Definitions

Hypertrophy=increase in cell size due to increased workload

Hyperplasia= increase in cell number, often secondary to hormones and growth factors e.g. breasts during puberty, BPH

Atrophy=decrease in cell size/number and metabolic activity

  • Causes: reduced blood flow, inadequate nutrients, denervation
  • Mechanisms: Degradation of cell proteins mainly occurs by the ubiquitin-proteasome pathway.
  • Examples: reproductive organs from lack of estrogen

Metaplasia= change in cell phenotype secondary to chronic irritation (adaptive, reversible) e.g. squamous to columnar cells in Barretts oesophagus, columnar to squamous in smoking

Dysplasia= disordered growth, loss of uniformity and organisation

Anaplasia= de-differentiation of cells, loss of functional differentiation

In what ways can a cell respond to injury

  1. Adaptation-->Hypertrophy, Hyperplasia, Atrophy, Metaplasia
  2. Reversible injury-->Recovery
  3. Irreversible injury-->Cell Death-->Apoptosis or Necrosis

By what process do intracellular accumulations occur? Give examples

Lipid deposition

Fatty change: manifestation of reversible cell injury. Accumulation of free triglycerides in cells

Cholesterol depostition: result of defective catabolism and excessive intake; deposition in macrophages(‘foam cells’) and smooth muscle cells of vessel walls in atherosclerosis

Protein deposition: ‘reabsorption droplets’ are seen in proximal renal tubules associated with protein loss in the urine (proteinuria), ‘Russell bodies’ formed when excessive immunoglobulin synthesis by plasma cells

Glycogen deposition: glycogen deposits in macrophages of patients with defects in lysosomal enzymes that break down glycogen

Pigment deposition: e.g. lipofuscin (‘wear-and-tear pigment’) is derived from lipid peroxidation and so is a telltale sign of free radical injury, or iron (hemosiderosis)

Calcium deposition: Deposition of calcium at sites of injury/necrosis, or deposition in normal tissues caused by hypercalcaemia (e.g. PTH excess, metastasis)

Explain dystrophic and metastatic calcification with examples

Dystrophic calcification Metastatic calcification
Tissue Damaged or necrotic Normal
Serum calcium Normal High
Mechanism Calcium deposition in injured tissue ↑ Ca²⁺ → precipitation
Examples Atherosclerotic plaques, damaged heart valves, old TB lesions, areas of fat necrosis Hyperparathyroidism, chronic renal failure, bone destruction, vitamin D excess

What are the mechanisms of cellular ageing?

Mechanisms of cellular aging include:

Accumulating cell damage (e.g. by free radicals) and reduced ability to repair damaged DNA

Reduced capacity to divide; replicative senescence can be caused by progressive shortening of telomeres

Defective protein homeostasis; unable to maintain proteins in correctly folded conformations (maintained by chaperones) or inability to degrade misfolded/damaged proteins by the autophagy-lysosome or ubiquitin-proteasome systems

Dysregulation of nutrient sensing; calorie restriction increases longevity (due to reduced IGF-1 signalling and increased sirtuins)

What are the different parts of cells that can be damaged?

Mitochondrial damage->leads to ATP depletion

Membrane damage: several ways membranes can be damaged e.g.

  • Oxygen free radicals (ROS) injure cell membranes via lipid peroxidation (O2-derived free radicals attack double-bonds in unsaturated fatty acids of membrane lipids)
  • Phospholipid membrane breakdown occurs with activation of calcium-dependent phospholipases (due to increase in cytosolic and mitochrondrial Ca2+)
  • Cytoskeletal breakdown by proteases activated by cytosolic Ca2+ and worsened by cell swelling

DNA damage-->activates p-53-->arrests cell in G1 phase-->triggers apoptosis

Oxidative stress-->due to increased production or decrease in ROS-scavenging enzymes (or antioxidants, or metal storage proteins such as transferrin, ferritin)

How do free radicals cause cell injury and what mechanisms prevent this?

Free radicals have a single unpaired electron in outer orbit, which is highly reactive with adjacent molecules such as proteins in plasma membranes. ROS are an oxygen-derived free radical. ROS are produced in mitochondrial respiration and are produced by neutrophils and macrophages (to kill microbes) and leukocytes (during inflammation). ROS are also produced by absorption of radiant energy such as Xray or UV light, and by free iron/copper. Increased production or less scavengers of ROS causes oxidative stress by causes lipid peroxidation in membranes, modification of proteins or creating lesions in DNA.

Removing ROS:

  • Antioxidants (block or inactivate) g Vit E and A
  • Transport/binding proteins for iron and copper e.g. transferrin
  • Enzymes: catalase (in peroxisomes), superoxidase dismutase/SOD, glutathione peroxidase

How does cytosolic calcium cause cell death/injury?

Ischaemia and toxins can cause increase in cytosolic Ca2+, which activates enzymes that damage cell components (e.g. phospholipases),

Accumulation of Ca2+ in mitochondria triggers the opening of the mitochondrial permeability transition pore, which causes loss of mitochondrial membrane potential and failure of oxidative phosphorylation-->depletion of ATP