Cellular Injury, Adaptations, and Maladaptive Changes Notes

Disease Etiology

  • All diseases and injuries start somewhere.
  • Etiology
    • Original cause of cell alteration or disease.
    • Commonly interchanged with “cause” in the clinical setting.
  • Etiologic Agents
    • Causes of the cell alteration or disease.
    • Examples: infection, trauma
  • In response to etiologic agents, a cell may:
    • Develop adaptive, compensatory changes that maintain homeostasis.
    • Develop maladaptive changes that impair structure or function.

Basic Terminology

  • Histology
    • Microscopic study of tissue.
    • Cancer cannot be diagnosed without a histological exam.
  • Biopsy
    • Collection of sample for histological analysis.
  • Autopsy
    • Examination of tissue of deceased organisms.
  • Pathognomonic Changes
    • Unique, identifying disease presentations.
    • Example: Crater-like formation in the stomach indicates an ulcer.
    • Example: Koplik spots on the roof of the mouth in measles.

Basic Cellular Adaptations and Maladaptive Changes

  • Cell Size Change
    • Atrophy
    • Hypertrophy (Physiological vs. pathological)
  • Cell Number/Appearance Change
    • Hyperplasia
    • Metaplasia
    • Dysplasia
  • Neoplasia
    • Benign
    • Malignant

Basic Cellular Adaptations

  • Atrophy
    • Cells revert to a smaller size due to a reduction in metabolic demand.
    • Example: Paralysis causing shrinkage of skeletal muscle.
    • Due to aging, disuse, inadequate nutrition, and ischemia.
  • Hypertrophy
    • Increase in individual cell size.
    • Attributed to increased workload or use.
    • Example: Strength training.

Types of Hypertrophy

  • Physiological (Yay)
    • Cells get bigger with adequate supporting tissues.
    • Example: Enlargement of cardiac cells with exercise training.
  • Pathological (Nay)
    • Increase in cell size without an increase in support structures (growth is occurring too quickly, so support structures do not have time to develop).
    • Example: Enlargement of heart tissue due to hypertension.

Hyperplasia

  • Increase in the number of cells.
  • The opposite is hypoplasia, or inadequate cell division.
  • Occurs only in cells capable of mitosis.
  • A classic example is a callus.
  • Can result from hormonal stimulation.
    • Example: Estrogen stimulates the growth of breast cells in pregnancy, and progesterone thickens the uterine lining, BPH.
  • May evolve into maladaptive compensation.
    • Cell number increases too much.
    • Example: Keloid formation.

Metaplasia

  • Replacement of one cell type with another.
  • Genetic reprogramming to ensure cell survival.
  • Often a response to chronic inflammation or damage.
  • Example: GERD.
    • Lower esophageal cells transform from squamous epithelium to columnar stomach-like cells.
    • This change, if untreated, can lead to cancer.

Dysplasia

  • Deranged or disorganized cellular growth.
  • Commonly referred to as the precursor for neoplastic or cancer-related changes.
  • Often a result of chronic inflammation or a precancerous condition.
  • Cells vary in size, shape, and organization compared with normal.
  • Example: Cervical dysplasia detected by Papanicolaou (Pap) test.

Neoplasia

  • “New Growth”.
  • Disorganized, uncoordinated, uncontrolled cell growth, “cancerous”.
  • Neoplasm: Often interchanged with the term “tumor”.
  • Neoplasms may be benign or malignant.

Benign and Malignant Neoplasms

  • Benign
    • Cells resemble normal cells.
    • Well-differentiated cells.
    • Do not metastasize.
    • Well-defined borders.
  • Malignant
    • Cells appear different from healthy cells.
    • Poorly differentiated cells.
    • Increased likelihood of metastasis.
    • Poorly defined borders.

Basic Concepts of Cell Injury

  • Cellular Disruption → Effect
  • Dysfunction of Na^+/K^+ pump → Disruption of electrochemical gradient → Cellular swelling.
  • Dysfunction of Ca^{++} pump → Accumulation of intracellular Ca^{++} → Cell degeneration.
  • Loss of plasma membrane integrity → Barrier disrupted → Harmful agents can enter the cell.
  • Defects in protein synthesis → Can lead to cell death.
  • Intracellular accumulations → Disrupt cell functioning (Examples: fatty liver, xanthomas, xanthelasma).
  • Genetic damage → DNA mutations.

Causes of Cell Injury

  • Hypoxia
    • Diminished oxygen to cells - most common cause of cell injury.
    • Due to ischemia (diminished circulation), problems with RBC’s (anemia), pulmonary issues.
    • Causes cells to enter anaerobic metabolism, leading to increased lactic acid levels What is the difference between hypoxia and hypoxemia?

Free Radical Injury

  • Reactive oxygen species formed during aerobic metabolism.
  • Contain unpaired electrons which interact with and disrupt the plasma membrane.
  • Cells have protective mechanisms
    • Series of enzymes called superoxide dismutases.
  • However, when free radicals overwhelm removal mechanisms, oxidative stress occurs.
  • Oxidative stress commonly occurs in cells that undergo transient ischemia.

Free Radicals Accumulation

  • Can accumulate due to environmental exposure or persistent chronic infection (neutrophils make free radicals to destroy pathogens).
  • Highly reactive oxidizing molecules which can injure the endothelium.
  • Cigarette smoking increases free radicals.

Cell Injury Causes

  • Physical agents: trauma, extreme temperatures.
  • Chemical agents: injure the plasma membrane, access cell, cause dysfunction to organelles.
    • Endogenous: DM, electrolyte imbalances.
    • Exogenous: drugs, pollutants, smoking.
  • Infectious agents: variety of microorganisms.
    • Bacteria, fungi, parasites.
    • HPV, H. pylori.
  • Nutritional imbalances: under/over nutrition, malnutrition.
  • Injurious immunological reactions
    • Autoimmune diseases.
    • Chronic inflammation.

Endothelium

  • Cells that line the interior of vessels.
  • The largest organ of the body – injury to it is very harmful.
  • An active tissue.
  • Secretes VEGF (forms new vessels), nitric oxide (vasodilates), & endothelin (vasoconstricts).
  • Injury to the endothelium causes atherosclerosis.
  • Common agents of injury to the endothelium
    • Hypertension.
    • Hyperglycemia.
    • Free radicals.
    • Hyperlipidemia.

Endothelial Injury

  • Hypertension
    • Stronger than normal shearing force, injury to the endothelium.
    • Aneurysm: Weakened area of arterial wall, may rupture.
  • Diabetic Hyperglycemia
    • Glucose reacts with the endothelium.
    • Advanced glycation end products form, which further damage the endothelium.
    • High glucose levels cause the release of endothelin, a potent vasoconstrictor.

Endothelial Injury Continued

  • Free Radicals
    • Highly reactive oxidizing molecules which can injure the endothelium.
    • Cigarette smoking increases free radicals.
  • Persistent Angiotensin II Secretion
    • A potent vasoconstrictor increases blood pressure force on the endothelium.
    • Elevated with heart disease.

Low-Density Lipoprotein (LDL) Cholesterol

  • Atherogenesis
    • Formation of atherosclerotic plaque initiated by endothelial injury.
    • Areas of injury attract LDL molecules.
    • LDL accumulates within micro-tears, and macrophages try to engulf these molecules but instead become foam cells.
    • Foam cells worsen plaque formation.
    • Endothelial NO (nitric oxide) levels are reduced, leading to further vessel blockage.

Atherosclerosis Explained

  • Hypertension and glycosylated RBCs cause micro-tears in arterial vasculature.
  • Circulating lipids, WBCs, and platelets enter these micro-tears.
  • As atherosclerotic plaque builds, ACS events follow.

Cell Degeneration: Apoptosis

  • Programmed cell death.
  • An organized process that does not cause inflammation or adversely affect surrounding tissues.
  • Some diseases may be associated with apoptosis dysfunction.
    • Prostate cancer: decreased apoptosis.
    • Spinal muscular atrophy: increased apoptosis.
    • Hashimoto’s thyroiditis: increased apoptosis.

Cell Degeneration: Necrosis

  • Cell death due to injury.
  • Irreversible process.
  • Membrane disintegrates, lysosomal activation, and autolysis.
  • Initiates inflammatory reaction.

Infarction

  • Ischemic necrosis.
  • Death of tissue results from prolonged ischemia.
  • Example: Myocardial infarction.
  • Cell contents (cardiac proteins) released into circulation.

Gangrene

  • When dead tissue becomes a growth medium for certain types of bacteria.
  • Prolonged ischemia leads to infarction, followed by necrosis.
  • Clostridium perfringens emits identifiable gas as it destroys tissues (gas gangrene).

Clinical Examples

  • Hypoxia > 6 minutes, brain cell damage
  • Micro-calcifications on Mammogram could Possibly indicate cancer
  • Protein starvation results in Reduced blood albumin levels Edema
  • Hypertension results in Left ventricular hypertrophy Displacement of PMI to the left
  • RBC breakdown results in Increased bilirubin Jaundice