Cell adaptation and cellular injury

Question 1

Reversible vs irreversible injury

Answer 1

Reversible injury - pathologic changes that can be reversed when the stimulus is removed or if the cause of injury is mild
Irreversible injury - pathologic changes that are “beyond the point of no return”, permanent and result in cell death

Question 2

What is hyperplasia and give examples

Answer 2

Increase NUMBER of cells due to increase functional capacity of the whole
- Eg (physiologic): compensation after partial hepatectomy
- Eg (pathologic): abnormal androgen response in BPH

Question 3

What is hypertrophy and give examples

Answer 3

Increase SIZE of cells and organs , resulting in large organ overall
- Eg (non dividing cells): cardiac myocytes
- Eg (dividing cells): uterus in pregnancy
- Eg (physiologic): increased demand on striated muscle in body-builders
- Eg (pathologic): disease causing volume overload and cardiac hypertrophy, BPH)

Question 4

What is atrophy and give examples

Answer 4

Decrease SIZE and NUMBER/MASS of each cells
- Eg (physiologic): embryologic development
- Eg (pathologic): disuse, denervation, ischemic, nutritive, endocrine-mediated, senile, and pressure atrophies

Question 5

What is metaplasia and give examples

Answer 5

REPLACEMENT of one differentiated cell type by another. Reversible changes.
- Eg: columnar to squamous metaplasia in trachea and bronchi of smokers; squamous to columnar in Barrett’s oesophagus
- effected by reprogramming of stem cells to differentiate along an alternate pathway
- an adaptation that allows new cells to better deal with altered environment, and occurs in response to a chemical or physical stressor

Question 6

Necrosis vs Apoptosis

Answer 6

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Question 7

Causes of cell injury

Answer 7

A - Anaerobic
- hypoxia secondary to ischemia , inadequate oxygenation and loss of O2-carrying capacity of the blood

B - Bacteria or other infection
- virus, rickettsiae, bacteria, fungi, parasites

C - Chemical insult
- paracetamol, lead, alcohol

D - Drugs

E - Environmental (radiation, temp, pH, trauma, electricity)

F - Food or nutritional deficit
- protein-calorie deficiency, lack of specific vitamins, nutritional excesses)

G - Genetics
- chromosomal alterations, specific mutations

Question 8

Mechanism of cell injury

Answer 8

• ATP depletion
• Na/K-ATPase fails -> rise intracellular [Na] and loos [K] with net gain of solute -> swelling of the cell
• Increase AMP levels stimulate anaerobic metabolism, depleting glycogen and produce lactate, reduce pH and inhibit many enzymes
• Ribosomes detach from RER -> reduce protein synthesis
• Irreversible mitochondrial damage and dysfunction
• Ca2+ influx
• Accumulation of O2 derived free radicals (oxidative stress)
• Defects in membrane permeability
• Damage to DNA and proteins

Question 9

Ischemic vs hypoxic injury

Answer 9

Ischemic injury:
- most common type of cellular injuries
- diminished blood flow to tissue. Injury is faster and more severe
- if persist, irreversible injury and necrosis occur
- a/w extensive mitochondria swelling, damage to plasma membrane, and swelling of lysosomes

Hypoxia injury: energy generation by anaerobic glycolysis
- reduce O2 -> reduce ATP generation
- loss of ATP –> failure of energy-dependent cellular systems
- major abnormalities: ATP generation, mitochondrial damage, accumulation of ROS

Question 10

What is ischemia-reperfusion injury?

Answer 10

Additional loss of cells when blood flow is restored to cells that have been previously ischemic
- important in myocardial, cerebral and GI infarct
- possibly caused by:
1. Incomplete oxygen reduction by damaged mitochondria and infiltrating neutrophils yielding reactive species, that promote the mitochondrial permeability transition
2. Local recruitment of inflammatory cells as part of an overwhelming inflammatory response
3. Complement pathway activation after IgM antibody deposition in ischemic tissues

Question 11

Chemical injury

Answer 11

Direct: binding to some critical molecular component
- eg: mercury of mercuric chloride binds to SH groups of cell membrane proteins -> increased permeability and inhibition of ATPase-dependent transport

Indirect: conversion to reactive toxic metabolites
- eg: carbon tetrachloride (CCl4) convert to CCL3- in P450 liver enzyme complex > initiates lipid peroxidation and autocatalytic reactions -> cell death

Question 12

Types of necrosis and the examples:
1. Denaturation of cytoplasmic proteins with preservation of the framework of the coagulated cell
2. Soft, friable, “cheesy” material
3. Necrosis in the adipose tissue
4. When autolysis and heterolysis prevail over protein denaturation -> necrotic area is soft and fluid-filled
5. Usually in immune reaction in which complexes of antigen and antibodies are deposited in the walls of arteries. The deposited immune complexes together with fibrin that has leaked out vessels produce a bright pink amorphous called fibrinoid.
6. Loss of blood supply and undergone coagulative necrosis involving multiple tissue layers.

Answer 12

1. Coagulation necrosis
   - eg: myocardium, kidney, liver
2. Caseous necrosis
   - eg: TB lesions (histologically amorphous eosinophilic material with cell debris)
3. Fat necrosis
   - histologically: shadowy outlines of cells, basophilic stippling
   - action of lipases > enzymatic release of fatty acids from TG > complex with Ca2+ > Ca2+ soaps > chalky white areas (fat saponifications)
4. Liquefactive necrosis
   - eg: bacterial infections (abscesses) in the brain
5. Fibrinoid necrosis
6. Gangrenous necrosis

Question 13

Subcellular response to injury

Answer 13

1. Lysosome catabolism
2. Hypertrophy of the smooth ER
3. Cytoskeletal abnormalities
4. Induction of heat shock proteins

Question 14

Intracellular accumulations

Answer 14

Metabolic alterations in cells may result in the accumulation of:
- normal cellular constituent in excess (eg: H2O, protein, carbohydrate)
- abnormal substance
» endogenous (eg: a product of abnormal metabolism)
» exogenous (eg: a product of an infectious agent)
- a pigment
» endogenous (eg: melanin, hemosiderin)
» exogenous (eg: coal dust)

Question 15

Process of intracellular accumulations

Answer 15

1. Normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it (eg accumulation of fat in liver cells)
2. Normal or abnormal endogenous substance accumulates because of genetic or acquired defects in metabolism, packaging, transport or secretion.
   - genetic defects
   - lysosomal storage disease
   - cytoskeletal abnormalities
3. Deposition of abnormal exogenous substances

Question 16

What is pathologic calcification and the types?

Answer 16

Pathologic calcification - abnormal deposition of calcium salts in soft tissues

Dystrophic calcification - occurs in nonviable or dying tissues in the presence of normal serum Ca2+ levels
- eg: arteries (arterosclerosis), damaged heart valves, areas of necrosis (coagulative, caseous, liquefactive)

Metastatic calcification - deposition of calcium salts in vital tissues, always associated with hypercalcemia
- causes of hypercalcemia:
» increased PTH (parathyroid hormones > hyperparathyroidism)
» destruction of bone tissue (eg: multiple myeloma, diffuse skeletal metastases, Paget’s disease)
» Vitamin D (eg Vit D intoxication, systemic sarcoidosis)
» renal failure (eg secondary hyperparathyroidism)

Question 17

Phases of calcification

Answer 17

Initiation:
- Intracellular: occurs in mitochondria of dead or dying cells
- Extracellular: membrane-bound vesicles derived from dead or dying cells

Propagation:
- Concentration of Ca2+ and Ph
- Presence of inhibitors
- Structural components of extracellular matrix
- other matrix proteins