Cellular adaptation, cell injury and cell death I
KAMPALA INTERNATIONAL UNIVERSITY
DAR ES SALAAM COLLEGE
Ssempijja Fred
Anatomy Department
OBJECTIVES
1.
2.
3.
4.
To know the different cellular responses to injury ,
and its causes.
To know the differents types of cell injury
Explain the mechanisms and morphological
changes in cell injury.
To know some examples of cell injury.
SUMMARY

Cellular responses to injury. Definition. Cellular
adaptation. Causes of cell injury.

Cell injury . Mechanisms.Reversible and
irreversible cell injury. Ischemic and hypoxic injury.
Cellular injury by free radicals. Chemical injury.
(Germany)1821- 1915.
Introduced histopathology as a
diagnostic branch by his
cellular theory
Microscopic study of the diseases
is necessary for the diagnosis,
each disease has specific
changes in the cells and tissues.
Book: Cellular pathology, 1858
Rudolf Virchow
INJURY AGENT
Any external or internal agent that acts
over the cells and affect their capacity to
keep the state called homeostasis.
Cellular response to injury
Nature and severity of injuriuos stimulus
Cellular response
Altered physiologic stimuli
-Increased demand, increased trophic
stimulation(grow factor, hormones)
-Decreased nutrients, stimulation
-Chronic irritation(chemical or physical
Cellular adaptations
-Hyperplasia, hypertrophy
Reduced O2 supply, chemical injury,
microbial infection
-Acute and self-limited
-Progressive and severe(including DNA
damage)
Cell injury
-Mild chronic injury
-Atrophy
-Metaplasia
-Acute reversible injury
-Irreversible injury (cell death)
•Necrosis
•Apoptosis
- Subcellular alteration in various
organelles.
Metabolic alteration, genetic or acquired
Intracellular accumulations,
calcifications
Prolonged life span with cumulative
sublethal injury
Cellular aging
CELL ADAPTATION
Is the new but altered states of the cells’s
structure and/or biochemical processes in
order to achieve a new "steady state" and
maintain near-normal physiologic
functions (homeostasis) preserving its
viability.
Adaptative response
NORMAL TISSUE
Stimulus
That increased
demand
Hyperplasia
Stimulus that
reduced
demand
Atrophy
Hypertrophy
End of stimuli
Chronic
irritation
Metaplasia
CELLULAR ADAPTATION
HYPERPLASIA
Is an increase in the number of parenchymal cells
resulting in enlargement of the organ or tissue.
Hyperplasia usually occurs together with
hypertrophy.
Takes place if the cellular population is capable of
synthesizing DNA, thus permitting mitotic
division.
HYPERPLASIA
Physiologic hyperplasia
1- Hormonal
Proliferation of glandular epithelium of the female
breast at puberty and during pregnancy
2- Compensatory
After partial hepatectomy
Pathologic hyperplasia
1- By excessive hormonal stimulation
Endometrial hyperplasia
Benign prostatic hyperplasia
Endometrial hyperplasia
CELLULAR ADAPTATION
HYPERTROPHY
Is an increase in the size of parenchymal cells
resulting in enlargement of the organ or tissue,
without any change in the number of cells.
It may be physiologic or pathologic.
HYPERTROPHY
Physiologic hypertrophy
• Growth of the uterus during pregnancy
•Hypertrophy of breast during lactation.
Pathologic Hypertrophy
• Hypertrophy of cardiac muscle
• Hypertrophy of smooth muscle
• Hypertrophy of skeletal muscle
• Compensatory hypertrophy
HYPERTROPHY
Normal muscle
Hypertrophy muscle
Cellular adaptation
ATROPHY
Reduction in the size of cells by loss of cell
substance.
When a sufficient number of cells are involved,
the entire tissue or organ diminishes in size or
become atrophic
It may occur from physiologic or pathologic
causes.
ATROPHY
Physiologic Atrophy
• Atrophy of thymus after puberty
• Atrophy of gonads after menopause
• Atrophy of brain with aging
• Notochord and thyroglossal duct during fetal
development
ATROPHY
Pathologic Atrophy
• Malnutrition atrophy
• Denervation atrophy
• Disuse atrophy
• Pressure atrophy
• Endocrine atrophy
• Ischaemic atrophy
ATROPHY
CELLULAR ADAPTATION
METAPLASIA
Is defined as a reversible change of one type of
adult cells (epithelial or mesenchymal) that are
replaced by another type of adult cells, usually
in response to abnormal stimuli, and often
reverts back to normal on removal of stimulus.
METAPLASIA
• Epithelial metaplasia
1. Squamous metaplasia
2. Columnar metaplasia
• Mesenchymal metaplasia
1. Osseous metaplasia
2. Cartilaginous metaplasia
METAPLASIA
Metaplasia, squamous, larynx, microscopic
METAPLASIA
If the influences that predispose to
metaplasia persist, they may
induce malignant transformation
in metaplastic epithelium.
CELL INJURY = DISEASE
CELLULAR STRESS
Intense of stimulus
ADAPTATION
Cellular vulnerability
CELL INJURY
Reversible
Point of no return --------------------------
Irreversible
CELLULAR
DEATH
INJURY AGENT
loload
ad
Lesión celular
irreversible
IF THE LIMITS OF ADAPTIVE RESPONSE TO A
STIMULUS ARE EXCEEDED OR WHEN THE CELL IS
EXPOSED TO
AN INJURIUS AGENT, CELL INJURY OCCUR.
CELL INJURY
Is the morphological and biochemical changes
in the cell that occur when the cells are
stressed so severely that they are no longer
able to adapt or when cells are exposed to
inherently damaging agents .
Causes of cell injury
• Hypoxia
and ischemia
• Physical agents
• Chemical agents and drugs
• Infection agents
• Immunologic reactions
• Genetic derangements
• Nutritional imbalances
Hypoxia and ischemia
Hypoxia is a deficiency of oxygen, which causes cell
injury by reducing aerobic oxidative respiration.
Is the most common cause of cell injury. May be
caused by anemia, Carbonmonoxide poisoning,
cardiorespiratory insufficiency, and increased demand
of tissues.
Ischemia is a reduction of blood flow, compromises the
supply not only of oxygen, but also of metabolic
substrates, including glucose. Usually as a
consequence of mechanical obstruction in the arterial
system, fall in blood pressure or loss of blood.
Physical agents
• Mechanical trauma (e.g. road accidents);
• Thermal trauma (e.g. by heat and cold);
• Electricity;
• Radiation (e.g. ultraviolet and ionising);
• Rapid changes in atmospheric pressure.
Chemicals and Drugs
• Chemical
poisons such as cyanide, arsenic,
mercury;
• Strong acids and alkalis;
• Environmental pollutants;
• Insecticides and pesticides;
• Oxygen at high concentration;
• Hypertonic glucose and salt;
• Social agents such as alcohol and narcotic
drugs;
• Therapeutic administration of drugs.
Infection agents
• Bacteria;
• Rickettsiae;
• Viruses;
• Fungi;
• Protozoa;
• Metazoa;
• Other parasites.
Immunologic reaction
Immunity is a “double-edged sword”
--- it protects the host against various
injurious agents but it may also turn lethal
and cause cell injury e.g.
• Hypersensitivity reactions;
• Anaphylactic reactions;
• Autoimmune reactions.
Genetic Derangements
Genetic defects as causes of cell injury are of
major interest to scientists and physicians
today.
• The genetic injury may result in a defect
caused by a chromosomal abnormality (e.g. the
congenital malformations associated with Down
syndrome).
• Variations in the genetic makeup can also
influence the susceptibility of cells to injury by
chemicals and other environmental insults.
Nutritional imbalances
A deficiency or an excess of nutrients may result
in nutritional imbalances.
• Nutritional deficiency diseases may be due to
overall deficiency of nutrients (e.g. starvation), of
protein calorie (e.g. marasmus, kwashiorkor), of
minerals (e.g. anaemia), or of trace elements.
• Nutritional excess is a problem of affluent
societies resulting in obesity, atherosclerosis,
heart disease and hypertension.
FACTORS THAT DEPEND CELL INJURY
INJURIOUS
STIMULI
• Type
• Mechanisms of action
• Duration
• Severity
CELL
Type of cell- stable
- labile
- permanent
• Nutritional state
•
• Adaptability of the cell to
injury
STAGES OF CELL INJURY
REVERSIBLE
CELL INJURY
IRREVERSIBLE
CELL
INJURY
OR CELL DEATH
REVERSIBLE CELL INJURY
Funtional and morphologic changes that
are reversible if the damaging stimulus is
removed.
IRREVERSIBLE CELL INJURY
Functional and morphologic changes in
the cell that are irreversible at which time
the cell cannot recover.
Invariably undergo morphologic changes
that are recognized as cell death.
Essential
cellular
components affected
in cell injury
SISTEMAS
INTRACELULARES
VULNERABLES
Integrity of cell
Membranes and
cytoskeleton
Protein synthesis
BIOCHEMICAL CHANGES
STRUCTURAL CHANGES
Aerobic
respiration
MORPHOLOGIC CHANGES
Integrity of
the genetic
apparatus
Mechanisms of cell injury
• Depletion
of ATP
• Membrane damage
• Influx of intracellular calcium and
loss of calcium homeostasis
• Accumulation of oxygen-derived
free radicals (oxidative stress)
ISCHEMIA
TYPES
OF
CELL
INJURY
TOXIC
FREE
RADICALS
Cellular swelling.
ISCHEMIC
Loss of microvilli
Blebs
ER swelling
Influx of
Ca2+,H2O, Na+ Myelin figures
MITOCONDRIA
Oxidative
phosphorylation
ATP
Loss of K+
Na pump
Glycolysis
Detachment of
Ribosomes
Clumping of
nuclear
Chromatin
pH
Glycogen
Protein
synthesis
REVERSIBLE INJURY
Lipid
deposition
ISCHEMIA
Membrane
injury
MITOCONDRIA
Loss of
Phospholipids
Cytoskeletal
alterations
Leakage
Enzymes,
(CK, LDH)
Lipids
breakdown
Ca2+ influx
Free radicals
Other
Oxidative
phosphorylation
ATP
pH
Intracellular release and
activation of lysosomal
enzymes
IRREVERSIBLE INJURY
Ca2+ en las
Mitocondrias
Basophilia ( RNP)
Nuclear changes
Protein digestion
Phenomena that characterize
irreversibility
 Inability to reverse michondrial
dysfunction.
 Profound disturbances in membrane
function.
Injury by free radicals
Are reactive oxygen forms produced in mitochondrial
respiration
(O2-) Superoxide anion radical
(H2O2) Hydrogen peroxide
(OH) Hydroxyl ions
They can damage protein, lipid and nucleid acid.
Free radical- mediated damage contributes to such varied
processes as :
-Chemical and radiation injury
-Ischemia-reperfusion injury
-Cellular aging
-Microbial killing by phagocytes
Enzymatic
metabolism
Chemicals
Drugs
ReductionOxidation
Reactions
Absorption of
radiant energy
FREE
RADICALS
Transition
metal
Nitric
oxide
O2
Oxidative
enzymes
O2.Fe2+
O2.-
superoxide
H2O2
dismutase
Lipid
peroxidation of
membranes
Fe3+
OH. + OH-
H2O
Oxidative modification
proteínas
Lesion in DNA
Cellular injury
MECHANISMS FOR
INACTIVATION FREE RADICAL
REACTIONS
ANTIOXIDANTS
ENZYMES
IRON AND COPPER
CHEMICAL INJURY
Induce cellular injury by two general
mechanisms
- Directly by combining with some critical
molecular component or cellular
organelle.(E.g,mercuric chloride
poisoning)
- Some chemical are not biologically active
but must be converted to reactive toxic
metabolites in the ER of the liver and
other organs.
CCL4
REL
Chemical injury
CCL3
LIPID RADICALS
+O2
LIPID PEROXIDATION
MEMBRANE DAMAGE
(RER)
DAMAGE TO PLASMA
MEMBRANE
-INACTIVATION:
APOPROTEIN
SYNTHESIS
FATTY
LIVER
.MITOCHONDRIA . CELL
ENZYMES
-DESNATURATION OF
PROTEINS
DIRECTLY
Chemical injury
FREE RADICALS
MORPHOLOGY OF REVERSIBLE
CELL INJURY
(DEGENERATION OR INTRACELLULAR ACUMULATION)
•Cellular swelling
• Fatty change
• Hyaline change
• Amyloidosis
• Pigments
• Pathologic calcification
Cellular Swelling
Cellular swelling is the first manifestation of almost all
forms of injury to cells. Other synonyms of cellular
swelling used in the past are:
cloudy swelling (for gross appearance of the affected
organ)
hydropic change (accumulation of water within the
cell)
vacuolar degeneration (due to cytoplasmic
vacuolation)
Cellular swelling
Grossly, the affected organ such as kidney,
liver or heart muscle is enlarged due to
swelling. The cut surface bulges outwards and
is slightly opaque
•
HYDROPIC CHANGE
HYDROPIC CHANGE
Fatty change (Steatosis)
The terms fatty change and steatosis describe
abnormal accumulations of triglycerides within
parenchymal cells.
• Fatty change is often seen in the liver because it
is the major organ involved in fat metabolism,
but it also occurs in heart, muscle, and kidney.
Causes:
- Toxins
- Protein malnutritions
- Obesity
- Diabetes mellitus
- Anoxia
Fatty change (Steatosis)
Causes
-
Toxins
Protein malnutritions
Obesity
Diabetes mellitus
Anoxia
Alcohol abuse
Fatty liver
Histochemical
–
–
–
–
–
–
Sudán
Oil Red
Sudan Black
Orange oil
PAS
If the stain is Negative for fat or glycogen
is water,
Hyaline Change
• The word “Hyaline” means glassy (hyalos =glass).
• Hyaline is a descriptive histologic term for glassy,
homogeneous, eosinophilic appearance of material
in H.E stained sections and does not refer to any
specific substance.
• Hyaline change is associated with heterogeneous
pathologic conditions and may be intracellular or
extracellular.
Intracellular Hyaline
• Intracellular hyaline is mainly seen in
epithelial cells. For example:
1. Hyaline droplets in the proximal tubular
epithelial cells in cases of excessive
reabsorption of plasma.
2. Mallory’s hyaline represents aggregates
of intermediate filaments in the hepatocytes
in alcoholic liver cell injury.
Intracellular Hyaline
3. Nuclear or cytoplasmic hyaline
inclusions seen in some viral infections.
4. Russel’s bodies representing excessive
immunoglobulins in the RER of the plasma
cells.
Extracellular Hyaline
• Extracellular hyaline is seen in connective tissues.
A few examples of extracellular hyaline change
are:
1. Hyaline degeneration in leiomyomas of the
uterus.
2. Hyalinised old scar of fibrocollagenous tissues.
3. Hyaline arteriosclerosis is renal vessels in
hypertension and diabetes mellitus.
4. Hyalinised glomeruli in chronic
glomerulonephritis.
REFERENCE
1.
2.
3.
Muir’s Textbook of Pathology, edition above 13th
General Pathology by Walter and Isreal
Robbins and Cotran, Pathologic Basis of disease, editions above 7th