Author Ketevan Gambashidze MD., Ph.D., D.

Sc

Associate-Professor
 Hypoxia - literally means a "deficiency in oxygen."

Hypoxia is a state of oxygen deficiency in the body which is sufficient to cause an

impairment of function.

Hypoxia is caused by the:

- Reduction in partial pressure of oxygen,

- Inadequate oxygen transport, or

- Inability of the tissues to use oxygen

It can refer to:

Hypoxia - a shortage of oxygen in the body.

Hypoxemia - is the reduction of oxygen specifically in the blood;

Anoxia - is when there is no oxygen available at all.

 Types of Hypoxia

1. Hypoxic / Environmental hypoxia - is a generalized hypoxia, an

inadequate supply of oxygen to the body as a whole.

Develops due to reduced partial pressure of O2 in an inhaled

air. Insufficient entry of O2 in blood initially results in hypoxemia
and subsequently - Hypoxia.

Thus, Hypoxemic hypoxia may be due to:

Low partial pressure of atmospheric oxygen such as found at

high altitude (Hypobaric), or

Normobaric - by replacement of oxygen in the breathing mix

either accidentally, or intentionally as in the recreational use of
nitrous oxide.
2. Respiratory hypoxia - is a reduction in the amount of oxygen passing into the blood
caused by a reduction in oxygen pressure in the lungs by the respiratory system disease:

- Reduced gas exchange area (mismatch of Surface area / Volume ratio)

due to pneumonia, emphysema, atelectasis, etc.

- Inadequate pulmonary ventilation e.g., in chronic Obstructive and Restrictive pulmonary

diseases, or Respiratory arrest.

- A decrease in oxygen saturation of the blood caused by Sleep apnea or Hypopnea.

- Shunts in the pulmonary circulation or a right-to-left shunt in the heart.

- Thickening of the alveolo-capillary membrane.

- Accumulation of interstitial fluid.

3. Hemic (Anemic) hypoxia - in which arterial oxygen pressure is normal,
but total oxygen content of the blood is reduced. It is caused by a reduction
in the amount of hemoglobin in the blood or a reduced number of red blood
cells.

A reduction in the oxygen transport capacity of the blood, or Hemic

hypoxia develops at :

- Anemia, when the blood fails to deliver oxygen to target tissues

- Blood donation

- Hemorrhage - bleeding

- Drugs, chemicals, or Carbon monoxide poisoning, which inhibits the

ability of hemoglobin to release the oxygen bound to it.

- Methemoglobinaemia - This hypoxia usually experienced by

smokers.

4. Circulatory hypoxia - is defined as the inability of the tissues to use oxygen

due to cardio-vascular insufficiency e.g. Heart failure, Shock, Collapse,
Vigorous infections etc.
 5. Histotoxic (tissue) hypoxia - is defined as the inability of the tissues to use

oxygen due to disabled Oxidative Phosphorylation Enzymes.

Examples are:

- Carbon monoxide

- Cyanide poisoning

- Certain narcotics

- Chewing tobacco

- Alcohol (this hypoxia usually experienced after drinking too much).

Essential role play also activation of POL and subsequent disorders of

mitochondrial and lysosomal membranes.

6. Ischemic, or stagnant hypoxia - in which there is a local restriction in the

flow of otherwise well oxygenated blood (generally due to constriction or

blocking of blood vessels). The oxygen supplied to the region of the body is

then insufficient for its needs.

Examples are:

- cerebral ischemia

- ischemic heart disease

- intrauterine hypoxia (which is an unchallenged cause of perinatal death)
- high "G" forces (blood shifting)

- prolonged sitting in one position or hanging in a harness

- cold temperatures

Stagnant hypoxia usually experienced when sitting for hours in a boring class.
7. Mixed form of hypoxia develops when several systems responsible
for O2 supply to cells and tissues are affected e.g. at traumatic shock
develop simultaneously:

- Circulatory hypoxia
- Respiratory hypoxia
- Hemic hypoxia (if bleeding is accompanied).

8. Hypoxia due to overload - usually develops in sportsmen during

strenuous physical exercise due to mismatch between supply and demand

for oxygen at the cellular level.

9. Substrate deficient - develops usually at glucose deficit.

 Hypoxia

Respiratory
Circulatory
Hypoxic Tissue
Overload
Hemic

Normobaric Hypobaric Substrate deficient

Types of hypoxia according to genesis

 Compensatory reactions at hypoxia directed to adaptation:

1. The depth of respiration increases.

2. The body produces more red blood cells to carry oxygen.

3. Pressure in pulmonary capillaries is increased, "forcing" blood into parts of

the lung which are not normally used when breathing at sea level.

4. Increases number of capillaries or density in tissues.

5. The body produces more of a particular enzyme that causes the release of
oxygen from hemoglobin to the body tissues.
 Immediate reactions of adaptation at acute Hypoxia

Acute Hypoxia

R
Passage of concentrated
Increase in Volume of Systolic ejection
blood from depot organs e
and Heart rate
and bone marrow Activation of tissue a
respiration and c
Increase in
glycolysis, t
Dilatation of increases
number of capillaries or
Coronary and brain processes of
i
Increase in
density in tissues
supplying blood oxidation o
dissociation of
vessels
oxy-hemoglobin
and n
phosphorilation
The depth of
respiration

Increases volume
Centralization of R
of alveolar
ventilation and O2 blood supply e
Increases efficacy
delivery of biological
s
Increases volume of systolic oxidation u
Increases oxygen
ejection, cardiac output, carrying capacity of the
l
Increases tissues
oxygenation
arterial Pressure, tissue blood t
perfusion
 Compensatory reactions at c h r o n i c
Hypoxia

Chronic Hypoxia is a pathological condition in which the body as a whole (generalized hypoxia) or region of the
body (tissue hypoxia) is deprived of adequate oxygen supply.

R
Quantitative
Increase in Increase in e
increase in
pulmonary Myocardial capillary density in a
mitochondria, Activation of
their crists, and
capillarity hypertrophy, tissues, increase in c
density increase in number of erythropoesis, tissue blood supply
ferments, erythrocytosis, t
mitochondria in
facilitation of
cardiomyocytes acceleration of i
oxydation / oxyhemoglobin o
phosphorilation dissociation
n
s

E
Increased volume f
of systolic ejection
Increased
Increased tissue f
Increased oxygenation of Increased oxygen
efficacy of blood in lungs carrying capacity of
perfusion, e
oxigenation and
biological the blood c
nutrition
oxidation t
s
Cellular Injury and
Adaptation
 THE CELL AND ITS FUNCTIONAL ORGANIZATION

Cells are the smallest functional unit of the body.

Composition:

Nucleus - contains most of the hereditary material.

The organelles include the:

- Mitochondria,
itochondria which supply the energy needs of the cell.

- Ribosomes,
ibosomes which synthesize proteins and other materials needed for cell function.

- lysosomes,
ysosomes which function as the cells digestive system

- Endoplasmic Reticulum functions as a tubular communication system.

- Golgi bodies modify materials synthesized in the ER and package them into secretory granules for
transport within the cell or for export from the cell.

- Microtubules are slender, stiff tubular structures that influence cell shape, provide a means of
moving organelles through the cytoplasm, and effect movement of the cilia and of chromosomes during
cell division.

The cell membrane encloses the cell and provides for intracellular and intercellular communication, transport of
materials into and out of the cell, and maintenance of the electrical activities that power cell.
When confronted with stresses that affect its normal structure and function,
the cell undergoes ADAPTIVE changes that permit survival and
maintenance of function.

When the stress is overwhelming or adaptation is ineffective the cell

INJURY and DEATH occur.

Cell injury can be reversible,

reversible allowing the cell to recover, or it can be
irreversible,
irreversible causing cell death necrosis or apoptosis.

In contrast to necrosis, which results from tissue injury, apoptosis is a

normal physiologic process designed to remove injured or worn-out
cells.
 Homeostatic cell

Metabolic changes, Ischemia, Toxins, etc.

Adaptation Injury

Reversible Irreversible
changes changes

Keep in mind that any Reversible changes can become irreversible when taken
to the extreme
A normal cell and the changes in reversible and irreversible cell injury (necrosis).
Injurious Stimulus
Time scale of reversible and irreversible cell injury.
 The relationship between normal, adapted, reversibly injured, and dead myocardial cells.
The cellular Adaptation depicted here is Hypertrophy, the type of Reversible injury is Ischemia and the
 Adaptive cellular responses

Cells may adapt by undergoing changes in SIZE (atrophy and hypertrophy),

NUMBER (hyperplasia), and TYPE (metaplasia).

These changes, occurring singly or in combination, may lead to:

- Atrophy

- Hypertrophy

- Hyperplasia

- Metaplasia

- Dysplasia

Adaptive cellular responses also include intracellular accumulations and

storage of products in abnormal amounts.
Causes of cellular injury

1. Hypoxia

2. Infection

3. Immunologic reaction

4. Congenital disorders

5. Chemical injury

6. Physical forms of injury

7. Nutritional or vitamin imbalance

1. Hypoxia lack of oxygen leads to the inability of the cell to
synthesize sufficient ATP by aerobic oxidation.
The most common cause of injury.
 The initial
functional and
morphologic
consequences of
decreased
intracellular
adenosine
triphosphate (ATP)
during cell injury.

ER, Endoplasmic
reticulum.
2. Infections Viruses, Bacteria, Parasites, and Fungi (and probably prions)
Mechanism of injury:

Direct infection of cell

Production of toxins

Host inflammatory response

3. Immunologic reactions Hypersensitivity reactions

- Autoimmune disease

4. Congenital disorders inborn errors of metabolism.

- Enzyme defects leading to the accumulation of toxic products

- Enzyme defects leading to a deficiency of an important product

- Genetic defects in structural proteins

- Cytogenetic disorders

- Congenital malformations caused by abnormal development

5. Chemical injury
Drags

Poisons - cyanide, arsenic, mercury, etc.

Pollution

Occupational exposure - CCl4, Asbestosis, Carbon monoxide, etc.

Social/lifestyle choices - alcohol, cigarette smoking, intravenous

drag abuse etc.

6. Physical forms of injury

Trauma

Burns

Frostbite

Radiation

Pressure changes
 7. Nutritional or Vitamin imbalance

Inadequate calorie/protein Vitamin deficiency

intake Vit. A night blindness, squamous metaplasia,
immune deficiency
- Marasmus and Kvashiorkor
Vit. C scurvy
- Anorexia nervosa
Vit. D rickets, osteomalacia
Excess caloric intake
Vit. K bleeding diathesis
- Obesity
- Atherosclerosis Vit. B12 megaloblastic anemia, neuropathy,
spinal cord degeneration

Folate - megaloblastic anemia, neural tube defects

Niacin pellagra, (diarrhea, dermatitis, dementia)

Or

Hypervitaminosis
 Cellular changes during injury
1. General
Cellular responses to injury:

- Adaptation
- Reversible injury

- Irreversible injury and cell death

(necrosis/apoptosis)

Cellular responses to injury depends on several important factors:

- The type of injury

- The duration of injury

- The severity and intensity of injury

- The type of cell injured

- The cells metabolic state

- The cells ability to adapt

The critical intracellular systems that are
susceptible to injury

DNA

Production of ATP via aerobic respiration

Cell membranes

Protein synthesis
Generation of free radicals
Free Radical Scavengers

O 2
Superoxide dismutase

Catalase
H2O2 H 2O
Fenton

Reaction

Fe
2+/3+
OH- Vitamin E
Vitamin C
-caroten
 Important mechanism of cell injury

2. ATP depletion

3. Increase cell membrane permeability

4. Mitochondrial dysfunction
- Decreased oxidative phosphorylation
- Formation of mitochondrial permeability transition (MPT) channels

- Release of cytochrome-C is a trigger for apoptosis

 Important mechanism of cell injury

5. Influx of Calcium
- Second messenger
- Activates a wide spectrum of enzymes

- Proteases protein breakdown

- ATP-ases contributes to ATP depletion

- Phospholipases cell membrane injury

- Endonucleases DNA damage

 Atrophy - Decrease in cell size and functional ability.

The general causes of atrophy

1. Decreased workload / Disuse, Immobilization

2. Denervation

3. Loss of endocrine stimulation

4. Inadequate nutrition / malnutrition

5. Ischemia or a decrease in blood flow

6. Aging
Atrophy
Atrophy
A, Normal brain of a young adult.

B, Atrophy of the brain in an 82-year-old male with atherosclerotic disease. Atrophy of the brain is
due to aging and reduced blood supply. Note that loss of brain substance narrows the gyri and
widens the sulci. The meninges have been stripped from the right half of each specimen to reveal the
surface of the brain.
 Hypertrophy

Hypertrophy represents an increase in cell size and functional ability .

Hypertrophy may occur as the result of normal physiologic or abnormal

pathologic conditions.
Myocardial hypertrophy.
hypertrophy Cross-section of the heart in a patient with

long-standing hypertension.

(From Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 9]. Philadelphia: Lippincott- Raven)
 Hyperplasia

Hyperplasia refers to an increase in the number of cells in a tissue or organ.

It occurs in tissues with cells that are capable of mitotic division, such as the:

- Epidermis

- Intestinal epithelium

- Glandular tissue.

Nerve cells and Skeletal and Cardiac muscle DO NOT divide and

therefore have no capacity for hyperplastic growth.

 Metaplasia

Metaplasia represents a reversible change in which one adult cell type

(epithelial or mesenchymal) is replaced by another adult cell type.

It has been suggested that the replacement cell is better able to tolerate
the environmental stress.

Metaplasia usually occurs in response to chronic irritation and inflammation

and allows for substitution of cells that are better able to survive under
circumstances in which a more fragile cell type might succumb.

However, the conversion of cell types never oversteps the boundaries of

the primary groups of tissue (e.g., one type of epithelial cell may be
converted to another type of epithelial cell, but not to a connective
tissue cell).
An example of metaplasia is the adaptive substitution of stratified
squamous epithelial cells for the ciliated columnar epithelial cells in
the trachea and large airways (bronchi) of a habitual cigarette
smoker.

A vitamin A deficiency also induces squamous metaplasia of the

respiratory tract. Although, the squamous epithelium is better able
to survive in these situations, the protective function that the ciliated
epithelium provides for the respiratory tract is lost.

In addition, continued exposure to the influences that cause metaplasia

may predispose to cancerous transformation of the metaplastic
epithelium.
 Metaplasia of normal
columnar (left) to
squamous epithelium
(right) in a bronchus,

Shown (A) schematically and

(B) histologically.
 Dysplasia

Dysplasia is an abnormal proliferation of cells that is characterized by

changes in cell size, shape, appearance and loss of cellular
organization.

Minor degrees of dysplasia are associated with chronic irritation or

inflammation.

Although dysplasia is abnormal, it is adaptive in that it is potentially

reversible after the irritating cause has been removed.
Adaptive tissue (large circles) and cell responses involving a change in number (hyperplasia), cell size (hypertrophy
and atrophy), cell type (metaplasia), or size, shape, and organization (dysplasia).
 Intracellular Accumulations
The accumulation of normal cellular constituents occurs when a substance is produced at a rate that exceeds its
metabolism or removal. An example of this type of process is fatty changes in the liver caused by intracellular
accumulation of triglycerides. Liver cells normally contain some fat, which iseither oxidized and used for energy
or converted to triglycerides.

Fatty liver

A - The possible mechanisms leading to accumulation of triglycerides in fatty liver. Defects in any of the steps of uptake,
catabolism, or secretion can lead to lipid accumulation.

B - High-power detail of fatty change of the liver. In most cells the well-preserved nucleus is squeezed into the displaced
rim of cytoplasm about the fat vacuole.

(B, Courtesy of Dr. James Crawford, Department of Pathology, University of Florida School of Medicine, Gainesville,
Florida.)
 Accumulation of intracellular lipofuscin.
A photomicrograph of the liver of an 80-year-old man shows golden
cytoplasmic granules, which represent lysosomal storage of lipofuscin.
(From Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 13]. Philadelphia: Lippincott-Raven)
 Hemosiderin granules in liver cells.
A - H&E section showing golden-brown, finely granular pigment.
B - Prussian blue reaction, specific for iron.

Lipofuscin granules in a
cardiac myocyte.
A - Light microscopy (deposits
indicated by arrows).
B - Electron microscopy. Note
the perinuclear, intralysosomal
location.
 Cell Death

Cell death can involve apoptosis or necrosis.

Apoptotic - Programmed cell death involves controlled cell destruction and is

involved in normal cell deletion and renewal.

Necrotic cell death is a pathologic form of cell death resulting from cell injury.

It is characterized by cell swelling, rupture of the cell membrane, and

inflammation.
 Apoptosis: Programmed Cell Death

Apoptosis results in the:

- Condensation of the chromatin / nuclues, and the cell shrinking

- DNA fragmentation

- Formation of apoptotic bodies

The end result of apoptosis is cell death without inflammation of the

surrounding tissue.
Apoptosis is regulated by genes:

1. bcl-2 (inhibits apoptosis)

- prevents release of cytochrome-C from mitochondria

- binds pro-apoptotic protease activating factor Apaf-1

2. p-53 (stimulates apoptosis)

- elevated by DNA injury and arrests the cell cycle

- if DNA repair is impossible, p-35 stimulates apoptosis

 Mechanisms of Apoptosis

1. Hypoxia, activation of ced-3, ced-4, bcl-2, heat shock proteins, increase in

cytosolic Ca++ etc.

2. Activation of Caspases

3. Activation of endo-nucleases

4. Inactivation of DNA-ses inhibitor proteins

5. DNA fragmentation

6. Inhibition of processes of DNA reparation, replication and reorganization

7. Condensation of the chromatin / nuclues

8. Cell shrinking

9. Formation of Apoptotic bodies

 Physiologic examples of apoptosis

1. Embriogenesis organogenesis and development

2. Hormone dependent apoptosis menstrual cycle

3. Thymus selective death of lymphocytes

Pathological examples of apoptosis

1. Viral diseases viral hepatitis (Councilman body)

2. Graft versus host disease

3. Cystic fibrosis duct obstruction and pancreatic atrophy

Mechanisms of apoptosis
The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of "executioner"
caspases. The induction of apoptosis is dependent on a balance between pro- and anti-apoptotic signals and intracellular
proteins. The figure shows the pathways that induce apoptotic cell death, and the anti-apoptotic proteins that inhibit
mitochondrial leakiness and cytochrome c-dependent caspase activation and thus function as regulators of mitochondrial
apoptosis
 Necrosis

Necrosis is death due to unexpected and accidental cell damage. A number of toxic chemical
or physical events can cause necrosis:

- Toxins

- Radiation

- Heat

- Trauma

- Lack of oxygen (due the blockage of blood flow, etc.)

As necrotic cells begin to die, they swell holes appear in the plasma membrane and
intracellular materials spill out into the surrounding environment.
 Necrosis
As the cell dies, its ability to maintain the integrity of the plasma membrane and to pump
ions is lost.

Ca2+ acts as an allosteric effector of many proteins, drastically altering their activity.

Unregulated Ca2+ induces the generation of toxic chemicals and activates enzymes that lead
to the degradation of cellular molecules.

As the cell is disassembled, various breakdown products are produced and released into the
neighborhood.

Among these are derivatives of membrane phospholipids, such as arachidonic acid, which is a
free fatty acid or FFA.

The presence of these molecules is interpreted by neighboring cells as a sign of tissue

damage.

The FFAs generated by damaged and dying cells are themselves substrates for enzymes, in
particular the cyclooxygenases.

These enzymes transform FFAs into prostaglandins and other molecules, known collectively
as eicosanoids, which mediate inflammatory responses.

A number of conditions are characterized by chronic inflammation, for example rheumatoid

arthritis.
 Cellular features of
Necrosis (left)

and

Apoptosis (right).

Necrosis Apoptosis