Cellular Injury, Adaptations, and

Death
 The Cell and the Environment

Stimuli

Cell
Adaptation
Cell Injury

Reversible
Irreversible (cell death)

apoptosis necrosis
Adaptive Responses

Irreversible Cell Injury

 Causes of Cell Injury
1. Hypoxia: (Oxygen deficiency), causes cell injury by
reducing the oxidative respiration & Mainly due to:
 ischemia (impaired blood supply), ischemia compromises the
supply not only of oxygen, but also of metabolic substrates,
including glucose, I.e., ischemic tissues are injured rapidly
and severely than hypoxic tissues. most common
 inadequate oxygenation of blood (cardio-respiratory failure)
 loss of oxygen carrying capacity (anaemia)
 Carbon monoxide poisoning
2. Physical Agents
 Trauma, radiation, extremes of temperatures( burns
and deep cold), electric shock
3. Chemicals and Drugs
 Wide variety
 Causes of Cell Injury

4. Immunologic Reactions
 Allergic reactions, autoimmune diseases
5. Genetic Defects
 Obvious congenital malformations (Down
syndrome)
 Subtle single amino acid substitution (hemoglobin S
of sickle cell anemia)
6. Nutritional Imbalances
 Deficiency of nutrients/ or excess
7. Aging
8. Microbiologic Agents
 Viruses, worms, bacteria …..
Mechanism of Cell Injury
 General Principles of Cell Injury
 The cellular response to injurious stimuli depends on:
 the type of injury, its duration, and its severity

 The consequences of cell injury depend on:

 the type, state, and adaptability of the injured cell

 Intracellular site of injury, 4 systems:

1) Cell membrane integrity
2) Aerobic respiration (ATP generation)
3) Protein synthesis
4) Genetic apparatus integrity
 General Principles of Cell Injury
 The structural and biochemical elements of the cell are so
integrated connected that regardless of the initial locus of
initial injury, multiple secondary effects rapidly occur.

 Cellular function is lost far before cell death occur, and

morphologic changes of cell injury appear later

 The “point of no return” at which cell death has irreversibly

occurred is difficult to determine
Possible Biochemical Mechanisms
of Cell Injury

1) ATP depletion.

2) Acumulation of oxygen-derived free radicals.

3) Influx of Cacium.

4) Defect in plasma membrane permeability.

5) Damage to mitochondrial.

6) Damage to DNA and proteins.

 Mechanisms of Cell Injury
Generation of reactive oxygen free radicals Activated
Oxygen Species (superoxide O2.-, hydrogen peroxide H2O2, hydroxyl
OH.)

 Ischemia
 Radiation
 Inflammation
 Oxygen toxicity
 Chemicals
 Reperfusion injury
The role of oxygen in cell injury:
Mechanisms of Cell Injury

1) ISCHEMIC & HYPOXIC INJURY

 Reversible injury
 Irreversible injury
Sequence of events in Ischemic injury
 Ischemic and Hypoxic Injury

Reversible Injury

Mechanism:

1) Decreased oxidative phosphorylation

2) Increased anaerobic glycolysis
3) Detachment of ribosomes
4) Worsening mitochondrial function
5) Increasing membrane permeability
6) Cytoskeleton dispersion
7) Swelling of mitochondria, endoplasmic reticulum, and entire cells
 Ischemic and Hypoxic Injury

Reversible Injury

Mechanism:

1) Decreased oxidative phosphorylation:

“it is the first effect of hypoxia”
 Results in reduced intracellular ATP
 increased cytosolic free calcium

 reduced activity of “sodium pump”

 accumulation of sodium by cell
 isosmotic gain of water (swelling)
 diffusion of potassium from cell
Increased Cytosolic Calcium, source and
consequences
 Ischemic and Hypoxic Injury
Increased Cytosolic Calcium:
 Sources
 mitochondria
 endoplasmic reticulum
 external to the cell

 Consequences (activates enzymes)

 ATPase
 decreased ATP
 phospholipase
 decreased phospholipids
 protease
 disruption of membrane and cytoskeletal proteins
 endonuclease
 nuclear chromatin damage
 Ischemic and Hypoxic Injury

(continue)

Reversible Injury Mechanism:

2) Increased anaerobic glycolysis

 glycogen depletion
 lactic acid accumulation
 accumulation of inorganic phosphates
 reduced intracellular pH
3) Detachment of ribosomes
 reduced protein synthesis
4) Worsening mitochondrial function
 Ischemic and Hypoxic Injury

(continue)

Reversible Injury Mechanism:

5) Increasing membrane permeability

6) Cytoskeleton dispersion
 loss of microvilli
 formation of cell surface blebs
7) Swelling of mitochondria, endoplasmic reticulum, and entire
cells
** if oxygen is restored all the above changes are reversible
** if ischemia persisted  irreversible changes follows
 Ischemic and Hypoxic Injury

Irreversible Injury

Mechanisms :

 Phenomena characterizing irreversibility

(Point of NO return)
 inability to reverse mitochondrial dysfunction
 profound disturbances in membrane function is a central factor
 Ischemic and Hypoxic Injury
Mechanism of Irreversible Injury:
 Potential causes of membrane damage:
damage
1. progressive loss of membrane phospholipids due to:
 activation of phospholipase
 reduced synthesis of phospholipids

2. cytoskeletal abnormalities due to:

 activation of proteases
 cell swelling

3. toxic oxygen radicals due to:

 after restoration of blood flow (mainly from polymorphs)

4. lipid breakdown products as a result of:

 phospholipid degradation
 detergent effect on membranes

 Ultimately a massive influx of calcium due to membrane damage

 Ischemic and Hypoxic Injury
Irreversible Injury
Mechanism (continue)
 Massive influx of calcium (on reperfusion)
 Continued loss of cell proteins, coenzymes, ribonucleic acids and
other metabolites

 Injury to lysosomal membranes

 leakage of degradative enzymes  degrade cytoplasmic and nuclear
components

 Prominent leakage of cellular enzymes  measured in serum

 Influx of macromolecules from interstitium
 Ischemic and Hypoxic Injury
Irreversible Injury

Cellular changes:
 Mitochondrial changes

 severe vacuolization
 amorphous calcium-rich densities
 Extensive plasma membrane damage
 Prominent swelling of lysosomes
 “Myelin figures”-whorled phospholipid masses
Mechanisms of Cell Injury

FREE RADICAL MEDIATION OF

CELL INJURY
 Free Radical Mediation of Cell Injury
 Definition Of Free Radicals
Extremely unstable, highly reactive chemical species with a single
unpaired electron in an outer orbital

 readily react with organic and inorganic chemicals

 In cells they attack and degrade nucleic acids, proteins, lipids and
carbohydrates

 They initiate autocalytic reaction, i.e. molecules that react with

free radicals are converted into free readicals

 Examples Of Free Radicals

 Hydroxyl (OH. )
 Hydrogen (H. )
 Superoxide (O2.- )
 Free Radical Mediation of Cell Injury

 Free radicals constitutes an important mechanism of cell

injury

 It Contributes To:
 Chemical and radiation injury
 Oxygen and other gaseous toxicity
 Cellular aging
 Microbial killing by phagocytic cells
 Inflammatory damage
 Tumor destruction by macrophages
 Others
 Free Radical Mediation of Cell Injury

 Source of Free Radicals

 Hydrolysis of water into hydroxyl (OH . ) and hydrogen (H. )
free radicals by ionizing radiation (e.g. ultraviolet, x-ray)
 Reduction-oxidation (Redox) reactions in normal physiology
 Respiration generates  (O2.), (H2O2), (OH.)
 intracellular oxidases action
 transition metal reactions (Fenton reaction)
 Metabolism of exogenous chemicals
 e.g. carbon tetrachloride
 Macrophages and inflammatory reactions
How Free Radicals injure Cells?

Effects (consequences) of free radicals on cells.

Three Mechanisms:

1. Lipid peroxidation of membranes

 Free radicals attack double bonds in polyunsaturated lipids 
peroxides (unstable)  autocatalytic reaction
2. Lesions in DNA
 reactions with thymine with single-strand breaks  cell killing /
malignant transformation
3. Cross-linking of proteins
 sulfhydryl-mediated protein cross-linking  enhance degradation /
loss of enzyme activity
 Free Radicals Degradation
 As Free radicals are produced in radiation and chemical cell injury, they
are also generated normally during respiration and cell activities

 Therefore cells should have mechanisms to degrade free radicals to

minimize the damage

Free Radical Degradation Mechanisms:

 Unstable with spontaneous decay

 Decay accelerated by
 superoxide dismutase
 glutathione
 catalase
 Antioxidants (vitamin E, ceruloplasmin)
 block formation or scavenger
Mechanisms of Cell Injury

CHEMICAL INJURY
 Chemical Injury
 Mechanisms of Chemical Injury

1. Direct mechanism:
Combination with cell component
 mercury binding to sulfhydryl groups in cell membrane 
inhibit ATPase-dependant transport  increase permeability

2. Indirect mechanism:
Conversion to reactive toxic metabolite
 principally involves liver
 usually by P-450 mixed function oxidases in SER
 Metabolites react either directly with proteins and lipids
 Or more commonly involves free radical formation
e.g. Carbon tetrachloride (CCl4 ) conversion to free radicals CCl3. in the liver ...…
“fatty liver”