Cellular Pathology - Cellular Injury, Necrosis의 종류, Apoptosis

I. Cellular Injury

- Occurs when a stress exceeds the cell's ability to adapt
- Ischemic injury : neuron(high susceptible), skeletal muscle(more resistant)
- slow developing ischemia → atrophy(e.g.renal artery atherosclerosis)
- acute ischemia → injury(e.g.renal artery embolus)

Hypoxia의 원인

II. Hypoxia

■ mechanism
- cause of hypoxia : ishemia, hypoxemia, O2 carrying capacity ↓
- Lack of ATP leads to cellular injury
■ Ischemia
- decrease arterial perfusion : atherosclerosis
- decrease venous drainage : Budd-Chiari syndrome
- shock : generalized hypotension
■ Hypoxemia(PaO2 < 60 mmHg, SaO2 < 90%)
- High altitude : PaO2 ↓
- Hypoventilation :  PaO2 ↑  PaCO2 ↑
- Diffusion defect : Pao2 not able to push into the blood (e.g. IPF)
- V/Q mismatch : Blood bypasses oxygenated lung (e.g. R to L shunt, atelectasis)
■ Hemoglobin dysfunction
- Anemia : PaO2 & SaO2 normal
- CO poisoning : CO binding Hb more avidly _ PaO2 normal, SaO2 ↓
- Methemoglobinemia : Iron in heme is oxidized to Fe3+, can't bind oxygen : PaO2 normal , SaO2 ↓

III. Reversible and Irreversible cellular injury

■ Low ATP disrupts key celluar functions including
- Na-K pump → sodium and water retention
- Ca pump : Calcium retention in the cytosol
- switch to anaerobic glycolysis → Lactic acid ↑  → low pH , protein & DNA 변형
■ reversible injury
- hallmark of reversible injury : cellular swelling
- loss of microvilli and membrane blebbing
- swelling of RER and dissociation of ribosome → protein synthesis lowering
■ irreversible injury
- hallmark of irreversible injury : membrane damage
- Cytosolic enzymes leaking into the serum (e.g. cardiac troponin)
- calcium entering into cell
- mitochondrial membrane damage : loss of the electron trasport chain, Cytochrome c leaking into cytosol(activates apoptosis)
- Lysosome memebrane damage : hydrolytic enzymes leaking into cytosol(activated by the high intracellular calcium)
- end of result of irreversible injury ➡️ Cell Death

 

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I. Cell Death

pyknosis → karyorrhexis → karyolysis

- hallmark of cell death : loss of nucleus
- pyknosis → karyorrhexis → karyolysis  
- Necrosis or Apoptosis

II. Necrosis

- Death of large groups of cells followed by acute inflammation
- pathololgic process
- several type based on gross feature

Necrosis vs Apoptosis

■ Coagulative necrosis

Coagulative necrosis

- necrotic tissue that remains firm
- cell shape and organ structure are preserved by coagulation proteins, but the nucleus disappers
- ischemic infarction of any organ except the brain
- infarction tissue is often wedge-shaped and pale

■ Liquefactive necrosis

Liquefactive necrosis

- enzymatic lysis of cells and protein results in liquefaction
- brain infarction : proteolytic enzymes from microglial cells
- Abscess : proteolytic enzymes from neutrophils liquefy tissue
- Pancreatitis : proteolytic enzymes from pancreas liquefy paranchyma

■ Gangrenous necrosis

Gangrenous necrosis

- coagulative necrosis that resembles mummified tissue(dry gangrene)
- ischemia of lower limb and GI tract
- If superimposed infection of dead tissues → liquefactive necrosis(wet gangrene)

■ Caseous necrosis

Caseous necrosis

- soft and friable necrotic tissue
- combination of coagulative + liquefactive necrosis
- TB or fungal infection : characteristic of granulomatous inflammation

■ Fat necrosis

- necrotic adipose tissue with chalky-white appearance (Ca_deposition)
- Trauma to fat(e.g.breast), peripancreatic fat damage
- saponification : fatty acid or lipase join with calcium, example of dystrophic calcification, normal serum calcium & phosphate
- metastatic calcification : occurs when high serum calcium or phosphate level (e.g. hyperparathyroidism leading to nephrocalcinosis)

■ Fibrinoid necrosis

Fibrinoid necrosis

- Necrotic damage to blood vessel
- Leaking of proteins : into vessel wall result in bright pink
- malignant hypertension and vasculitis

 

III. Apoptosis

- ATP dependent, programmed cell death

■ clinical points

- Endometrial shedding during menstrual cycle
- Removal of cell during embryogenesis
- CD8+ T cell mediated killing virally infected cells

■ morphology

- dying cell shrink, cytoplasm become more eosinophilic
- nucleus condenses and fragment in an organized manner
- apoptotic bodies fall from the cell and are removed by macrophages(not inflammation)

■ mechanism

- mediated by caspase → active protease and endonucleases

1] Intrinsic mitochondrial pathway

> inactivation of Bcl2 → cytochrome c to leak from mitochondrial matrix
> activate caspases

2] Extrinsic receptor-ligand pathway

> FAS ligand binds FAS death receptor (CD95) → active caspases
> TNF bind TNF receptor on the cell → active caspases

3] Cytotoxic CD8+ T cell-mediated pathway

> Perforins secreted by CD8 T cell create pores in membrane
> Granzyme from CD8+ T cell enters pores and activates caspases
> CD8 T cell virally infected cell