Dr Iram Khurshid
Assistant professor,
CKMC
MECHANISM OF IRREVERSIBLE
INJURY:
1. ATP Depletion
2. Mitochondrial damage
3. Influx of calcium ions
4. Accumulation of Oxygen-Derived Free
Radicals (Oxidative Stress)
5. Defects in Membrane Permeability
6. Damage to DNA and Proteins
1. ATP DEPLETION
1. Failure of Na+/K+ pump → influx of
sodium n water and efflux of
potassium → cellular n ER swelling.
2. Failure of Ca2+ pump → Ca2+
influx → increase mitochondrial
permeability.
3. Disaggregation of ribosomes from
RER → Decrease protein synthesis.
4. Anaerobic glycolysis →
increase lactic acid→ dec PH →
Nuclear chromatin clumping.
5. Accumulation of misfolded
proteins n DNA → triggers
APOPTOSIS.
[Link] Damage
Mitochondrial damage can occur
directly due to hypoxia or toxins or
as a consequence of increased
cytosolic Ca2+.
Damage results in:
MITOCHONDRIAL 1. Disruption of
mitochondrial membrane
DAMAGE potential → dec ATP
2. Increase reactive
oxygen species (ROS)
3. Release of
cytochrome c →
APOPTOSIS
[Link] of Calcium and Loss
of Calcium Homeostasis:
❖Cytosolic calcium is maintained at
extremely low levels intracellularly by
energy dependent transport;
❖ Ischemia and toxins can cause Ca2+ influx
across the plasma membrane and release
of Ca2+ from mitochondria and
endoplasmic reticulum (ER).
❖Increased cytosolic calcium activates :
[Link] that degrade membrane
phospholipids.
2. Proteases that break down membrane and
cytoskeletal proteins
3. ATPases that hasten ATP depletion.
4. Endonucleases that cause chromatin
fragmentation.
5. INCREASE MITOCHONDRIAL
PERMEABILITY → Decrease ATP.
4. Accumulation of Oxygen-Derived
Free Radicals (Oxidative Stress)
Free radicals are unstable, partially reduced
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
in biological systems.
The major forms are superoxide anion (O2 • ",
one extra electron), hydrogen peroxide (H2O2,
two extra electrons), hydroxyl ions.
FREE RADICAL
GENERATION OCCURS
BY
Ionizing Nitric oxide
Normal Production
radiation (NO),
(e.g., UV Light metabolic by Transition
processes leukocytes chemical metals (e.g.,
and x-rays) mediator, can
can hydrolyze such as the during act directly as iron and
water into reduction of inf lammati a free radical copper) can
hydroxyl oxygen to on to or be catalyze free
(OH#) and water sterilize converted to radical
hydrogen during sites of other highly formation.
(H#) free reactive forms
respiration. infection.
radicals.
Fortunately, free radicals are inherently
unstable and generally decay
spontaneously.
In addition, several systems contribute
to free radical inactivation:
❖1. Antioxidants either block the
initiation of free radical formation or
scavenge free radicals; these include
vitamins E and A, ascorbic acid, and
glutathione.
❖2. The levels of transition metals that
can participate in free radical formation
are minimized by binding to storage
and transport proteins (e.g.,
transferrin, ferritin, lactoferrin, and
ceruloplasmin)
❖ 3. Free radical scavenging enzyme
systems catabolize hydrogen peroxide
(catalase, glutathione peroxidase) and
superoxide anion (superoxide
dismutase).
Free radicals readily propagate
additional free radical formation with
other molecules in an autocatalytic
chain reaction that often breaks
chemical bonds.
Thus, 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
mitochondr
ia, DNA,
proteins
and lipids
5. Defects in Membrane
Permeability
❖ Membranes can be damaged directly by toxins,
physical and chemical agents, lytic complement
components, and perforins, or indirectly as
described by the preceding events (e.g., ROS,
Ca2+ activation of phospholipases).
❖ Increased plasma membrane permeability
affects intracellular osmolarity as well as
enzymatic activity;
Increased mitochondrial membrane
permeability reduces ATP synthesis and
can drive apoptosis;
Altered lysosomal integrity unleashes
extremely potent acid hydrolases that can
digest proteins, nucleic acids, lipids, and
glycogen.
[Link] to DNA and Proteins
❖ Damage to DNA that exceeds normal repair capacity
(e.g., due to ROS, radiation, or drugs) leads to
activation of apoptosis. Similarly, accumulation of
large amounts of improperly folded proteins (e.g., due
to ROS or heritable mutations) triggers apoptotic
pathways.
❖ Within limits, all the changes of cell injury
described previously can be offset, and cells can
return to normal after injury abates (reversible
injury).
Persistent or excessive injury causes cells to
pass a threshold into irreversible injury
associated with extensive cell membrane
damage, lysosomal swelling, and
mitochondrial vacuolization with deficient
ATP synthesis.
NECROSIS
1. COAGULATIVE NECROSIS
Coagulative necrosis is the most common
pattern, predominated by protein
denaturation with preservation of the cell
and tissue framework. This pattern is
characteristic of hypoxic death in all tissues
except the brain.
Necrotic tissue undergoes either heterolysis
(digestion by lysosomal enzymes of
invading leukocytes) or autolysis (digestion
by its own lysosomal enzymes).
Normal Renal tubule
MICROSCOPY
Renal
infarction with
coagulative
necrosis.
Note renal
tubules and
glomerular
necrotic cells
are deeply
eosinophilic
stained and
anucleated.
2. LIQUEFACTIVE NECROSIS
Liquefactive necrosis occurs when
autolysis or heterolysis predominates
over protein denaturation.
The necrotic area is soft and filled with
fluid. This type of necrosis is most
frequently seen in localized bacterial
infections (abscesses) and in the brain.
Liquefactive
Necrosis in the
brain which is
marked by
(i)loss of neurons
and neuroglial
cells and
(ii)the formation
of a clear space
at the center
surrounded by
inflammatory
cells.
Caseous necrotic centers surrounded
with epithelioid cells and Langhans’
giant cells.
