cell injury - ou.ac.lk 1 part 1.pdf · adaptation cell injury inability cell death to adapt...

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


2. Physical agents

1

Mechanical trauma

2

Radiation 3

Extremes of temperature (deep cold, burns)

4

5 Sudden changes in atmospheric pressure


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)


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


4. Infectious agents– Viruses– Bacteria – Fungi– Parasites-rickettsiae and helminthes – Other infectious agents

• Cause cell injury of great morphologic diversity.


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.


• 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.


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.


7. Nutritional Imbalances• Nutritional deficiencies- cause cell injury with

much morbidity and mortality.

Ex.Protein calorie deficiencies, vitamin deficiencies cause disease in underprivileged populations.


• 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.

http://www.pathopedia-india.com/Cellinjury_image.htm

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.

cell injury - ou.ac.lk 1 part 1.pdf · adaptation cell injury inability cell death to adapt...

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