CM

Cellular Adaptation, Injury, and Death

Cellular Adaptation

  • Cells adapt to changes in the internal environment to maintain homeostasis and ensure survival. These adaptations can be crucial for protecting cells from injury and maintaining their function.

  • Cells adapt to increased work demands or environmental stressors by changing in:

    • Size (atrophy and hypertrophy):

      • Atrophy: Decrease in cell size due to reduced metabolic activity. This can occur in response to disuse, denervation, ischemia, nutrient starvation, persistent cell injury, or aging.

      • Hypertrophy: Increase in cell size due to increased workload. This can be physiologic (e.g., muscle growth in response to exercise) or pathologic (e.g., cardiac hypertrophy due to hypertension).

    • Number (hyperplasia):

      • Hyperplasia: Increase in the number of cells due to increased cell division. This can be physiologic (e.g., hormonal hyperplasia in the breast during pregnancy) or pathologic (e.g., endometrial hyperplasia due to excessive estrogen).

    • Form (metaplasia):

      • Metaplasia: Replacement of one adult cell type with another. This is usually an adaptive response to chronic irritation or inflammation, allowing for better survival in the altered environment (e.g., replacement of columnar epithelium with squamous epithelium in the trachea of smokers).

Results of Cell Adaptation

  • Atrophy: Decrease in cell size. Cells reduce their oxygen consumption and protein synthesis.

  • Hypertrophy: Increase in cell size. Results from increased synthesis of intracellular proteins.

  • Hyperplasia: Increase in the number of cells. Occurs in tissues capable of mitotic division.

  • Metaplasia: Replacement of adult cells. Involves the reprogramming of undifferentiated stem cells.

  • Dysplasia: Deranged cell growth of a specific tissue. Results in cells that vary in size, shape, and organization. Dysplasia is a precursor to cancer.

*Example: Chronic cigarette smokers: Metaplasia occurs as cells are damaged; a hardier version replaces the normal strata of cells.

Three Sources of Intracellular Accumulations

  • Normal Body Substances: Substances that are produced at a normal rate but the rate of removal is inadequate- Lipids, proteins, carbohydrates, melanin, etc.

  • Abnormal Endogenous Products: Accumulation of substances due to genetic or acquired defects in the metabolism, folding, transport, or secretion of these substances- Those resulting from inborn errors of metabolism

  • Exogenous Products: Accumulation of pigments or particles that the cell is unable to degrade, environmental agents and pigments not broken down by the cell

Pathologic Calcifications

  • Definition: Abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals. Can occur in areas of necrosis or in normal tissues.

  • Types:

    • Dystrophic calcification: Occurs in dead or dying tissue as a result of local tissue damage and inflammation. This can happen in areas of necrosis, old trauma, or advanced atherosclerosis.

    • Metastatic calcification: Occurs in normal tissue due to hypercalcemia (high levels of calcium in the blood). This can be caused by hyperparathyroidism, vitamin D intoxication, or certain cancers.

*Example: Dystrophic calcification can result from prolonged ischemia because ischemia stresses the tissue, it dies, and calcium precipitates out of solution.

Causes of Cell Injury

  • Injury from Physical Agents:

    • Mechanical forces: Trauma, crushing injuries.

    • Extremes of temperature: Burns, frostbite.

    • Electrical forces: Disruption of neural and cardiac impulses, tissue damage.

  • Radiation Injury:

    • Ionizing radiation: Directly breaks chemical bonds and can cause mutations.

    • Ultraviolet radiation: Damages DNA.

    • Nonionizing radiation: Causes thermal injury.

  • Chemical Injury:

    • Drugs: Direct damage or metabolic conversion to toxic metabolites.

    • Carbon tetrachloride: Converted to toxic free radicals in the liver.

    • Lead toxicity: Interferes with neurotransmitter synthesis.

    • Mercury: Binds to proteins and alters their configuration.

  • Injury from Biologic Agents: Bacteria, viruses, fungi, and parasites can cause cellular injury through various mechanisms, including direct damage, toxin production, and immune responses.

  • Injury from Nutritional Imbalances: Deficiencies or excesses of nutrients can result in cellular injury. For example, protein-calorie malnutrition can cause atrophy, while obesity can lead to metabolic disorders and cellular stress.

Reversible Cell Injury

  • Impairs cell function but does not result in cell death. If the injury is mild or short-lived, the cell may recover.

  • Two patterns of reversible cell injury occur:

    • Cellular swelling: Impairment of the energy-dependent Na^+/K^+ ATPase membrane pump, usually as the result of hypoxic cell injury. This leads to an influx of sodium and water into the cell, causing it to swell.

    • Fatty change: Linked to intracellular accumulation of fat. Occurs because normal cells are presented with an increased fat load or because the cell is injured, and the injury interferes with the metabolism of the fat.

Mechanisms of Cell Injury

  • Free radical and reactive oxygen species (ROS) formation: Free radicals are highly reactive chemical species; having an unpaired electron causes them to be unstable and highly reactive. They can damage cellular structures, including lipids, proteins, and DNA.

  • Free radical injury:

    • Lipid peroxidation: Free radicals react with lipids in cell membranes, causing damage and impairing membrane function.

    • Oxidative modification of proteins: Free radicals can modify proteins, leading to loss of function or abnormal protein aggregation.

    • DNA effects: Free radicals can damage DNA, leading to mutations and potentially cancer.

Hypoxic Cell Injury

  • Deprives cell of oxygen and interrupts oxidative metabolism and the generation of ATP. Hypoxia can lead to a cascade of events that ultimately result in cell injury and death.

    • Acute cellular swelling (edema)

  • The longer tissue is hypoxic, the greater chance of irreversible cellular injury. Prolonged hypoxia can lead to necrosis or apoptosis.

  • Causes of hypoxia:

    • Inadequate amount of oxygen in the air

    • Respiratory disease

    • Inability of the cells to use oxygen

    • Edema

    • Ischemia

Impaired Calcium Homeostasis

  • Calcium functions as an important second messenger and cytosolic signal for many cell responses. It regulates various cellular processes, including muscle contraction, enzyme activity, and cell signaling.

  • Cytosolic calcium levels are kept low by energetic mechanisms. This is crucial for preventing inappropriate activation of calcium-dependent enzymes.

    • Ischemia-induced calcium disruption

    • Inappropriate activation of enzymes

*Membrane damage can occur due to: Inactivation of Na^+/K^+ ATPase, oxidation of phospholipid, ischemic activation of Ca^{2+}-regulated protease

Programmed Cell Death

  • Apoptosis: A highly regulated process of cell self-destruction that plays a crucial role in development, tissue homeostasis, and removal of damaged cells.

    • This process eliminates cells that:

      • Are worn out

      • Have been produced in excess

      • Have developed improperly

      • Have genetic damage

  • Necrosis: Refers to cell death in an organ or tissues that is still part of a living person. It is often characterized by inflammation and cellular breakdown.

    • Often interferes with cell replacement and tissue regeneration.

    • Gangrene occurs when a considerable mass of tissue undergoes necrosis.

Gangrene

  • The term gangrene is applied when a considerable mass of tissue undergoes necrosis. It is often associated with loss of blood supply and bacterial infection.

  • Dry gangrene: The affected tissue becomes dry and shrinks, the skin wrinkles, and its color changes to dark brown or black. The spread of dry gangrene is slow. Often seen in individuals with arterial occlusive disease.

  • Wet gangrene: The affected area is cold, swollen, and pulseless. The skin is moist, black, and under tension. Blebs form on the surface, liquefaction occurs, and a foul odor is caused by bacterial action.

    • The spread of tissue damage is rapid. Often associated with bacterial infection and can be life-threatening.