12/7/2023

CELL INJURY

Masum Shahriar
Professor, Department of Pharmacy
Jahangirnagar university

Reading Assignment
Robbins: Pathologic Basis of Disease, Saunders, 9th edition,
Chapter 1 (ISBN 0-7216-0187-1)

Learning Objectives:
At the end of this lecture, candidates should be able to:
– Describe the progression of cell response from initial
alterations to cell injury and death
– Define reversible cell injury and mechanisms
– Describe the alterations that occur in cells with
ischemia/hypoxia and define mechanisms, which are
thought to be involved; define reperfusion injury
– Describe cellular changes in free-radical and chemical-
induced injury and define mechanisms

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RESPONSES TO INJURY

Stages in the cellular response to stress and injurious stimuli.

CELL INJURY

Cell injury is a sequence of events that occur if the limits of

adaptive capability are exceeded or no adaptive response is
possible or when cells are exposed to inherently damaging
agents or suffer from intrinsic abnormalities (e.g., in DNA or
proteins)..

CAUSES OF CELL INJURY:

Internal stresses
 metabolic imbalances, nutritional deficiencies or excesses
 genetic abnormalities
 acquired derangements –> hypoxia, ischemia

External
 physical agents (heat, cold, radiation, …)
 natural toxins, venoms
 drugs, "chemicals"

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Cell Injury
• With increased
demand, reduced
nutrient supply, or
other forms of
Normal Cell "stress", cellular
(homeostasis) adaptations often
Stress occur
Injurious Increased
Stimuli demand
• When the limits of the
adaptive response are
Adaptation
Cell Injury reached (or if
Cell Death
Inability adaptation is not
to adapt
possible), a sequence
of effects follows
which are loosely
termed cellular injury

Principles of Cell Injury

The cellular response to injurious stimuli depends upon the type of
injury, its duration and its severity

 Reversible: If removal of the "stress" allows return of the

cell to normal, the injury is termed reversible

 Irreversible: If the stress is so severe that it reaches the

"point of no return", the cell suffers irreversible cell injury
and sometimes cell death.

“The consequences of cell injury depend on the type, state and

adaptability of the injured cell”.

For example: if the blood suply to heart muscles is cut off for 10-15
minutes- the myocardial cell experiences injury but it can recover to
normal function, if the blood flow is cut off for longer period- the
myocardial fiber dies-necrosis

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Relationships between normal, adapted, reversibly

injured, and dead myocardial cells.
• In this (myocardial
hypertrophy), the left
ventricular wall is more
than 2 cm in thickness
(normal is 1 to 1.5 cm)

• In the specimen
showing necrosis, the
transmural light area in
the posterolateral left
ventricle represents an
acute myocardial
Sections were stained with triphenyltetrazolium chloride
an enzyme substrate that colors viable myocardium
infarction
magenta.

Different cells show different sensitivities/thresholds.

Examples:
 Brain cells, heart cells susceptible to hypoxia and
ischemia; liver cells susceptible to chemical injury.
 Calf muscle tolerates 2-3h of ischemia, cardiac muscle
dies in 20-30 min.
 Highly differentiated surface epithelial cells of the
respiratory tract more susceptible to cigarette smoke than
less differentiated basal epithelia.
 Nutritional status – glycogen-replete hepatocyte more
resistant to ischemia than depleted one.

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Causes of Cell Injury

The causes of cell injury range from the gross physical trauma of a motor
vehicle accident to the single gene defect that results in a nonfunctional
enzyme underlying a specific metabolic disease. Most injurious stimuli can
be grouped into the following categories.

Oxygen Deprivation - Ischemia/Hypoxia

Hypoxia, or oxygen deficiency, interferes with aerobic oxidative
respiration and is an extremely important and common cause of cell
injury and death. Ischemia is the most common cause of hypoxia,
oxygen deficiency can also result from inadequate oxygenation of the
blood, as in pneumonia, or reduction in the oxygen-carrying capacity of
the blood, as in blood-loss, anemia or carbon monoxide (CO) poisoning.

Chemical Agents and Drugs

An enormous number of chemical substances can injure cells.
Agents commonly known as poisons cause severe damage at the
cellular level by altering membrane permeability, osmotic
homeostasis, or the integrity of an enzyme or cofactor, and
exposure to these poisons can culminate in the death of the whole
organism. Many potentially toxic agents are encountered daily in
the environment; these include air pollutants, insecticides, CO,
asbestos. Even therapeutic drugs can cause cell or tissue injury in
a susceptible patient or if used excessively or inappropriately

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Infectious Agents
These range from submicroscopic viruses to meter-long
tapeworms; in between are the rickettsiae, bacteria, fungi, and
protozoans.

Immunologic Reactions
Although the immune system defends the body against pathogenic
microbes, immune reactions can also result in cell and tissue
injury. Examples include autoimmune reactions against one’s own
tissues and allergic reactions against environmental substances
ingenetically susceptible individuals

Genetic Derangements
Genetic defects can result in pathologic changes as conspicuous as the
congenital malformations associated with Down syndrome or as subtle as
the single amino acid substitution in hemoglobin S giving rise to sickle cell
anemia. Genetic defects may cause cell injury because of deficiency of
functional proteins, such as enzymes in inborn errors of metabolism, or
accumulation of damaged DNA or misfolded proteins, both of which
trigger cell death when they are beyond repair.

Physical Agents
Trauma, extremes of temperatures, radiation, electric shock, and sudden
changes in atmospheric pressure all have wide-ranging effects on cells.

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Nutritional Imbalances –
Nutritional deficiencies remain a major cause of cell injury. Protein-calorie
insufficiency among underprivileged populations is only the most obvious
example; specific vitamin deficiencies are not uncommon. Ironically, excesses of
nutrition are also important causes of morbidity and mortality; for example,
obesity markedly increases the risk for type 2 diabetes mellitus. Moreover, diets
rich in animal fat are strongly implicated in the development of atherosclerosis
as well as in increased vulnerability to many disorders, including cancer.

Aging
Cellular senescence leads to alterations in replicative and repair abilities of
individual cells and tissues. All of these changes result in a diminished ability to
respond to damage and, eventually, the death of cells and of the organism.

Intracellular systems vulnerable to cell damage

and contribute to pathology
– Cell membranes - Maintenance of ionic gradients and
osmotic homeostasis

– Aerobic respiration - Maintenance of oxidative metabolism

and ATP

– Protein synthesis - Proteins are constantly turning over in the

body and being synthesized

– Genetic machinery and apparatus - DNA, chromosomes,

etc....

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THE MORPHOLOGY OF CELL (Reversible Injury)

The two main morphologic correlates of reversible cell injury are cellular
swelling and fatty change.

The ultrastructural changes of reversible cell

injury are
(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;
and
(4) nuclear alterations, with clumping of
chromatin.

The cellular derangements of reversible injury can be corrected, and if the injurious
stimulus abates, the cell can return to normalcy.

Persistent or excessive injury, however, causes cells to pass the nebulous “point
of no return” into irreversible injury and cell death. Although there are no
definitive morphologic or biochemical correlates of irreversibility, two
phenomena consistently characterize irreversibility: the inability to reverse
mitochondrial dysfunction (lack of oxidative phosphorylation and ATP
generation) even after resolution of the original injury, and profound
disturbances in membrane function. Injury to lysosomal membranes results in
the enzymatic dissolution of the injured cell that is characteristic of necrosis.

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Morphologic changes in reversible and irreversible

cell injury (necrosis).

Biochemical Mediators of "Cell Injury"

Cell injury results from functional and biochemical abnormalities in one or more of several

essential cellular components. The principal targets and biochemical mechanisms of cell

injury are:
(1) mitochondria and their ability to generate ATP and ROS under pathologic conditions;
(2) disturbance in calcium homeostasis;
(3) damage to cellular (plasma and lysosomal) membranes; and
(4) damage to DNA and misfolding of proteins.

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Consequences of decreased intracellular ATP during

cell injury
Depletion of ATP to less than 5% to 10% of normal levels has
widespread effects on many critical cellular systems.
ischemia
Mitochondrion

Na Pump Oxidative Phosphorylation Other Effects

Influx of Ca++ ATP Detachment of

H2O2 & Na+ Ribosome
Efflux of K+
Anaerobic Glycolysis Protein
Synthesis
ER Swelling
Cellular Swelling Glycogen pH
Loss of Microvilli Lipid
Clumping of Deposition
Blebs
Nuclear Chromatin

Damage to Mitochondria
Mitochondrial damage may result in several biochemical abnormalities:

• Failure of oxidative phosphorylation leads to

progressive depletion of ATP, culminating in
necrosis of the cell.
• Abnormal oxidative phosphorylation also leads
to the formation of reactive oxygen species,
which have many deleterious effects.
• Damage to mitochondria is often associated
with the formation of a high-conductance
channel in the mitochondrial membrane, called
the mitochondrial permeability transition pore.
The opening of this channel leads to the loss of
mitochondrial membrane potential and pH
changes, further compromising oxidative
phosphorylation.
• The mitochondria also contain several proteins
that, when released into the cytoplasm, tell the
cell there is internal injury and activate a
pathway of apoptosis

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Consequences of loss of calcium homeostasis during

cell injury • Ischemia and certain toxins cause an
increase in cytosolic calcium
concentration, initially because of
release of Ca2+ from the intracellular
stores, and later resulting from
increased influx across the plasma
membrane.
• Intracellular calcium, when increased,
can activate a number of enzymes
including proteases, phospholipases,
ATPases, and endonucleases
• Increased intracellular Ca2+ levels
also result in the induction of
apoptosis, by direct activation of
caspases and by increasing
mitochondrial permeability.
• Intracellular free calcium is
maintained <0.1 mM compared to
extracellular [Ca2+] (~1 mM)

The role of reactive oxygen species in cell injury

Cells produce energy by reducing molecular oxygen to water. During
the process some amounts of partially reduced reactive oxygen species
can be formed (H2O2, O2-, OH.)
»These reactive oxygen species react with proteins, lipids and nucleic acids,
producing cell damage
»The cell has scavenging systems to react with and deactivate these reactive
oxygen species

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Defects in Membrane Permeability

Early loss of selective membrane

permeability leading ultimately to overt
membrane damage is a consistent feature
of most forms of cell injury. The plasma
membrane can be damaged by ischemia,
various microbial toxins, lytic
complement components, and a variety of
physical and chemical agents. Several
biochemical mechanisms may contribute
to membrane damage

Decreased phospholipid synthesis

Increased phospholipid breakdown
ROS
Cytoskeletal abnormalities.
Lipid breakdown products.

Damage to DNA and Proteins

Cells have mechanisms that repair damage

to DNA, but if this damage is too severe to
be corrected (e.g., after radiation injury or
oxidative stress), the cell initiates its suicide
program and dies by apoptosis. A similar
reaction is triggered by improperly folded

proteins, which may be the result of inherited mutations or

external triggers such as free radicals. Since these
mechanisms of cell injury typically cause apoptosis, they are
discussed later in the chapter.

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