Cell injury (causes)

When the limits of adaptive capacity are exceeded or when no adaptive response is possible then it is termed as cell injury.

A.     Reversible cell injury:

It denotes pathologic changes that can be reversed when the stimulus J(or stress) is removed or if the cause of injury is mild.

B.     Irreversible cell injury:

It denotes pathologic changes that are permanent and cause cell death.

Causes of cell injury:

1.       Hypoxia

2.       Chemical agents

3.       Metabolic

4.       Genetic

1.     Hypoxia:

Low oxygen to the tissue, which is due to:

Ø  Ischemia (loss of blood supply) due to arterial occlusion

Ø  Problem in respiratory system

Ø  Problem in circulatory system

Ø  Abnormality of hemoglobin

Ø  Decreased tissue perfusion as in hypotension, shock and cardiac failure

All leads to hypoxic cell injury, which may be reversible or irreversible.

Reversible injury:

If the nucleus is intact then it is termed as reversible cell injury. Hypoxia affects mitochondria which results in decreased synthesis of ATP. The reversible changes include:

         i.            Cellular swelling

       ii.            Desegregation of ribosomes and failure of protein synthesis

      iii.            Reduced intracellular pH

     iv.            Appearance of myelin figures and cell blebs

        i.            Cellular swelling:

Ø  Failure of Na, K ATPase pump due to deficiency of ATP results in accumulation of Na ions inside and K ions outside the cell.

Ø  Excess Na ions inside the cell exert osmotic pressure and pulls water inside, resulting in cellular swelling.

      ii.            Ribosomal desegregation:

Ribosomes become detached from the rough endoplasmic reticulum due its swelling and therefore protein synthesis is reduced.

   iii.            Reduced intracellular pH:

Ø  Lack of ATP synthesis increases rate of anaerobic respiration (anaerobic glycolysis) which leads to production of pyruvic acid and subsequently (at last) lactic acid.

Ø  Accumulation of lactic acid decreases intracellular pH which causes clumping (aggregation) of nuclear chromatin and further disruption (breakdown) of cytoplasmic organelles.

    iv.            Appearance of Myelin Figures and Cell Blebs:

Myelin Figures:

Intracellular whorl likes structures originating from damaged membrane.

Cell Blebs:

An outward cell membrane deformity

Irreversible injury:

If the nucleus is not intact then it is termed as irreversible injury. The irreversible changes are:

         i.            Nuclear changes

       ii.            Cytoplasmic changes

Nuclear changes:

Nucleus may show one of the following three patterns of changes.

Pyknosis:

The nucleus becomes shrunken due to clumping of chromatin called pyknosis.

Karyorrhexis:

The pyknotic nucleus may break (disintegration) into numerous small particles, the process called karyorrhexis.

Karyolysis:

The nucleus undergoes lysis (disintegration) without pyknosis called karyolysis.

Cytoplasmic changes:

§  Mitochondrial Vacuolization

§  Loss of plasma membrane (cell membrane, nuclear membrane etc)

§  Excess influx of calcium into cell

§  Release of lysosomal enzymes causing Autolysis (self breaking)

2.     Chemical injury:

Chemical causes cell injury by the following mechanisms:

a)     Direct attack:

Some chemicals attack directly on critical molecular component or cellular organelle (cell membrane, ribosome, mitochondria etc).

b)     Attack through free radicals:

Mostly chemicals cause injury by the formation of free radicals.

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Mechanisms of cell injury

Different pathogenic stimuli attack on these systems through different mechanisms. These important systems are;

         i.            Maintenance of the integrity of cell membrane

       ii.            Aerobic respiration and production of ATP

      iii.            Synthesis of enzymes and structural proteins

     iv.            Intact genetic material

These systems are closely related and thus injury to one system leads to wide range of secondary effects. High intensity and prolong stress cause injury to the cell due to changes in the above systems.

There are several pathogenic mechanisms through which cell injury can takes place.

A.      Impaired cell membrane function

B.      Decreased ATP (energy) production

C.      Genetic alteration

D.      Metabolic derangement

A.    Impaired cell membrane function:

a)      Free radicals production

b)      Impairment of calcium homeostasis

c)       Activation of complement system

d)      Lysis of enzymes

e)      Lysis of infection (viruses), heat, cold etc

a)    Production of free radicals:

Oxygen derived free radicals are chemical species with a single unpaired electron in an outer orbit.

When generated in the cells, they rapidly arrack and degrade nucleic acids and membrane molecules.

Examples of free radicals are; i) superoxide, ii) hydrogen per oxide

Mechanism of cell injury by Free Radicals

o   Lipid peroxidation of membrane resulting in cellular and mitochondrial membrane damage

o   DNA damage

Free Radical Degradation

Once free radicals are formed, body has protective mechanism to get rid of them. These are neutralizes by:

o   Intracellular protective enzymes e.g. glutathione peroxidase (liver), catalase etc

o   Antioxidants e.g. Vit E & C

b)    Loss of calcium homeostasis and increased intracellular calcium:

Ischemia and certain toxins cause influx of calcium across the plasma membrane and release calcium from mitochondria and endoplasmic reticulum. This increased intracellular calcium activates phospholipases that degrade membrane phospholipids and this causing cell membrane damage.

c)     Activation of complement system:

Activation of complement system will enzymatically damage the cell membrane.

d)    Lysis of enzymes:

Enzymes with lipase damage cell membrane e.g. clostridium perfringes bacteria produces enzymes that damage the cell membrane.

e)    Lysis by viruses, heat, cold etc:

Effects of cell membrane damage:

o   Loss of structural integrity

o   Loss of cellular function

B.    Decreased ATP (energy) production:

Hypoxia and hypoglycemia (ischemia) result in deficient ATP production. ATP is required to such important processes as membrane transport, protein synthesis etc.

C.     Genetic Alteration:

DNA in chromosomes control cellular function such as synthesis of structural protein, growth regulating proteins and enzymes. DNA abnormalities may be inherited from generation to generation or acquired by any of several agents e.g. ionizing radiation, viruses, drugs and chemicals. These will lead to cell injury.

D.    Metabolic derangement:

Exposure to many exogenous agents such as alcohol, drugs, heavy metals, infectious agents and accumulation of some endogenous substances can damage the cell. Metabolic derangement may be due to exposure to some exogenous toxic agents or accumulation of some endogenous substances.

Exogenous substances:

Some exogenous substances cause cellular damage by interfering directly with various specific biochemical reactions. These substances include alcohol, drugs, heavy metals and infectious agents.

Accumulation of endogenous substances:

Proteins, carbohydrate and lipids can accumulate in cells and sometimes cause cellular injury. In this condition a normal or increased endogenous substance is produced but the rate of metabolism is inadequate to remove it i.e. ^production and normal clearance or Normal production and defective clearance. The processes that result in abnormal intracellular accumulation includes:

A.     Fatty change (Steatosis):

The abnormal accumulation of triglycerides or cholesterol in the hepatocytes leading to increase in intracellular lipids is called Steatosis.

Common sites:

Ø  Liver: Due to involvement of fat metabolism

Ø  Heart

Ø  Skeletal muscles

Ø  Kidney

Ø  Any other organ

Causes:

ü  Increased blood fats level

ü  Alcohol abuse

ü  Diabetes mellitus

ü  Obesity

ü  Protein energy malnutrition (starvation)

ü  Pregnancy

ü  Some mushrooms

Morphology of liver:

·         Liver becomes enlarged, yellow and greasy.

·         Under microscope the fatty change is seen as small fat vacuoles in the cytoplasm, later on fuse to form large to form big vacuole.

Significance of fatty change:

Mild: No effect on cellular function.

Moderate: May impair cellular function e.g. indigestion, impaired liver function

Severe: Cellular injury

In most of the conditions the fatty change is reversible if the cause is corrected.

B.     Pathologic Calcification:

The excessive abnormal accumulation of calcium in the body is called pathologic calcification.

Types of pathologic calcification:

Abnormal deposition of calcium salts occur in two ways:

        i.            Dystrophic calcification:

Excessive abnormal accumulation of calcium in the dead or dying tissue with the normal serum calcium level (9mg-11mg) is called dystrophic calcification.  

Common sites:

o   Necrotic tissue that is not absorbed e.g.

o   Old granulomas lesion by tuberculosis

o   Old infarcts

o   Old abscesses (collection of pus)/ cysts (localized collection of fluids)

o   Old thrombi

o   Hematomas (collection of blood) associated with bone

o   Cancers (breast)

o   Thyroid cartilage

o   Chondrocalcinosis: Deposition of calcium in costo-chondral cartilage

o   Monckeberg’s disease: Calcification of tunica media of artery converting it into a rigid tune.

      ii.            Metastatic calcification:

Excessive abnormal deposition of calcium due to hypercalcemia is called metastatic calcification.

Causes of hypercalcemia:

v  Increase absorption of calcium from the intestine due to: hypervitaminosis D, excessive milk intake (if it is due to peptic ulcer then it is Milk alkali syndrome)

v  Increase calcium mobilization from bone (hyperthyroidism)

v  Bone malignancy (most common cause of hypercalcemia)

v  Increased renal absorption of calcium (thiazide diuretics, familial hypocalciuric hypercalcemia)

Common sites:

§  Kidney: Deposition of calcium in the kidney called nephrocalcinosis (kidney stone)

§  Lungs

§  Blood vessels

§  Cornea of the eye

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Under normal conditions cells are in a homeostatic or steady state. When stimulus arrived to the cell, first the cell will adapt but if this stimulus crosses the boundary of adaptation it will cause cell injury. So cells respond to the stimulus by the following two ways:

Cellular adaptation:

Adaptation is an adjustment of the cell to the environmental change which disturbs the homeostasis. Cellular adaptations are of the following types.

A.     Atrophy:

A reduction in the size of the cell due to loss of cell contents which leads to decrease in the size of an organ or tissue. The number of cells remains unchanged. Cell shrinks and become smaller in size.

Causes:

        I.            Ischemia:

The atrophy may be due to low blood flow to organ, tissue or cell. Such type of ischemia is called ischemic atrophy.

Example:

Narrowing of coronary arteries results in ischemic atrophy of myocardium

      II.            Disuse (reduced functional activity):

The atrophy due to disuse or immobilization of an organ, tissue or cell is called disuse atrophy. As we now that blood flow to the tissue, organ or cells depends on the metabolic needs and inactivity or immobilization reduces the nutritional demand.

Example:

Atrophy in paralytic limb.

Obstruction of gland duct leads to atrophy of gland.

   III.            Interrupted (discontinue) nerve supply:

Skeletal muscle depends on their nerve supply for normal function and structure. Damage to the nerve supply leads to rapid atrophy of the muscle fibers supplied by that nerve. This type of atrophy is called denervation atrophy.

Example:

Atrophy of skeletal muscle after destruction of nerves in poliomyelitis.

    IV.            Endocrine deficiency:

Hormonal deficiency causes reduced metabolic activity leading to atrophy.

Example:

Deficiency of pituitary hormones leads to atrophy of thyroid, adrenal glands, gonads and genital organs.

      V.            Pressure:

Atrophy is produced by persistent pressure on a tissue or organ which may either causes injury to the cell or interferes with its blood supply or lymphatic drainage.

Example:

Tumor pressuring on the surrounding tissues

    VI.            Lack of nutrients:

Atrophy is produced by lack of nutrients such as in protein calorie malnutrition.

Example:

Iron deficiency anemia

 VII.            Senile atrophy:

The atrophy which occurs at old age is called senile atrophy.

Normal old age of male is above 60 years while that of female is after menopause (45 years).

B.     Hypertrophy:

Increase in the size of the cells resulting in an enlargement of a tissue or organ without any change in the number of cells is called hypertrophy.

Types of hypertrophy:

        i.            Physiological hypertrophy:

The growth of uterus during pregnancy stimulated by estrogen hormone is called physiological hypertrophy. Hypertrophy in the muscle cells of the heavy exercising individuals like body builders.

      ii.            Adaptive hypertrophy:

It is enlargement of cardiac and skeletal muscle due to over work. They enlarge because they are unable to form more cells by mitotic division to share the work. 

a.       Left ventricular hypertrophy in hypertension

b.      Right ventricular hypertrophy in pulmonary hypertension

C.     Hyperplasia:

Increase in the number of cells resulting in an increased volume of the organ or tissue. Hyperplasia can only occur in the cells capable of mitotic division in postembryonic life, when stressed or stimulated to increase activity.

Types of hyperplasia:

        i.            Physiological hyperplasia:

It is further divided into:

a.       Hormonal:

Hyperplasia of female breast at puberty, during pregnancy and lactation

Uterus during pregnancy shows hyperplasia in response to increased level of ovarian steroids

b.       Compensatory:

Hyperplasia in the remaining kidney when the other is removed or destroyed due to increased demand on the remaining kidney.

      ii.            Pathologic hyperplasia:

It occurs due to excessive hormonal stimulation of the target cell e.g.

a)      Adenomatous hyperplasia of endometrium due to excessive estrogen stimulation

b)      Thyroid hyperplasia: In primary hyperthyroidism

c)       Epidermal hyperplasia: In chronic irritation of the skin

Note: Hyperplasia may produce clinical diseases e.g. endometrial bleeding, thyroid hyper function etc

D.    Metaplasia:

·         The replacement of normal cell type by abnormal cell type is called Metaplasia.

·         It is reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.

·         The normal pseudo stratified columnar ciliated epithelium of the trachea and bronchi are replaced by stratified squamous epithelium in response to chronic irritation in chronic cigarette smokers.

·         Squamous epithelium of esophagus is replaced by columnar secretory epithelium as a result of acid reflux into esophagus causing Barrett’s esophagus).

In metaplasia there is chance of malignancy. The only difference in metaplasia and Neoplasia (cancer) is that the metaplasia is reversible while the Neoplasia is irreversible.

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