Basic Pathology

Chapter: Cell Injury

Prof. Md. Ruhul Kuddus, PhD.

Cell injury
• Cell damage (also known as cell injury) is a
variety of changes of stress that a cell suffers
due to external as well as internal
environmental changes.
• Amongst other causes, this can be due to
physical, chemical, infectious, biological,
nutritional or immunological factors.
Causes of cell injury
• Genetic causes
• Acquired causes:
▪ Hypoxia and ischemia
▪ Physical agents
▪ Chemical agents and drugs
Microbial agents
Immunological agents
Nutritional derangements
(anorexia, insulin resistance, and increased muscle
protein breakdown)
Psychological factors
 Causes of cell injury
1. Oxygen deprivation/hypoxia

❑ Ischemia ( loss of blood supply from impeded arterial

flow or reduce venous drainage)
Local e.g. embolus
Systemic e.g. cardiac failure
❑ Hypoxia ( deficiency of oxygen causing cell injury by
reducing aerobic oxidative respiration)
Oxygen problems e.g. altitude
Haemoglobin problems e.g. anaemia
❑ Oxidative phosphorylation
E.g. cyanide poisoning
 Causes of cell injury
2. Physical agents

❑ Direct Physical effect

Exposure of tissue to extreme heat or cold results in

direct injury that is often irreversible, resulting in a
pattern of coagulative necrosis.

Sudden changes in pressure can cause cellular

disruption (e.g. a hammer blow to the thumb).

Electrical currents can cause direct breakdown of

cellular membranes that may be irreversible.
Causes of cell injury
• Chemical agents & drugs: Common poisons
(arsenic, cyanide, mercury) interfere with
cellular metabolism. If ATP levels drop below
critical levels, affected cells will die.

• The list of pharmaceuticals that may have toxic

effects on cells is enormous. Some act directly,
but most have their effect through breakdown
metabolites. Metabolism of alcohol (a type of
drug) to acetaldehyde is one example.
4. Microbial agent Injuries by microbes include
infections caused by Fungi, Rickettsiae,
Bacteria, parasites and Viruses

5. Immunologic agents: Double –edged sword’-

protects the host against various injurious agents
but it may also cause cell injury.
• Hypersensitivity reactions
• Anaphylactic reactions to a foreign body
Autoimmune diseases
 • 6. Nutritional Imbalances:
Dietary insufficiency of protein, vitamins and/or
minerals can lead to injury at the cellular level due to
interference in normal metabolic pathways.

• Dietary excess
can likewise lead to cellular and tissue alterations
that are detrimental e.g. fat is the biggest offender, or
excess ingestion of "health supplements"
Aging
● Programmed aging whereby after a defined
number of divisions the cell undergoes
terminal differentiation.
● Development of an increasing population of
cells irreversibly committed to death.
● Increased susceptibility to somatic mutation
and a build-up of errors leading to an
eventual’ error catastrophe.
● Faulty DNA repair mechanisms
 Targets of cellular injury
▪ DNA damage: In human cells, both
normal metabolic activities and environmental factors such
as ultraviolet light and other radiations can cause DNA
damage, resulting in as many as
one million individual molecular lesions per cell per day.
▪ Membrane damage: Damage to the cell membrane disturbs
the state of cell electrolytes, e.g. calcium, which when
constantly increased, induces apoptosis.
▪ Mitochondrial damage: May occur due to ATP decrease or
change in mitochondrial permeability.
▪ Ribosome damage: Damage to ribosomal and cellular
proteins such as protein misfolding, leading to apoptotic
enzyme activation.
Types of damage/cell injury
• Reversible & Irreversible cell injury

• Cell injury: If the cell’s adaptive capability is

exceeded or if adaptive response is not possible,
cell injury develops.

Two types
• Reversible cell injury ( Degeneration ):stress is mild
to moderate ; injured cell may recover.

• Irreversible cell injury ( Necrosis ) : Persistent &

severe form of cell injury leads to cell death.
 Reversible injury
Reversible injury is the stage of 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
in the plasma membrane, leading to an inability to maintain
ionic and fluid homeostasis. In some forms of injury,
degenerated organelles and lipids may accumulate inside
the injured cells.
Reversible cell injury
Fatty change
• The cell has been damaged and is unable to
adequately metabolize fat. Small vacuoles of fat
accumulate and become dispersed within cytoplasm.
Mild fatty change may have no effect on cell function;
however, more severe fatty change can impair
cellular function.
• In the liver, the enlargement of hepatocytes due to
fatty change may compress adjacent bile canaliculi,
leading to cholestasis. Depending on the cause and
severity of the lipid accumulation, fatty change is
generally reversible. Fatty Change is also known as
fatty degeneration, fatty metamorphosis, or fatty
steatosis.
Cellular swelling
• Cellular swelling (or cloudy swelling) may occur due
to cellular hypoxia, which damages the sodium-potassium
membrane pump; it is reversible when the cause is
eliminated.
• Cellular swelling is the first manifestation of almost all
forms of injury to cells. When it affects many cells in an
organ, it causes some pallor, increased turgor, and
increase in weight of the organ.
• On microscopic examination, small clear vacuoles may be
seen within the cytoplasm; these will affect
the endoplasmic reticulum. This pattern of non-lethal injury
is sometimes called hydropic change or vacuolar
degeneration.
• Hydropic degeneration is a severe form of cloudy swelling.
It occurs with hypokalemia due to vomiting or diarrhea.
Cyanosis of the hand in someone
with low oxygen saturations
• The ultrastructural changes of reversible cell
injury include:
• Blebbing
• distortion of microvilli
• loosening of intercellular attachments
• mitochondrial changes
• dilation of the endoplasmic reticulum
Irreversible injury
• Cell death is a state of irreversible injury,
• It may occur in the living body as a local or
focal change: autolysis, necrosis and apoptosis
• The changes that follow it: gangrene and
pathologic calcification
NECROSIS
• Necrosis is characterized by cytoplasmic swelling,
irreversible damage to the plasma membrane, and
organelle breakdown leading to cell death.
• The stages of cellular necrosis include pyknosis;
clumping of chromosomes and shrinking of the
nucleus of the cell, karyorrhexis; fragmentation of the
nucleus and break up of the chromatin into
unstructured granules, and karyolysis; dissolution of
the cell nucleus.
• Cytosolic components that leak through the
damaged plasma membrane into the extracellular
space can incur an inflammatory response.
Necrosis
• Necrosis is invariably accompanied by
inflammatory reaction.
• Various agents such as hypoxia, chemical and
physical agents, microbial agents,
immunological injury, etc
• Two essential changes characterize irreversible
cell injury in necrosis of all types
Cell digestion by lytic enzymes
Denaturation of proteins
Type of necrosis
There are six types of necrosis:
• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat necrosis
• Fibroid necrosis
• Gangrenous necrosis
 Coagulative necrosis
• It’s a form of tissue necrosis in which the component cells
are dead but the basic tissue architecture is preserved
for at least a couple of days.
• The affected tissues take on a firm texture.
• Presumably the injury denatures not only structural proteins
but also enzymes and so blocks the proteolysis of the dead
cells
✔ as a result, eosinophilic, anucleate cells may persist
for days or weeks
✔ Ultimately, the necrotic cells are removed by
phagocytosis of the cellular debris.
• Coagulative necrosis occurs in most bodily organs, excluding the
brain. Different diseases are associated with coagulative necrosis,
including acute tubular necrosis and acute myocardial infarction
• Regeneration: labile cells adjacent to the affected tissue will replicate
and replace the cells that have been killed during the event.
Liquefactive necrosis
• Liquefactive necrosis, also called colliquative
necrosis, is characterized by partial or complete
digestion of necrotic tissues and transformation into
a viscous liquid mass and is seen with infections.
• Hydrolytic enzymes released by bacteria or
lysosomes dissolve organelles in cells experiencing
necrosis, leading to morphological appearance.
• The necrotic tissue is sometimes creamy yellow
due to pus formation.
• Liquefactive necrosis occurs mainly in tissues that
contain less protein and more lipids (e.g., brain) or
produce more proteases (e.g., pancreas)

https://www.cusabio.com/c-21042.html#a01
Apoptosis (programmed cell death)
• a form of ‘coordinated and internally programmed
cell death’
• pathway of cell death that is induced by a tightly
regulated suicide program in which cells destined
to die
• activate enzymes capable of degrading the cells'
own nuclear DNA and nuclear and cytoplasmic
proteins
• Apoptosis is responsible for mediating cell death
in a wide variety of physiologic and pathologic
processes
• The plasma membrane of the apoptotic cell remains intact,
but the membrane is altered in such a way that the cell and
its fragments become avid targets for phagocytes.

• The dead cell is rapidly cleared before its contents have

leaked out, and therefore cell death by this pathway does
not elicit an inflammatory reaction in the host
• Thus, apoptosis differs from necrosis

• However, apoptosis and necrosis sometimes coexist, and

apoptosis induced by some pathologic stimuli may
progress to necrosis
The different stages of apoptotic cell death start by cellular shrinkage and
chromatin condensation, concomitant with formation of membrane blebs.
Organelles and nucleus fragment and the blebs begin formation of apoptotic
bodies which are eventually engulfed by macrophages or neighboring cells by
endocytosis/phagocytosis. The lack of release of cellular components to the
extracellular fluid results in the absence of inflammation.
Apoptosis vs Necrosis
 Cell injury by Oxidative stress
• Oxidative stress refers to cellular abnormalities that
are induced by ROS, which belong to a group of
molecules known as free radicals.
• Free radical-mediated cell injury is seen in many
circumstances, including chemical and radiation injury,
hypoxia, cellular aging, tissue injury caused by
inflammatory cells, and ischemia-reperfusion injury.

• In all these cases, cell death may be by necrosis,

apoptosis, or the mixed pattern of necroptosis.
Principal Free Radicals Involved in Cell Injury

A: hydroxyl radical (HO•);

B: hydroxide ion (HO−);
C: triplet oxygen (O22•);
D: superoxide anion (O2•-);
E: peroxide ion (O2−2);
F: hydrogen peroxide (H2O2);
G: nitric oxide (NO•)
Ref: https://doi.org/10.1007%2Fs12291-014-0446-0
https://www.muhadharaty.com/lecture/14584/D--Lamyaa/Cell-Injury-pptx
The generation, removal, and role of reactive
oxygen species (ROS) in cell injury.
Cells have developed mechanisms to remove free radicals
Cells have developed mechanisms to remove free radicals and thereby
minimize their injurious effects. Free radicals are inherently unstable and
decay spontaneously. There also are nonenzymatic and enzymatic
systems, sometimes called free radical scavengers, serving to inactivate
free radicals.

• The rate of decay of superoxide is significantly increased by the

action of superoxide dismutase (SOD).

• Glutathione (GSH) peroxidases are a family of enzymes whose major

function is to protect cells from oxidative damage. The most abundant
member of this family, GSH peroxidase 1, is found in the cytoplasm of
all cells. It catalyzes the breakdown of H2O2 by the reaction 2GSH +
H2O2 → GS-SG + 2H2O. The intracellular ratio of oxidized GSH to
reduced GSH is a reflection of this enzyme’s activity and thus of the
cell’s ability to catabolize free radicals.
 Cells have developed mechanisms to remove free
radicals………..

● Catalase, present in peroxisomes, catalyzes the

decomposition of hydrogen peroxide (2H2O2 → O2 +
2H2O). It is one of the most active enzymes known,
capable of degrading millions of molecules of H2O2 per
second.

● Endogenous or exogenous anti-oxidants (e.g., vitamins E,

A, and C and β-carotene) may either block the formation
of free radicals or scavenge them after they have formed.
 ROS causes cell injury by damaging multiple
components of cells
• Lipid peroxidation of membranes

• Crosslinking and other changes in proteins

Free radicals promote sulfhydryl-mediated protein crosslinking,
resulting in enhanced degradation or loss of enzymatic activity. Free
radical reactions also may directly cause polypeptide fragmentation.
Damaged proteins may fail to fold properly.

• DNA damage
Free radical reactions with thymine residues in nuclear and
mitochondrial DNA produce single strand breaks. Such DNA damage
has been implicated in apoptotic cell death, aging, and malignant
transformation of cells.