of cell injury
Features: Plasma Membrane: blebbing, blunting, loss of microvilli;
Mitochondria: swelling; Endoplasmic Reticulum: detachment of polysomes,
myelin figures; Nuclear Alterations
2. FATTY CHANGE
Excessive entry or defective metabolism and export of lipids

INTRACELLULAR ACCUMULATIONS
- in cases of chronic injury and metabolic alterations
ENDOGENOUS
Normal substance
Fatty change;
produced at normal rate Protein droplets in renal
but rate of metabolism
tubular cells in proteinuria
cannot remove it
Normal substance due to Storage diseases
defect in enzyme
required for metabolism
Abnormal substance
Product of mutated gene
(misfolded 1 antitrypsin)

EXOGENOUS
Abnormal
Tattoo
substance and Carbon
enzymatic
machinery
cannot
degrade it

CELL DEATH

NECROSIS vs APOPTOSIS

NECROSIS
Nuclear Changes in Necrosis
Pyknosis- nuclear shrinkage with increased basophilia
Karyorrhexis nuclear fragmentation
Karyolysis loss of DNA

PATTERNS OF NECROSIS
1. Coagulative Necrosis
Architecture of tissue is preserved for some more days and thereafter
removed by infiltrating leukocytes
Infarct localized coagulation necrosis
Ischemia will lead to coagulation necrosis except in the brain
2. Liquefactive Necrosis
Digestion of dead cells with formation of liquid viscous mass; seen in CNS
Necrotic material is called pus
3. Caseous Necrosis
Seen in tuberculous infection
Grossly appears as cheese-like, histologically as necrotic area with
inflammatory border with scattered lymphocytes, epithelioid cells and
multinucleated giant cells (granuloma)

4. Fibrinoid Necrosis
Immune complexes with fibrin are deposited within arterial walls
5. Gangrenous Necrosis
Limb with coagulation necrosis
Wet Gangrene gangrenous necrosis with superimposed liquefactive
necrosis
6. Enzymatic Fat Necrosis
Seen in acute pancreatitis with release of lipase
Focal areas of fat destruction

APOPTOSIS
-Programmed cell death
-Chromatin condensation - most characteristic feature of apoptosis
PHYSIOLOGIC
Embryogenesis
Involution of hormone-dependent tissue
upon withdrawal
Immature lymphocytes in BM and thymus;
B cells in germinal centers
Host cells that have served their function in
immune response

CALCIFICATION
DYSTROPHIC
Necrotic tissue,
Tissue with cells with membrane damage

Heterotopic bone may form

Psamomma bodies

PATHOLOGIC
DNA damage
Misfolded proteins
Atrophy after duct obstruction
Viral infection

METASTATIC
Hypercalcemia
1. Increase PTH
2. Increase bone destruction
3. Increase Vitamin D
4. Increase phosphate in renal failure
Can accentuate dystrophic calcification

CELLULAR AGING

A result of a progressive decline in cellular function and viability caused by genetic
abnormalities and the accumulation of cellular and molecular damage due to the
effects of exposure to exogenous influences.
Mechanisms:
1. Decreased cellular replication
Telomere (repeated sequences of TTAGGG) shortening which ultimately
results in cell cycle arrest. Telomerase is highest in germ cells, lower in
stem cells and is usually undetectable in somatic cells.
2. Accumulation of metabolic and genetic damage
Werner syndrome - premature aging, defective gene product is a DNA
helicase which is involved in DNA replication and repair and other
functions requiring DNA unwinding resulting in accumulation of
chromosomal damage