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