Lecture 1. Cellular and tissue

injury

Causes of cellular injury 1. Hypoxia

2. Physical forms of injury

3. Chemical injury

4. Immunologic reactions

5. Nutritional or vitamin imbalance

6. Congenital disorders

7. Infections

Hypoxia Hypoxia – deprivation of oxygen supply leading to decreasing of aerobic oxidation

Hypoxia deprives the cell of oxygen and interrupts oxidative metabolism and the generation of ATP. This is the main reason of cell damage.

Main reasons of hypoxia:

- Ischemia (atherosclerosis, thrombus)

- Decreased oxygen-carrying capacity of the blood (anemia, respiratory insufficiency)

Physical forms of injury Trauma (blunt/penetrating/ crush

injuries, etc.)

Burns

Frostbite

Radiation

Pressure changes

Chemical agents Acids, alkali

Accumulation/deficiency of ions,

oxygen, carbon dioxide, etc.

Pollution, occupational exposure

Immunologic reactions Autoimmune diseases

Hypersensitivity reactions

Nutritional imbalance Inadequate calorie/protein intake

Excess caloric intake

Vitamin deficiencies

Congenital disorders inborn errors of metabolism

congenital defects

Morphological and functional changes may be

reversible at the early stages of injury or in case of

moderate injury.

Characteristics of reversible injury

1. Of oxidative phosphorylation

2. Cell swelling

3. Fatty degeneration

Features of cellular injury

1. Cellular response depends on etiology,

duration and severity of stimuli

2. Cellular reactions on injury depend on cell’s

type, condition, ability to adaptation

3. Cellular injury is a result of various

biochemical mechanisms’ influence over

vital components of cell

4. Any injurious agent may induce few

interrelated mechanisms simultaneously

Mechanisms of cell injury

1. Depletion of ATP

2. Damage to Mitochondria

3. Influx of Calcium

4. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

5. Defects in Membrane Permeability

6. Damage to DNA and Proteins

1. Depletion of ATP • ATP - the energy store of

cells o required for almost all

synthetic and degradative processes within the cell • membrane transport, protein

synthesis, lipogenesis

• The major causes of ATP depletion o reduced supply of oxygen and

nutrients (ischemia)

o mitochondrial damage,

o toxins (e.g., cyanide).

2. Damage to Mitochondria

• Mitochondria -critical players in

cell injury and death.

• Mitochondria can be damaged

by

o cytosolic Ca2+,

o reactive oxygen species (ROS)

o oxygen deprivation (hypoxia, toxins).

• Two major consequences of

mitochondrial damage: o loss of mitochondrial membrane potential

and pH changes, resulting in failure of oxidative phosphorylation and progressive depletion of ATP

o leakage of cytochrome c and other

proteins into the cytosol and death by apoptosis.

3. Influx of Calcium

• Increased cytosolic Ca++ o activates a number of enzymes,

with potentially deleterious cellular effects

o induction of apoptosis by direct activation of caspases and by increasing mitochondrial permeability

• Increase in cytosolic Ca++ by: o increased influx across the

plasma membrane

o ischemia and certain toxins

o release of Ca2+ from the intracellular stores

4. Accumulation of Oxygen-Derived Free

Radicals (Oxidative Stress)

• Free radicals have an unpaired electron in their outer orbit o cause autocatalytic reactions (molecules that react with free

radicals are in turn converted into free radicals, thus propagating the chain of damage)

• Oxidative stress – a condition called in production of ROS or degradation - an excess of free radicals

• Generated by: o Absorption of radiant energy

o Oxidation of endogenous and exogenous compounds

o Oxidation of exogenous compounds

4. Accumulation of Oxygen-Derived Free

Radicals (Oxidative Stress)

• Reactions relevant for cell injury by ROS o Lipid peroxidation damage to cellular and organellar

membranes

o Protein cross-linking and fragmentation due to oxidative

modification of amino acids and proteins

o DNA damage due to reactions of free radicals with thymine

5. Defects in Membrane Permeability

• The plasma membrane can be

damaged by: o ischemia,

o various microbial toxins,

o lytic complement components,

o physical and chemical agents.

• The most important sites of membrane damage during

cell injury are: o Mitochondrial membrane

damage

o Plasma membrane damage • leads to loss of osmotic balance

and influx of fluids and ions, as well as loss of cellular contents.

o Injury to lysosomal membranes • leads to leakage of their enzymes

into the cytoplasm and enzymatic digestion of cell components, necrosis.

6. Damage to DNA and Proteins

Body reactivity • Reactivity is ability of the organism to alter

functional activity of the systems and organs for the

adaptation of organism to new conditions of the

environment for the survival. The concept

“reactivity” is connected with the concept

“resistance”

Types of reactivity 1) Biological reactivity (primary/physiological) is a

result of the morphological and physiological

peculiarities of all individuals, which are of the

same biological species.

2)Individual reactivity: is the reactivity of every

individual. Individual reactivity is determined by age,

sex, heredity, constitution, and functional conditions of

organism’s regulatory systems, external environmental

influences.

CLASSIFICATION of THE REACTIVITY

Biological determined by the morphological and physiological peculiarities of all individuals, which are originate from some species

Individual reactivity

sex

age

constitution

SPECIFIC

physiological pathological

UNSPECIFIC

physiological pathological

heredity

regulatory systems

environment

- shock - collapse - necrosis

- immunodepressive conditions

- allergy

In normal conditions

(specific resistance to

some antigens:

bacteries, viruses,

etc.)

In normal

conditions

during disease

during disease

Are formed by immune system

Clinical classification of reactivity

• NORMERGICAL: Common course and symptoms of

disease.

• HYPERERGICAL: Intensive rapid course, with greatly

marked symptoms.

• HYPOERGICAL: Inactive course, poorly marked

symptoms.

Ergon means act (action)

Resistance • Resistance is a state of stability of an organism to

the influence of pathogenic factors

CLASSIFICATION OF THE RESISTANCE

1) active

2) passive

3) primary

4) secondary

5) specific and unspecific

Resistance 1) Active resistance is a result of the organism adaptation

to the long time pathological factor influences.

2) Passive resistance is a result of anatomical and physiological peculiarities of each organism.

3) Primary (congenital) resistance is a result of the inherited peculiarities of an organism and it manifest itself after birth of the person.

4) Secondary (acquired) resistance is a result of organism functional reactions changes, which occur during the whole life.

5) Unspecific resistance is the opposition to the influence of many pathological agents. Specific resistance is the opposition to the defined agent influence, for example, microorganisms; its result is activation of the immune system.