CELL INJURY
B.M.C.Randika WimalasiriB.Sc in MLS(Peradeniya)
Lecturer(Probationary)Department of Medical Laboratory Sciences
INTRODUCTION
• The basis of disease: Injury to normal cells
• Normal cell has a narrow range of function
• This function is decided by –– genetic programs which control its
metabolism
– cell differentiation and specialization
– the activities of the neighbouring cells and
– the availability of metabolic substrates.
INTRODUCTION CONTD..
• Homeostasis- ability to handle physiologic demands by maintaining a steady state
NORMAL CELL(Homeostasis)
ADAPTATIONCELL INJURYCELL DEATHInability
to adapt
Physiologic stresses,
pathologic events
Injurious stimulus
CAUSES OF CELL INJURY
1. Reduction in the supply of Oxygen to tissues
Insufficient oxygenation of blood
Decreased oxygen
blood
Decreased oxygen carrying capacity of the
blood
Ischemia
Hypoxia -any condition reducing the availability of
oxygenC
ause
sC
ause
s
CAUSES OF CELL INJURY CONTD..
• Hypoxic injury
– Loss of oxygen
– Comparatively less rapid and mild
• Ischemic injury
– Loss of oxygen
– Loss of metabolic substrates like glucose
– more rapidly and severely injured
CAUSES OF CELL INJURY CONTD..
2. Physical agents
1
Mechanical trauma
2
Radiation 3
Extremes of temperature (deep cold, burns)
4
5 Sudden changes in atmospheric pressure
CAUSES OF CELL INJURY CONTD..
3. Chemical agents and drugsI. Harmful to cells even in small concentrations.
Ex. Arsenic, Mercurial salts, Cyanide (destroy sufficient numbers of cells within minutes or hours to cause death).
II.Simple chemicals harmful in high concentrations
Ex. glucose and salt in hypertonic solutions (cause cell injury directly or by deranging electrolyte balance in cells)
CAUSES OF CELL INJURY CONTD..
III. Harmful when regular exposure in small concentrations over a long period of time
Ex. insecticides, herbicides, environmental and air polluting industrial waste, asbestos, alcohol and recreational drugs
IV. Drugs that are difficult to determine the border of therapeutic and injurious levels
Ex. therapeutic drugs
CAUSES OF CELL INJURY CONTD..
4. Infectious agents– Viruses– Bacteria – Fungi– Parasites-rickettsiae and helminthes – Other infectious agents
• Cause cell injury of great morphologic diversity.
CAUSES OF CELL INJURY CONTD..
5. Immunologic reactions• The immune system -serves an essential
function in defending the body against infectious pathogens.
• However, cause cell injury by immune reactions
– Ex. Anaphylactic reactions to foreign proteins and drugs, autoimmune disease as a result of reactions to self antigens are a few examples.
CAUSES OF CELL INJURY CONTD..
• Anaphylaxis is a life-threatening type of allergic reaction. Anaphylaxis is a severe, whole-body allergic reaction to a chemical that has become an allergen.
CAUSES OF CELL INJURY CONTD..
6. Genetic Derangements• Defects in certain chromosomes occur during cell
division
• Results: various genetic defects range from addition or loss of whole chromosomes
• Examples:– addition of an extra chromosome 21 as in Downs
syndrome – replacement of a single amino acid in Hb resulting in
decreased lifespan of red blood cells in sickle cell anemia.
CAUSES OF CELL INJURY CONTD..
7. Nutritional Imbalances• Nutritional deficiencies- cause cell injury with
much morbidity and mortality.
Ex.Protein calorie deficiencies, vitamin deficiencies cause disease in underprivileged populations.
CAUSES OF CELL INJURY CONTD..
• Nutritional excesses- result in cell injury and cause disease
– Ex. excess of lipids can cause atherosclerosis leading myocardiac ischemic injury.
MECHANISMS OF CELL INJURY
• Principles1.The response of the cells to injurious stimuli
depends on the type of injury, its duration and its severity.
Small stimulus /short duration
Reversible injury
Irreversible injury
Large doses /long duration
Cell death
MECHANISMS OF CELL INJURYCONTD..
2. The consequences of the injury depend on the type of cell and its ability to adapt to the injury.
• Injury to heart muscle vs Injury to skeletal muscle
MECHANISMS OF CELL INJURYCONTD..
3. Functional and biochemical abnormalities occur in one or more cellular components cause cell injury
• Ribosomes- protein synthesisX Cytoskeleton-
maintains cell structure
MECHANISMS OF CELL INJURYCONTD...
• Cell membrane- ionic balance and transport
Cellular respiration takes place
MITOCHONDRIAL DAMAGE • Mitochondria : ATP production
• Hypoxia / chemical injury - ATP production reduced or stopped.
• ATP is necessary for the synthetic and degradative processes– Membrane transport– Protein synthesis– Lipogenesis– Gluconeogenesis– Phagocytosis and etc.
• ATP depletion: many critical systems will not function properly as given below.
EFFECTS OF ATP DEPLETION
ATP depletion
Improper functioning of Na+ / K+ pump
Sodium accumulates in the cell
Water enters the cell by osmosisCell
swelling
Dilatation of the endoplasmic reticulum.
1.
EFFECTS OF ATP DEPLETIONCONTD…
2. Anaerobic glycolysis
Reduces the pH in the cell
Rapid depletion of glycogen stores
Lactic acid production+
Enzymes inactivation at low pH.
EFFECTS OF ATP DEPLETIONCONTD..
Reduction in protein synthesis
3. Ribosomes detach from the rough endoplasmic reticulum
EFFECTS OF ATP DEPLETIONCONTD..
4. Reduced ATP
Disturb integrity of the
cytoplasmic membrane
Mitochondria and endoplasmic reticulum
is released into the cytoplasm
Increasing its intracellular
Ca2+ concentration
1.4 REVERSIBLE AND IRREVERSIBLE CELL INJURY
• Reversible cell injury- the cell can revert back to normal if the injury is within limits, if the cell can withstand and if the injurious stimulus is discontinued.
• If the stimulus is persistent or the injury is excessive and the cell passes over this threshold and the injury becomes irreversible.
• The earliest changes (biochemical changes)associated with various forms of cell injury are,
1.Reduced synthesis of ATP: See previous section.
2.Loss of cell membrane integrity.
.
Early loss of selective membrane permeability
Membrane damage
Affect the functions and integrity of all cellular membranes
• The reasons for membrane damage: – reactive oxygen species
– decreased phospholipid synthesis
– increased phospholipid breakdown
– cytoskeletal abnormalities
3. Defective protein synthesis due to inherited mutations or external triggers Eg. free radicals.
4. Damage to cytoskeleton
• increased cytosolic calcium causes activation of proteases
5. Damage to DNA by
• radiation
• cytotoxic anticancer drugs and
• hypoxia- directly or via production of free radicals.
Ultra structural changes ofreversible cell injury
Changes in1. Plasma membrane-cytoplasmic extrusions
called blebs occur in the membrane and these can be broken off. Furthermore, blunting and loss of microvilli may be occur.
2. Mitochondria-swelling of the mitochondria occur with deposition of phopholipid. At a later stage these deposits may get calcified.
3. Endoplasmic reticulum (ER) - Dilatation and detachment of ribosomes.
4. Nucleus-changes in the nucleolus by clumping of nuclear chromatin
Irreversible cell injury
• Characterized by– Extensive damage to all cell membranes– Lysosomal swelling– Vacuolation of mitochondria– Release of extra and intracellular calcium
resulting in enzyme activation. These enzymes then degrade the cells own proteins. The damaged cell membrane leaks these degraded proteins and enzymes causing further irreversible cell damage and cell death.
Detection of cell injury
• The enzymes or proteins leaked out from damaged cells get into the blood stream and can be detected in the blood.– tissue-specific cellular injury and necrosis
markers in blood serum samples.
– Example: hypoxic or ischemic damage to cardiac muscle reflected by increased levels of enzyme Creatine Kinase and a contractile protein called trophonin in blood.