Cellular Adaptation, Injury, and Death

Cellular Adaptation, Injury, and Death

Cellular Adaptation to Injury or Stress

• Injury or stress can lead to adaptation.

• Increased demand leads to hypertrophy.

• Decreased stimulation or lack of nutrients leads to atrophy.

• Chronic irritation leads to metaplasia.

Adaptations

• Hypertrophy

• Hyperplasia

• Atrophy

• Metaplasia

Hypertrophy

• Increase in the size of cells results in increased size of the organ.

• May be physiologic or pathologic.

Examples of Physiologic Hypertrophy

• Increased workload (e.g., skeletal muscle, cardiac muscle).

• Hormone induced (e.g., pregnant uterus).

Hyperplasia

• Increase in the number of cells results in increase in size of the organ.

• May be physiologic or pathologic.

Physiologic Hyperplasia

• Hormonal hyperplasia (e.g., female breast during puberty and pregnancy).

• Compensatory hyperplasia (e.g., unilateral nephrectomy, liver regeneration).

• Erythroid hyperplasia of bone marrow due to chronic hypoxemia, high altitude stays, chronic lung diseases, cyanotic heart defects.

Pathologic Hyperplasia

• Excessive hormone stimulation (e.g., endometrial hyperplasia, prostatic hyperplasia).

• Viral infections (e.g., papilloma virus/warts).

• Side effects of drugs (e.g., gingival hyperplasia).

Atrophy

• Reduced size of an organ due to a decrease in cell size and number.

Physiologic Atrophy

• Notochord (embryo development; differentiates into spine in fetal development).

• Post-partum uterus.

Pathologic Atrophy

• Local or generalized.

Causes and Examples of Atrophy

• Decreased workload (disuse atrophy due to stroke).

• Loss of innervation (denervation atrophy; amyotrophic lateral sclerosis).

• Diminished blood supply (ischemia).

• Inadequate nutrition.

• Loss of endocrine stimulation (menopause).

• Pressure (enlarging benign tumor).

• Aging (senile atrophy).

• Normal atrophy.

Metaplasia

• Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type.

• Usually occurs in response to stress or chronic irritation.

• Abnormal change of cells.

Causes and Examples of Metaplasia

• Tobacco smoke: Squamous metaplasia in the respiratory tract (most common).

• Gastric acid reflux: Gastric metaplasia of distal esophagus (Barrett esophagus).

  • Barrett Esophagus - A condition in which the normal squamous epithelium of the esophagus is replaced by columnar epithelium (similar to the lining of the intestine) due to chronic acid exposure. - It is primarily a complication of chronic gastroesophageal reflux disease (GERD). -

• Repeated skeletal muscle injury with hemorrhage: Muscle replaced by bone (myositis ossificans).

Mechanisms of Metaplasia

• Re-programming of stem cells that exist in normal tissue, induced by cytokines, growth factors, and other environmental factors.

• Retinoic acid (derived from retinol/Vitamin A) may play a role; it has important roles in cell growth, differentiation, and organogenesis.

• Exact mechanism is unknown.

Mechanisms of Cell Injury

• Cellular response to injury depends on nature, duration, and severity of injury.

• Consequences of injury depend on type, state, and adaptability of the injured cell.

• Cell injury results from different biochemical mechanisms acting on essential cellular components.

Cell Injury and Death

• Reversible:

  • Reduced ATP - Increase ATP

  • Hypoxia - More Oxygen

  • Cellular Swelling - Help Reduce Swelling

• Irreversible:

  • Two types of cell death:

    • Necrosis: Always pathologic.

    • Apoptosis: May be physiologic or pathologic.

Causes of Cell Injury

• Oxygen deprivation (hypoxia or ischemia).

• Physical agents (trauma).

• Chemical agents and drugs (arsenic, cyanide, mercury).

• Infectious agents.

• Immunologic reactions (autoimmune diseases).

• Genetic derangements (chromosomal abnormalities, gene alterations, amino acid alteration).

• Nutritional imbalances (protein and calorie deficiencies, vitamin deficiencies, eating disorders like anorexia nervosa, excess food, type of food).

• Aging (replicative and repair abilities).

General Characteristics of Necrosis

• "Accidental".

• Usually affects large areas of contiguous cells.

• Cells and organelles swell.

• Control of intracellular environment is lost.

• Cells rupture and spill contents.

• Induces inflammation.

Patterns of Tissue Necrosis

• Coagulative Necrosis

• Liquefactive Necrosis

• Fat Necrosis

• Caseous Necrosis

• Fibrinoid Necrosis

Coagulative Necrosis

• Pattern of cell death characterized by progressive loss of cell structure.

• Coagulation of cellular constituents.

• Persistence of cellular outlines for a period of time until inflammatory cells arrive and degrade the remnants.

• Myocardial infarction is an example.

Liquefactive Necrosis

• Pattern of cell death characterized by dissolution of necrotic cells.

• Typically seen in an abscess or other infectious conditions.

• Large numbers of neutrophils present, which release hydrolytic enzymes that break down the dead cells.

• Pus forms (liquefied remnants of dead cells, including dead neutrophils).

• Can also be seen in cerebral infarction.

Caseous Necrosis

• Pattern of cell injury that occurs with granulomatous inflammation in response to certain microorganisms (tuberculosis).

• Host response to the organisms is a chronic inflammatory response.

• Center of the caseating granuloma is an area of cellular debris.

• Appearance and consistency of cottage cheese.

Fat Necrosis

• Lipases are released into adipose tissue.

• Triglycerides are split into fatty acids.

• Fatty acids bind and precipitate calcium ions.

• Insoluble salts are formed.

• Salts appear chalky white on gross histological examination.

Fibrinoid Necrosis

• Pattern of cell injury that occurs in the wall of arteries in cases of vascular inflammation (vasculitis).

• The body's immune system attacks the blood vessel by mistake.

• Necrosis of smooth muscle cells of the tunica media.

• Endothelial damage allows plasma proteins (primarily fibrin) to be deposited in the necrotic area of the tunica media.

Programmed Cell Death: Apoptosis

• Apoptosis (fallen apart) - equated with suicide.

• This process eliminates cells that:

  • Are worn out.

  • Have been produced in excess.

  • Have developed improperly.

  • Have genetic damage.

Causes of Apoptosis

• May be physiologic or pathologic.

Physiologic Apoptosis

• Embryogenesis and fetal development.

• Hormone dependent involution (prostate glandular epithelium after castration, regression of lactating breast after weaning).

• Cell loss in proliferating cell populations (immature lymphocytes, epithelial cells in the GI tract).

• Death of cells that have served their function (neutrophils, lymphocytes).

Pathologic Apoptosis

• DNA damage due to radiation, chemotherapy.

• Accumulation of misfolded proteins leads to stress which ends with apoptosis.

• Cell death in viral infections that induce apoptosis such as HIV and adenovirus or by the host immune response such as hepatitis.

• Organ atrophy after duct obstruction.

ATP Depletion

• Decreased ATP synthesis are common with both hypoxic and toxic (or chemical) injury.

• Reduction in Na^+, K^+-ATPase pump activity.

• Increase in anaerobic metabolism.

• Failure of Ca^{++} pump.

• Reduced protein synthesis.

DNA Damage and Protein Mis-folding

• If DNA damage to cell is too severe, apoptosis is initiated.

• Improperly folded proteins can also initiate apoptosis.

• Linked to degenerative disease.

Consequences of Mitochondrial Damage

• Necrosis: Loss of membrane potential due to membrane permeability; results in failed oxidative phosphorylation and loss of ATP.

• Apoptosis: Membrane damage leads to leakage of cytochrome C and other pro-apoptotic proteins.

Calcium Influx

• Intracellular Ca^{++} is normally low and is sequestered in mitochondria and endoplasmic reticulum.

• Extracellular Ca^{++} is high.

• Gradients are normally maintained by Ca^{++}Mg^{++}ATPase pumps.

• Increased Ca^{++} within the cell activates enzymes that can lead to cell injury and death.

• Increased Ca^{++} is also pro-apoptotic.

Reactive Oxygen Species (ROS)

• The process of oxidation in the human body produces unstable chemicals called free radicals, which damage cell membranes and other structures.

• Free radicals have been linked to a variety of diseases (including heart disease and certain cancers).

• Antioxidants are compounds in foods that scavenge and neutralize free radicals.

• Evidence suggests that antioxidant supplements do not work as well as the naturally occurring antioxidants in foods such as fruits and vegetables.

• Free radicals are unpaired electrons which makes the atom or molecule extremely reactive

• React with and modify cellular constituents

• Initiate self-perpetuating vicious cycle when they react with atoms and molecules

• Electrons are frequently added to O_2 to create biologically important ROS.

Reactive Oxygen Species “Normal” ROS Functions:

• Normal metabolism and respiration.

• Absorption of radiant energy.

• Inflammation.

• Enzymatic metabolism of chemicals or drugs.

• Nitric oxide synthesis.

Dietary Anti-Oxidants

• Vegetables and legumes or beans.

• Fruit.

• Whole grain foods and cereals.

• Lean meat, poultry and protein.

• Fish, eggs, tofu, legumes, nuts and seeds.

• Dairy and dairy alternatives.

• Reduced fat.

Practice Questions

Question 1

A nurse in the emergency department admits a male client who has experienced severe frostbite to his hands and toes after becoming lost on a ski hill. The nurse recognizes that which of the following phenomena has contributed to his tissue damage?

a) Decreased blood viscosity has resulted in interstitial bleeding.
b) Reactive vasodilation has compromised perfusion.
c) Autonomic nervous stimulation has resulted in injury.
d) Decreased blood flow has induced hypoxia. -

Question 2

A nurse is teaching a group of older adults about the value of including foods containing antioxidants in their diet. Which of the following statements best captures the rationale underlying the nurse’s advice?

a) Antioxidants inhibit the actions of reactive oxygen species.
b) Antioxidants prevent the formation of superoxide dismutase.
c) Antioxidants react nonspecifically with molecules.
d) Antioxidants prevent the occurrence of cell dysplasia.