Cell Injury 2

Dr Iram Khurshid
MBBS, FCPS (Histopath)
Assistant Professor, CKMC
 Learning Objectives
At the end of session, students should be able to:
1. Differentiate cell injury from adaptations.
2. Enlist types of cell injury.
3. Describe the causes of cell injury.
4. Desceribe the patterns of 3 types of injury.
❖ As cells encounter physiologic stresses (such
as increased workload in the heart in
hypertension) they can undergo adaptation,
achieving a new steady state.
❖ If the adaptive capability is exceeded or if the
external stress is harmful or excessive, cell injury
develops.
❖ Within certain limits, injury is reversible, and
cells return to their stable baseline; however, if
the stress is severe, persistent, or rapid in onset,
it results in irreversible injury and death of the
affected cells.
Cellular Response
Causes of cell injury

1. Acquired causes
2. Genetic causes
 A. ACQUIRED CAUSES OF CELL INJURY
Most injurious stimuli can be grouped into the following categories:

1. Hypoxia and ischemia:

Hypoxia, which refers to oxygen deficiency, and ischemia, which

means reduced blood supply, are among the most common causes of
cell injury. The most common causes of hypoxia is:

1. Ischemia resulting from an arterial obstruction,

2. Inadequate oxygenation of the blood (Cardio respiratory failure)

3. Reduction in the oxygen-carrying capacity of the blood (Anemia and

CO) poisoning.
2. Toxins.
Daily encountered toxic agents include:
1. Air pollutants
2. Insecticides
3. CO
4. Asbestos
5. Cigarette smoke
6. Ethanol
7. Drugs. Many drugs in therapeutic doses can cause cell
or tissue injury if used excessively or inappropriately.
3. Infectious agents.
All types of disease-causing pathogens can injure
cells, including:
❖ Viruses
❖ Bacteria
❖ Fungi, and
❖ Protozoans.
4. Nutritional imbalances.
Protein–calorie insufficiency and specific vitamin
deficiencies are not uncommon in developing
countries. Ironically, excessive dietary intake may
predispose to many diseases, such as type 2
diabetes mellitus and atherosclerosis. Vitamin D
intoxication is also an example.
5. Physical agents.
❖ Trauma
❖ Extremes of temperature,
❖ Radiation,
❖ Electric shock, and
❖ Sudden changes in atmospheric pressure all have wide-
ranging effects on cells.
6. Aging.
Cellular aging → diminished ability of cells to respond
to stress → death of cells and of the organism.
7. Abnormal Immunological Reactions:
• The immune process is normally protective.
- Hypersensitivity to various substances can lead to
anaphylaxis or to more localized lesions such as
asthma.
- In other circumstances the immune process may act
against the body cells – Autoimmunity.
 B. Genetic Causes
Genetic defects may cause cell injury as a
consequence of :
1. Deficiency of functional proteins,
such as enzymes in inborn errors of
metabolism, or
2. Accumulation of damaged DNA or
misfolded proteins, both of which trigger
cell death when they are beyond repair.
 Reversible injury
Reversible injury → Cell injury at which the
deranged function and morphology of the injured
cells can return to normal if the damaging stimulus
is removed .
In reversible injury, cells and intracellular
organelles typically become swollen because they
take in water as a result of the failure of energy-
dependent ion pumps (Na/K pump) in the plasma
membrane, leading to an inability to maintain ionic
and fluid homeostasis.
 MORPHOLOGY
The two main morphologic features of reversible cell injury are
cellular swelling and fatty change.
• 1. Cellular swelling :
is commonly seen in cell injury associated with increased
permeability of the plasma membrane.
When it affects many cells in an organ, it causes pallor (as a result
of compression of capillaries), and an increase in organ weight.
Microscopic examination may show small, clear vacuoles within the
cytoplasm; This pattern of injury is sometimes called hydropic
change or vacuolar degeneration.
Microscopic appearance of normal kidney
The tubular epithelial cells are distended with
cytoplasmic clear vacuoles while the interstitial
vasculature is compressed.
2. Fatty change:
is manifested by the appearance of triglyceride
containing lipid vacuoles in the cytoplasm of cells.
Also known as Steatosis.
It is principally encountered in organs that are
involved in lipid metabolism, such as the liver.
Gross: The organ enlarges, and become yellow, soft
and greasy.
Microscopy: Clear vacoule within parenchymal cells.
 Other minor intracellular changes associated with cell
injury include:
(1) Plasma membrane alterations such as blebbing,
blunting, or distortion of microvilli, and loosening of
intercellular attachments;
(2) Mitochondrial changes such as swelling and the
appearance of phospholipid-rich amorphous densities.
(3) Dilation of the ER with detachment of ribosomes and
dissociation of polysomes.
(4) Nuclear alterations, such as clumping of chromatin.
The cytoplasm may contain so-called “Myelin figures,”
which are collections of phospholipids derived from
damaged cellular membranes.
 1. Hypoxia and Ischemia
❖ Hypoxia and ischemia →Deficiency of oxygen → failure
of many energy dependent metabolic pathways → death
of cells by necrosis.
❖ Most cellular ATP is produced from (ADP) in
mitochondria by oxidative phosphorylation.
❖ ATP is required for membrane transport, protein
synthesis, lipogenesis. (cells of a healthy human burn
50 to 75 kg ATP/day).
❖ Cells subjected to the hypoxia that do not immediately
die activate adaptive mechanisms.
1. HIF-1 → protein synthesis like VEGF → growth of new vessels
to increase blood flow and the supply of oxygen.
2. Anaerobic glycolysis can generate ATP in O2 absence using
glucose either from the circulation or from the hydrolysis of
intracellular glycogen. (Tissues with abundant glycogen (e.g., the
liver and striated muscle) are more likely to survive hypoxia than
tissues with limited glucose stores (e.g., the brain).
Although glycolysis yields less ATP but metabolites generated by
glycolysis serve as precursors for the synthesis of cellular
constituents (e.g., proteins, lipids, and nucleic acids) needed for
cell growth and division.
 Persistent or severe hypoxia and ischemia
ultimately lead to depletion of ATP in cells.
1) Reduced activity of plasma membrane ATP-
dependent sodium pumps → intracellular
accumulation of sodium and efflux of potassium
accompanied by gain of water → cell swelling
and dilation of the ER.
2) The compensatory increase in anaerobic
glycolysis leads to lactic acid accumulation,
decreased intracellular pH, and decreased
activity of many cellular enzymes.
3) Prolonged depletion of ATP causes structural
disruption of the protein synthetic apparatus
manifested as detachment of ribosomes from the
rough ER (RER) → Reduced protein synthesis.
4) Ultimately, there is irreversible damage to
mitochondrial and lysosomal membranes, and the
cell undergoes necrosis. Although necrosis is the
principal form of cell death caused by hypoxia,
apoptosis by the mitochondrial pathway is also
thought to contribute.
The functional
and
morphologic
consequences
of hypoxia and
ischemia.
❖ The functional consequences of hypoxia
and ischemia depend on the severity and
duration of the deficit. For instance, the
heart muscle ceases to contract within 60
seconds of coronary occlusion.
❖ If hypoxia continues, worsening ATP
depletion causes further deterioration.
 2. Ischemia-Reperfusion Injury
The restoration of blood flow to ischemic but viable
tissues (Reperfusion) paradoxically, results in
increased cell injury. This so-called “Ischemia-
reperfusion injury” may contribute significantly to
tissue damage, especially after myocardial and
cerebral ischemia.
Several mechanisms contributing in exacerbation of
cell injury resulting from reperfusion of ischemic
tissues:
1) Reoxygenation →
generation of ROS (Free
Radicals). Free radicals are
unstable molecules with
unpaired electrons in outer
orbitals that make them
particularly reactive with other
molecules. O2-derived free
radicals (also called reactive
oxygen species or ROS) are the
most common including

a) Superoxide anion (O2 • ", one

extra electron)

b) Hydrogen peroxide (H2O2,

two extra electrons)

c) Hydroxyl ions (OH#)

(i) ROS may be generated by injured cells with damaged
mitochondria that cannot carry out the complete
reduction of oxygen, alongwith defective cellular anti-
oxidant defense mechanisms by ischemia, exacerbating
the situation.
(ii) ROS are also generated by infiltrating leukocytes
contributing to the damage of cells.
Free radicals damage lipids (per oxidizing double
bonds and causing chain breakage), proteins (oxidizing
and fragmenting peptide bonds), and nucleic acids
(causing single strand breaks).
Free radical
damages
mitochondria,
DNA, proteins
and lipids
2) The inflammation induced by ischemic
injury may increase with reperfusion because it
enhances the influx of leukocytes and plasma
proteins. Complement proteins may bind to the
injured tissues, and subsequent complement
activation generates byproducts that exacerbate
the cell injury and inflammation (will discuss in
next chap).
 3.Cell Injury Caused by Toxins
Toxins, including environmental chemicals and substances
produced by infectious pathogens, induce cell injury that
results in necrotic cell death.

CHEMICAL
INJURY

CONVERSION TO
DIRECT TOXICITY TOXIC
METABOLITES
• (A) DIRECT
TOXINS: MERCURIC
CHLORIDE
POISONING

Some chemicals
Greatest
can directly damage is to
Mercury
cells that
injure cells by absorb and
excrete the
binds to
cell
combining with chemicals e.g
GIT and
membrane
proteins

molecular KIDNEY.

components or Increased
permeability
cellular and
inhibition of
organelle. ion transport
(B) LATENT TOXINS:
Most toxic chemicals are inactive, and
converted to reactive toxic metabolites →
act on target molecules. These toxic
metabolites cause membrane damage and
cell injury by FORMATION OF FREE
RADICALS e.g CCl4 and
ACETAMINOPHEN (Analgesic Drug)