• hormonal stimulation (uterus in pregnancy)
• ↑ functional demand (exercise, myocardial failure, ↑ cardiac workload)
• ↑ cell size from cellular protein accumulation, not fluid (heart, kidneys)
• physiologic hypertrophy reversible
• triggers: mechanical (stretch) and trophic (growth factor and vasoactive agents) signals

Mechanisms of Hyperplasia

• loss of epithelial cells → ↑ rate of cell division
• physiologic: compensatory (liver regeneration) and hormonal (↑ estrogen & mam glands during preg) [note: nerves, skeletal muscle, myocardial cells, & optical lenses DO NOT regenerate]
• pathologic: endometrial hyperplasia or neoplasms
• may occur with hypertrophy (except in such non-dividing cells as myocardial fibers)
  

Mechanisms of Metaplasia

• reprogramming of stem cells (epithelia) or undifferentiated mesenchymal cells (connective tissue)
• different cell maturation pathway signaled by cytokines and growth factors
• bronchial: smoking (reversible v. neoplasm)
       -ciliated, columnar epithelial cells replaced with    stratified squamous epithelial cells

• ↓ ATP: cellular swelling, ↓ protein synthesis, ↓ membrane transport, lipogenesis
• ROS: destroy cell membranes and structure
  - inactivate enzymes, damage cell membrane,
     injure nucleic acids (DNA)
• ↑ Ca in cell: intracellular damage from enzyme activation
• membrane permeability defects: ↓ protein, co-enzymes, RNA, and ATP substrates
  

• toxin- cell membrane interaction
  -direct toxicity
  -free radicals, lipid peroxidation
  -cellular responses
        -lipid accumulation
        -membrane defects → cellular swelling
        - ↓ ATP, Ca++ influx into mitochondira (↓oxidative metabolism)
        - DNA degradation
        - Lysosomal membrane injury→enzyme leak into cytoplasm→digestion of all cell organelles→DNA synthesis halted
  -air pollutants, insecticides, social drugs, etc.
• Lead toxicity
  -heavy metal, lungs and GI absorption
  -↑ intracellular Ca++→ neurotransmitter interference (alters fetal & pediatric neurodevelopment, learning disorders, hyperactivity, attention deficit, convulsions)
  -↓ enzymes for Hgb synthesis & RBC lysis (hemolysis)→anemia
  -renal deposits→tubular dysfunction (glycosuria, proteinuria, hyperphosphaturia)
  -lead based paint/toys, glazed pottery, print shop, plumbing, engine repair
• CO poisoning:
  -odorless, colorless gas
  -incomplete combustion of fuel
  -interferes with cellular respiration
  -affinity for Hgb 300X > than O2
  -binds to Hgb (carboxyhemoglobin)-prevents O2 binding→hypoxia (HA, giddiness, tinnitus, N/V)
  -↑fetal risk
  

• ischemia/anoxia (arteriosclerosis, thrombosis)
  -↓ ventilation, perfusion, diffusion, & O2 binding to Hgb
  -resp diseases, MI, hemorrhagic shock, poisons, toxins
  -cellular responses
         -↓ ATP→anaerobic metabolism
         - Na+ K+ pump failure→↑ Na+ & Ca++ & ↓ K+ in cell
         - cellular swelling (Na+ influx)
  -Reperfusion injury
         -enzyme conversion
         - ↑ATP consumption during ischemia → catabolites → ↑ ROS
             reperfusion → cell membrane damage, ATP loss, apoptosis
         -Rx: antioxidants, anti-inflammatories

1. progessive loss of O2
2. shift from aerobic to anaerobic
3. buildup of lactic acid
4. rapid ↓ in mitochondrial phosphorylation, due to lack of O2
5. LOSS OF ATP
6. Na+, K+ pump and Na+, Ca++ exchange failure
7. influx of Na+ & Ca++, release of K+
8. cellular swelling as H2O enters cell
9. dilation of ER, detachment of Ribosomes, loss of protein synthesis
   **at this point, process is reversible**
10. vacuolation
11. activation of multiple enzymes & lysosomes
12. DNA degradation
13. Cell death

• Free radicals
  -electrically unstable molecule(s)
  -disrupt chemical bonds of cell membranes (b/c free radical will bond with proteins, lipids, carbs)
  -destroy cell membrane & structure
• ROS
  -low levels beneficial?
  -high levels → apoptosis, necrosis
  -lipid peroxidation (destruction of unsaturated fatty acids, also lipid-radical interactions yield peroxides), alterations of proteins causing fragmentation of polypeptide chains) & DNA alterations
  -inactivation of free radicals (antioxidants, enzymes)
  -all cells capable of making ROS, but effects of inflammatory & CV disease (e.g. HTN, ischemic heart disease) widespread

• collection of blood in soft tissue v. enclosed space
• subdural: blook bt brain & surface dura
  -venous blood, slow
  -fall, blow, sudden acceleration, deceleration
• epidural: blood bt dura & skull
  -arterial blood, fast
  -skull fracture

• Cellular accumulations (infiltrations)
  -water, lipids, carbs, glycogen, proteins, pigments, Ca++, urate
  -crowd organells, release metabolites
• excess endogenous production, ineffective catabolism, or exogenous exposure
• migration of phagocytes→tissue swelling
• reversible (liver cirrhosis) or irreversible (exogenous poisoning)

• fever- endogenous pyrogens, acute inflammatory response
• ↑ HR- ↑ metabolism
• ↑WBC- infection
• pain- bradykinins, pressure
• ↑ enzymes (LDH, CK, AST, ALT, ALP, amylase)

• ↓ ATP production
• Na+ - K+ pump (active transport) failure
• cellular swelling (NaCl influx into cells)
• ribosome detachment from ER
• ↓ protein synthesis
• intracellular Ca++ → mitochondrial swelling
• cytoplasmic vacuolation
• lysozome leakage of digestive enzymes
• autodigestion of intracellular structures (nucleus, nucleolus, halting DNA/RNA synthesis)
• plasma membrane lysis

• sum of cellular changes after local cell death & process of cellular autodigestion
• widespread
• cell swelling
• rupture of cellular organisms
• inflammatory response
• causes: prolonged hypoxia, infection, cell membrane damge

• definition: sum of cellular changes following cell death occuring primarily in the kidneys, heart & adrenal glands; commonly results from hypoxia
• etiology: protein denaturation of plasma proteins, which causes albumin to change from a gelatinous state to a firm, opaque state
• pathogenesis:
  -severe ischemia
  -chemical injury (HgCl)
  -abnormalities in intracellular levels of Ca++

• definition: refers to death of tissue
• etiology: hypoxic injury, commonly associated with arteriosclerosis, especially in the lower leg
• pathogenesis
  -arterial blockage
  -subsequent bacterial invasion
  -Dry gangrene- result of coagulative necrosis
  -wet gangrene- develops when neutrophils invade the site; causes liquefactive necrosis
  -gas gangrene- caused by infection by Clostridium

• definition: necroses which commonly results from injury to neuron and glial cells in the brain
• etiology: hydrolytic enzymes (hydrolases) from dead brain cells digest surrounding brain cells; liquified tissue is then walled off from healthy tissue, forming cysts
• pathogenesis:
  -ischemic injury to neuron/glial cells
  -bacterial infection, causing release of neutrophil hydrolases; pus accumulation

• commonly results from TB infection; is a combo of coagulative & liquefactive necrosis
• the dead cells disintegrate, but the debris isn't digested completely by hydrolases
• tissues resemble clumped cheese
• a granulomatous inflammatory wall encloses areas of causeous necrosis

• programmed cellular death (scattered, single cells)
• enzyme synthesis, protease-induced shrinkage, cell fragmentation, phagocytosis
• apoptosis (physiologic or pathologic)
  -single cell, nuclear/cytoplasm shrinkage, quick & clean; no swelling or inflammation
• vs. necrosis (pathologic)
  -tissue cells swell & lyse, slow & messy, inflammation of neighboring cells

• osmotic forces (passive transport)
  -primary control/regulation
• aquaporins (H2O channel proteins, provide permeability to H2O)
• starling hypothesis
  -NET Filtration
           -movement of H2O from capillary to interstitial space
           *F favoring filtration-F opposing filtration
           *(cap hydrostatic + interstitial oncotic) - (plasma oncotic + interstitial hydrostatic)

• mediated, needs energy
• Na+, K+, Ca++, amino acids moved by active transport w/carrier against concentration gradient
• Na+ K+ pump carrier protein
• Na+ K+ ATPase: enzyme splits ATP for energy
  -proteins/organic substances cannot cross cell membrane (↑ ICF osmotic pressure, H2O diffuses into cell)
• 3 Na+ ions from ICF→ECF; 2 K+ ions from ECF→ICF (↓ ICF osmotic pressure & H2O diffusion)
• electrical gradient (membrance potential)
  -nerve & muscle function, APs

• forces favoring filtration (arterial end)
  -cap hydrostatic P (BP)
  -interstitial oncotic P (H2O pulling)
• forces favoring reabsorption (venous end)
  -plasma oncotic P (H2O pulling)
  -interstitial hydrostatic P
• capillary membrane damage
  -movement of proteins to interstitial→edema

• accumulation of fluid in interstitial space
• local or systemic: not available for perfusion/metabolism (3rd space)
  -lymphodema, pitting edema, cerebral edema, pulmonary edema, ascites
  -weight gain, swelling, puffiness, impaired wound healing
• causes:
  -↑ cap hydrostatic P (venous constriction, Na+ & H2O retention)
  -↓ plasma albumin (liver disease, protein malnutrition)
  -↑ cap permeability (inflammatory & immune cell injury causes)
  -lymph obstruction (infection, tumor, surgical removal)→ lymphedema
• Rx: elevation, compression, ↓ Na + intake, diuretics, underlying cause

• ↑ glomerular filtration rate (GFR)
• renin-angiotensin-aldosterone (RAA)
  -aldosterone secreted when
         - ↓ Na+
         - ↑ K+
         - ↓ blood volume
• natriuretic peptides (RAA antagosnists: ↓BP, ↑Na+ & H2O excretion)
  -atrial natriuretic peptide (ANP - atria)
  -brain natriuretic peptide (BNP - ventricles)
  -urodilantin (kidneys)

• infants, obese, & elderly - ↑ risk for imbalance
• isotonic alterations
  -total body water change, proportional electrolyte & H2O change, no cellular shrinking or edema
  -hypovolemia→ ↓ atrial P → ↑ ADH secretion
  -isotonic volume depletion (hemorrhage, wound drainage, diaphoresis, intestinal loss) → ↓ weight, dry skin & mucous membranes), ↑ HR, ↓ U.O.
  -isotonic volume excess (IV, ↑ aldosterone secretion with renal Na+ & H2O retention, corticosteroids, renal failure)

• intracellular dehydration →hypovolemia
  -dehydration
  -pure H2O deficits
  -renal free H2O clearance
  -hyperglycemia
• manifestations
  -tachycardia, ↓ BP, thirst, fever
  -↑ hematocrit & serum Na+
• Rx: slow D5W

• serum sodium >147 mEq/L
• related to sodium gain or water loss
• water movement from the ICF to the ECF
  -intracellular dehydration (cells shrink)
  -hypervolemia
• manifestations:
  -convulsions, pulmonary edema, fever, tachycardia, confusion, coma
• Rx with D5W

• major intracellular cation
• concentration maintained by Na+ K+ pump
• regulates intracellular electrical neutrality in relation to Na+ & H+
• essential for transmission and conduction of nerve impulses, normal cardiac rhythms, and skeletal and smooth muscle contraction

• changes in pH & K+ balance
  -H+ accumulates in ICF with acidosis
  -K+ shifts out to maintain cation balance across membrane
• aldosterone, insulin, and catecholamines influence serum potassium levels

• Potassium level > 5.5 mEq/L
• Hyperkalemia is rare due to efficient renal excretion
• caused by shift of K+ (metabolic acidosis), ↓ renal excretion (renal failure), insulin deficiency, cell trauma (e.g. crush injuries), acidosis
• Rx: insulin (K+ & glucose from ECF→ICF)
• Mild
  -hyperpolarized membrane→neuromuscular irritability
         -tingling of lups and fingers, restlessness, intestinal cramping, and diarrhea
• Severe
  -cell unable to repolarize→muscle weakness, loss or muscle tone, flaccid paralysis, arrhythmia, peaked T wave, ↓ ST segment, wide QRS
• Rx: correct acid-base, Ca++ gluconate, glucose, NaHCO3, dialysis, insulin (K+ & glucose from ECF→ICF)

• ↓s block of Na+ into cell
• ↑ neuromuscular excitability (partial depolarization)
• muscle cramps, tetany
• Chvostek's & Trousseau's signs
• < 8.5 mg/dL
• inadequate intestinal absorption, blood administration, ↓ PTH