Reversible V/S Irreversible injury

Free Radical Injury

Cell Adaptations

Necrosis

Apoptosis

Intracellular accumulations

Cell Ageing

Cellular Injury & Adaptation:

Normal cell is in a dynamic state of “Homeostasis”

Normal physiologic stress : Normal homeostasis

Stress - Adaptation, e.g. hypertrophy, atrophy

Stress - Cell Injury

Reversible Irreversible Cell Death

Oxygen– deprivation: Hypoxia

Blood –deprivation : Ischemia

Physical—agents : Trauma, RTA

Chemical—agents : All drugs are poisons !

Infectious—agents : Bacterial, Viral, Fungal

Immunological—reactions : Autoimmune rn

Genetic-Rearrangements

Nutritional—imbalance: PEM, Malnutrition

1. Cell membrane integrity

2. Aerobic respiration

3. Protein synthesis

4. Genetic apparatus

Depending on : TypeDuration of Injury SeverityAdaptability

Injury at one locus leads to wide ranging

secondary effects

General Considerations:

Morphology becomes apparent late in cell injury.

Reaction of cell to injury depends on type of injury,

duration and severity.

Reaction of cell to injury also depends on the type, state

& adaptability of the cell.

Ultra-structural Changes

Light Microscopy Changes

Gross Morphological Change

Reduced oxidative phosphorylation & ATP depletion,

Cellular swelling & blebbing of plasma membrane

o Due to changes in ion concentrations and water influx,

Swelling of ER & Mitochondria,

Clumping of chromatin.

Point of No return: Lethal Hit– structural changes:

Amorphous densities in mitochondria: Myelin figure formation.

Loss of membrane permeability.

Swelling of mitochondria

Lysosome rupture

Nuclear condensation

Final result- cell adaptation /death.

Injurious Stimuli

Reversible stage

Apoptosis Necrosis

Reversible

Cell Injury

GENERAL BIOCHEMICAL MECHANISMS

Some pathogenic mechanisms are well defined for cell injury.

Ex: Cyanide inactivates the Cytochrome oxidase in

mitochondria

Bacteria elaborates phospholipases degrade cell

phospholipids

Many stimuli do not have precise mechanisms of cell injury..

Complex mechanisms involved.

ATP depletion

Oxygen deprivation and release of Reactive Oxygen

Species (ROS)

Loss of calcium Homeostasis

Defects in plasma membrane permeability

Mitochondrial damage

GENERAL BIOCHEMICAL MECHANISMS …Contd….

Ca++ : most imp. Mediator of cell injury.

Normal Levels of Calcium:

o Intracellular Ca++ < 0.1 mmol,

o Extracellular Ca++ 1.3 mmol.

Intracellular Ca++ is sequestered in Mitochondria & ER.

Increased cytosolic Ca++ activates various enzymes:

1. ATPases,

2. Phospholipases,

3. Proteases,

4. Endonucleases.

A CTIVATES

K+ Efflux Cellular Swelling

1st Reduced oxidative phosphorylation in

Mitochondria

2nd Depletion of ATP

3rd Reduced activity of Na pump

4th Increased glycolysis—decreased Ph

5th Detachment of ribosomes, reduced protein

synthesis, lipid deposition

6th Cellular swelling, Increased K efflux

Reversible injury– flow restored– may recover

Golden Period of ischemia

o Can save many lives

o Concept of emergency angiography in cath lab

Rarely the restoration may adversely damage the tissue This is Reperfusion Injury

Restored blood brings in high concentration of calcium

Increased local recruitment of inflammatory cells

Damaged mitochondria Increased ROS

INJURIOUS STIMULUS

Decreased ATP

LOSS OF ENERGY DEPENDENT CELULAR FUNCTIONS

MEMBRANE DAMAGE

MITOCHONDRIA DAMAGE

LYSOSOME RUPTURE

PLASMA MEMBRANE RUPTURE

INCREASED intracellular Ca++

REACTIVE OXYGEN SPECIES

PROTEIN BREAK DOWN DNA

DAMAGE

ENZYMATIC DIGESTION OF CELL COMPONENTS

LOSS OF CELL

CONTENTS

CELL DEATH