Robbins Chapter 2: Adaptions, Intracellular
Accumulations & Cell Aging
Hyperplasia: def. increase in cell number.
Can be physiologic or pathologic. Mechanisms include induction of transcription factors (c-fos, c-jun, NF-kB, STAT, myc, p53, cyclins), growth factors (HGF, TGF-a, EGF) and cytokines (IL-6, TNF-a). Cessation by growth inhibitors (TGF-b)
Hypertrophy: def. increase in cell size and organ size
Can be physiologic (gravid uterus, lactating breasts) or pathologic (myocardium). Cardiac hypertrophy results in ANF gene expression in ventricular myocardium. Mechanical triggers (stretch) & trophic triggers (growth factors and vasoactive agents e.g. angiotensin II, a-agonists)
Atrophy: def. decrease in cell size and function.
Physiologic (notocord, thyroglossal duct) or pathologic (disuse, denervation, ischemic, inadequate nutrition, loss of endocrine stimulation, aging, pressure). Increase in autophagic vacuoles and residual bodies (lipofuscin).
Metaplasia: def. alteration in cell differentiation. One adult cell type (epithelial or mesenchymal) replaced by another.
Deficiency of vitamin A (retinoic acid) leads to squamous metaplasia of respiratory epithelium.
Due to reprogramming of stem cells (reserve cells) by cytokines and growth factors (e.g. bone morphogenic proteins (BMP) induce chondroblastic and osteogenic expression.)
1. Normal cellular constituents
· rate of synthesis increased (e.g. Russell bodies in plasma cells)
· rate of metabolism is inadequate to remove a normal substance (e.g. fatty liver, lipid accumulation in heart from prolonged moderate hypoxia causing tigered myocardium, atherosclerosis, xanthomas, foamy macrophages, cholesterolosis, protein resorption droplets in renal tubules in proteinuria)
· genetic defects in metabolism, transport, packaging or secretion (e.g. in a-1-antitrypsin deficiency there is a slow-folding protein and accumulation of partially folded intermediates, glycogen accumulation in renal epithelium, liver and heart of diabetics or in glycogenoses)
2. Abnormal substance
· abnormal exogenous particle (e.g. carbon pigment - anthracosis, tattooing)
· hyaline change (intracellular protein or extracellular collagen, BM material or amyloid)
· calcification (dystrophic, metastatic - hypercalcemia)
CAUSES OF HYPERCALCEMIA
Increased PTH (parathyroid hyperplasia, adenoma, ectopic)
Metastatic lesions to bone (multiple myeloma, leukemia)
Vitamin D related disorders (Vit D intoxication, sarcoidosis, Williams Syndrome)
Renal failure (secondary hyperPTH)
· endogenous pigments (e.g. lipofuscin is a combination of lipids and phospholipids. It is yellow-brown and accumulates in liver and heart with aging. EM: perinuclear electron-dense aggregate; melanin, hemosiderin)
Cell functions that decrease with age: mitochondrial oxidative phosphorylation, synthesis of nucleic acids, structural and enzymatic proteins, capacity for DNA repair and nutrient uptake.
Cells have limited division potential, and may have a cellular clock (a way to count the # of divisions) leading to senescence, a terminally non-dividing state:
1. Telomere shortening (telomerase stabilizes chromosome length, reactivated in immortalized cells)
2. Clock genes (clk-1 in C. elegans)