Transcript CELL INJURY - Center

CELL INJURY (PART1)
Sufia Husain
Assistant Prof & Consultant
KKUH, Riyadh.
September 2014
CELL INJURY
 When
the cell is exposed to an injurious agent
or stress, a sequence of events follows that is
loosely termed cell injury. Cell injury is
reversible up to a certain point, but if the
stimulus persists or is severe enough from the
beginning, the cell reaches a point of no
return and suffers irreversible cell injury and
ultimately cell death.
 Cell death, is the ultimate result of cell injury
CELL DEATH
 There
are two principal patterns of cell death,
necrosis and apoptosis.
 Necrosis is the type of cell death that occurs
after ischemia and chemical injury, and it is
always pathologic.
 Apoptosis occurs when a cell dies through
activation of an internally controlled suicide
program.
CAUSES OF CELL INJURY
Causes of both reversible and irreversible injury are the same
1) Oxygen Deprivation (Hypoxic cell injury). It common cause of cell injury and
cell death. Hypoxia can be due to
a) Ischemia/hypoxia (obstruction of arterial blood flow), the most common cause
seen in myocardial infarction and atherosclerosis.
b) Inadequate oxygenation of the blood e.g. lung disease and carbon monoxide
poisoning
c) Decreased oxygen-carrying capacity of the blood e.g. anemia
d) Inadequate tissue perfusion due to cardiorespiratory failure, hypotension,
shock etc
Depending on the severity of the hypoxic state, cells may adapt, undergo injury,
or die. Also some cell types are more vulnerable to hypoxic injury then others
e.g. neurons are most susceptible followed by cardiac muscle, hepatocytes and
then skeletal muscles.
CAUSES OF CELL INJURY CONT.
2)Physical Agents e.g. mechanical trauma, burns and deep cold, sudden
changes in atmospheric pressure, radiation, and electric shock
3)Chemical Agents and Drugs e.g. oxygen in high concentrations,
poisons, pollutants, insecticides, industrial and occupational hazards,
alcohol and narcotic drugs and therapeutic drugs.
4)Infectious Agents
5) Immunologic agents e.g. thyroid damage caused by
autoantibodies.
6) Genetic Derangements eg sickle cell anemia.
7) Nutritional Imbalances
MECHANISM OF CELL INJURY
1.
2.
3.
Depletion of ATP
Cell membrane damage/defects in membrane permeability: Membrane
damage may be
 indirect via hypoxia, ATP depletion and activation of phospholipases.
 direct by certain bacterial toxins, viral proteins, complement mediated lysis
via membrane attack complex (MAC) and by free radicals (reactive oxygen
species).
Mitochondrial damage:
It is seen specially in hypoxic injury and cyanide poisoning.
MECHANISM OF CELL INJURY CONT.
4.
5.
6.
Ribosomal damage:
It is seen in alcohol associated damage of liver cells and with
antibiotic use bacterial infection.
Nuclear and DNA damage:
Influx of intracellular calcium and loss of normal calcium balance
(homeostasis): ischemia causes an increase in intracellular calcium
concentration. Increased Ca2+ in turn activates a number of enzymes
which cause damage.
MECHANISM OF CELL INJURY CONT.
Accumulation of oxygen-derived free radicals (oxidative stress): Free radicals are
highly reactive and harmful atoms that have single unpaired electron in an outer
orbit. They are referred to as reactive oxygen species/free radicals.
The production of free radicals are initiated within cells in several ways called as the
free radical generating systems. They are produced via:
i.
Normal metabolism/ respiration: Small amounts of harmful reactive oxygen forms are
produced as a bi-product of mitochondrial respiration (metabolic reduction-oxidation
reactions that occur during normal metabolic processes). During normal respiration,
small amounts of free radicals are produced.
ii.
Via ionizing radiation injury (absorption of radiant energy e.g. ultraviolet light, x-rays
or any other type of radiation).
iii.
Chemical toxicity: enzymatic metabolism of exogenous chemicals or drugs.
iv.
Oxygen therapy and reperfusion injury
v.
Immune response or inflammation (neutrophil oxidative burst)
vi.
Transition metals such as iron and copper can trigger production.
 The common free radicals are
7.




superoxide anion radical (O2-),
hydrogen peroxide (H2O2),
and hydroxyl ions (OH).
Nitric oxide (NO) is an important chemical mediator generated by various cells and it
can also act as a free radical.
MECHANISM OF CELL INJURY
CONT.


Free radicals cause damage to lipids, proteins, and nucleic acids. The main effects of
these reactive species/ free radicals are:
1. Lipid peroxidation of membranes: leads to damage of membranes, organelles etc.
2. Oxidative modification of proteins: leads to protein fragmentation.
3. DNA damage: can lead to cell aging and malignant transformation of cells.
Certain substances in the cells remove/ inactivate the free radicals in order to
minimize injury caused by them. They are called as the free radical scavenging
system. They are:
 Antioxidants: vitamins E, A and C (ascorbic acid).
 Enzymes: which break down hydrogen peroxide and superoxide anion e.g.
Catalase, Superoxide dismutases, Glutathione peroxidase and mannitol.
 Any imbalance between free radical-generating and radical-scavenging
systems results in oxidative stress causing cell injury.
Cellular and biochemical sites of damage in cell injury.
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MECHANISM IN HYPOXIC CELL INJURY
Hypoxia
Decreased oxidative
phosphorylation
Decreased ATP
Anaerobic respiration leading
to excess lactic acid production
Membrane damage and proton
pump failure
Membrane, organelle and
nuclear damage
Loss of ion gradient
Release of Calcium from
mitochondria
Calcium influx into cell from extracellular
space which leads to further injury
REVERSIBLE CELL INJURY
The type of injury, the time duration of injury and the severity of
injury will determine the extent of cell damage i.e. whether the injury
is reversible or irreversible.
 Earliest changes associated with cell injury are reversible. They
are:
1.
Swelling of cell cytoplasm with vacuolization of cytoplasm called hydropic
or vacuolar degeneration.
2.
Mitochondrial swelling.
3.
Fatty change.
4.
Plasma membrane blebbing.
5.
Dilation and degranulation of the rough endoplasmic reticulum leading to
loss of protien synthesis.
6.
Eosinophilia (due to decreased cytoplasmic RNA)

Within limits, the cell can compensate for these derangements and,
if the injurious stimulus is removed the damage can be reversed.
IRREVERSIBLE CELL INJURY
Persistent or excessive injury, however, causes cells to pass the
threshold into irreversible injury. Irreversible injury is marked by
1. severe mitochondrial dilatation and damage with the
appearance large, amorphous densities in mitochondria.
2. extensive damage and disruption of plasma/cell membrane
3. increased eosinophilia
4. Numerous myelin figures
5. swelling and rupture of lysosomes leakage and enzymatic
digestion of cellular contents
6. Nuclear damage:
i.
ii.
iii.
pyknosis (shrinkage),
karyolysis (dissolution)
karyorrhexis (break down)
n
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NECROSIS.

Necrosis is changes that follow cell death in living tissue, due to enzymatic
digestion and denaturation of intracellular protein in the injured cell.

It occurs in irreversible injury. It is usually associated with inflammation in the
surrounding tissue.

It involves the death of a group of cells in one area.

Necrosis can result in:
 Cessation of function of the involved tissue or organ
 Release of certain cellular enzymes that can be detected in blood. The level
of these enzymes can be used as markers to diagnose the injury and also
can help determine the time and the extent of injury eg. Cardiac enzymes in
myocardial infarction (heart attack).
 An inflammatory response




The enzymes used in this degradation come from either
the lysosomes of the dying cell itself (referred to as
autolysis) or from lysosomes of neighbouring leukocytes
(referred to as heterolysis).
Autolysis is the death/disintegration of cells or tissues by
it’s own enzymes.
Autolysis is also seen in cells after death/ post mortem.
Autolysis is also seen in some pathologic conditions in
living organisms.
TYPES OF NECROSIS

There are 5 types of necrosis:





coagulative necrosis
liquefactive necrosis
caseous necrosis
fat necrosis
fibrinoid necrosis
COAGULATIVE NECROSIS:
Coagulative necrosis is characteristically seen due to blood
loss leading to ischemic/hypoxic death of cells in all tissues
except brain.
 e.g. heart (myocardial infraction), kidney( renal cortical
necrosis/ infarct), spleen (infarct) etc.
 Coagulative necrosis is not seen in the brain.
 Gross: The affected organ looks pale and firm/solid. It looks
liked cooked meat or boiled egg.
 Microscopy: In it there is preservation of the general tissue
architecture and initially the basic ghost outline of the
coagulated cell remains preserved for a few days. The cell
cytoplasm is eosinophilic with loss of nucleus.
 Ultimately, the necrotic cells are removed by phagocytosis
by the macrophages.

KIDNEY:
COAGULATIVE
NECROSIS
Kidney:
coagulative
necrosis
Gross: tissue is
firm
Micro: Cell
outlines are
preserved (cells
look ghostly), and
everything looks
red
LIVER COAGULATIVE NECROSIS
LIQUEFACTIVE NECROSIS
is a type of necrosis which results in transformation of the
tissue into a liquid viscous mass.
 Is characteristically seen in hypoxic cell death in the central
nervous system/brain and in suppurative infections (pus or
abscesses) especially bacterial.
 The affected tissue is softened/liquefied by the action of
hydrolytic enzymes released from the lysosomes in the brain
cells or in case of an abscess due to the enzymes released from
the neutrophils.
 Ultimately, in a living patient most necrotic cells are
phagacytosed.
 The affected area is soft with liquefied creamy yellow centre
containing necrotic cells, and neutrophils and is called
pus/abscess.

LIQUEFACTIVE
NECROSIS
LIQUEFACTIVE NECROSIS (CENTER LABELED ONE IS NECROSIS AND
SURROUNDING IS NEUTROPHILS.
CASEOUS NECROSIS

is a type of coagulative necrosis
classically seen in tuberculous
infection.

Gross: White, soft, curd like,
cheesy-looking (“caseous”)
material.

On microscopic examination, the
necrotic area appears as
amorphous pink granular debris
surrounded by a collar of
epitheloid cells (modified
macrophages), lymphocytes and
giant cells. This is known as
granuloma.

Here the tissue architecture is
completely obliterated.
TUBERCULOUS LUNG WITH A LARGE AREA OF CASEOUS NECROSIS. THE
CASEOUS DEBRIS IS YELLOW-WHITE AND CHEESY
FAT NECROSIS





Is focal areas of fat destruction/ necrosis due to enzymatic action of
lipase (which is released from injured pancreatic tissue) into the
surrounding fat in the abdominal cavity.
It is typically seen in acute pancreatitis.
Damaged cells release lipases, which breakdown the fat cells into
glycerol and free fatty acids. The produced fatty acids combine with
calcium in the blood to produce calcium soaps (called as fat
saponification) which looks like chalky white spots in the necrotic fat.
The outlines of necrotic/dead fat cells can be seen. Inflammation is
minimal.
Fat necrosis can also be seen in breast fat and other fatty areas due to
traumatic injury.
Figure 1-21 Foci of fat necrosis with saponification in the mesentery. The areas of white chalky deposits represent calcium soap formation at sites of lipid breakdown.
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© 2005 Elsevier

Normal adipose tissue

Fat necrosis
FIBRINOID NECROSIS
Is necrosis in the blood vessels (arteries, arterioles and
capillaries)
 There is deposition of fibrin material in the arterial walls,
which appears smudgy and acidophilic/eosinophilic.
 It is seen in immune mediated diseases (autoimmune
diseases) and also seen in malignant hypertension.

FIBRINOID NECROSIS
GANGRENOUS NECROSIS




Gangrenous necrosis is term commonly used in clinical practice by surgeons.
It is usually seen in limbs, generally the lower leg, that has lost its blood supply
and has undergone coagulative necrosis, called dry
gangrene/mummification. It is the non-infected ischemic necrosis
accompanied with drying of tissue. It is seen as a complication in
atherosclerosis and diabetes mellitus.
When there is superadded bacterial (putrefactive) infection coagulative
necrosis is modified by the action of the bacteria into liquefactive necrosis,
called wet gangrene. So, initially there is coagulative necrosis and then there
is superadded liquefactive necrosis. The bacteria is usually gram-positive
Clostridia. Clostridia lives in the gut or the soil and it can thrive in low oxygen
states. The infection can spread to the rest of the body and be life threatening,
so the limb has to be amputated.
The limb becomes foul smelling and black and starts decomposing.