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Pathology > Cellular Reaction to Injury Necrosis: Mechanisms and Morphologic Changes > Flashcards

Cellular Reaction to Injury Necrosis: Mechanisms and Morphologic Changes Flashcards

1
Q

characteristics of reversible cell injury

A
  • reduced energy production via oxidative process

- osmotic imbalance leading to water influx and cell swelling

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2
Q

irreversible cell injury

A
  • results from persistent or excessive injury
  • mitochondrial injury cannot be corrected
  • disturbed irreparable membrane function
  • cell cannot recover and dies (necrosis or apoptosis)
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3
Q

Types of Cell Injury

A
  1. physical
  2. oxygen deprivation
  3. chemical
  4. infectious
  5. immunologic
  6. genetic
  7. nutritional
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4
Q

define physical

A

direct physical trauma, thermal injury, radiation, electric shock

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5
Q

define oxygen deprivation

A

decreased oxygen state

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6
Q

define chemical

A
  • wide range of agents

- environmental pollutants, drugs, aberrations in normal cell solutes leading to osmolar imbalances

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7
Q

define infectious

A

prions to parasites

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8
Q

define immunologic

A

immune reactions to external injury and autoimmune disease

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9
Q

define genetic

A

genetic aberrations, abnormal protein expression causing direct cell injury or increased susceptibility to deleterious agents

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10
Q

define nutritional

A

deficiencies and excess may lead to cell injury and disease

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11
Q

types of oxygen deprivation

A
  1. hypoxemia
  2. ischemia
  3. hemoglobin loss/dysfunction
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12
Q

define hypoxemia

A
  1. low partial pressure of oxygen in blood! ***

2. PaO2 < 60mmHg, SaO2 < 90%

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13
Q

causes of hypoxia

A
  1. high altitude with decreased atmospheric oxygen
  2. hypoventilation
  3. diffusion defect (pneumonia, interstitial lung disease)
  4. ventilation perfusion mismatch (right to left shunt)
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14
Q

describe the Right to Left Shunt (Tetralogy of Fallot)

A
  1. pulmonic stenosis
  2. right ventricular hypertrophy
  3. overriding of aorta
  4. ventricular septal defect

“PROVE”

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15
Q

what is ischemia

A
  1. hypo-perfusion of tissue with blood

2. both reduced supply of oxygen & substrates for glycolysis

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16
Q

causes of ischemia

A
  • decreased arterial perfusion (atherosclerosis)
  • decreased venous drainage (hepatic vein thrombosis)
  • shock-generalized hypotension
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17
Q

Causes of Hb loss of dysregulation

A
  1. anemia (decreased RBC mass)
  2. carbon monoxide poisoning (CO binds HB instead of O2)
  3. methemoglobinemia
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18
Q

what is methemoglobinemia

A
  1. sulfate and nitrate drugs cause oxidant stress
  2. generates Fe3+, which cannot bind oxygen
  3. methylene blue can covert Fe3+ back to Fe2+
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19
Q

oxygen deprivation can lead to cell injury due to

A

reduced intracellular ATP production

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20
Q

mechanisms of injury/necrosis

A 
ATP Depletion
Mitochondrial Damage
Loss of Calcium Homeostasis
Oxidative Stress
Membrane Permeability Defects
DNA and Protein Damage
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21
Q

ATP is synthesized by

A
  • ADP phosphorylation in mitochondria (aerobic)

- glycolysis (anaerobic)

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22
Q

causes of ATP depletion

A

decreased oxygen and nutrients, mitochondrial damage, toxins

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23
Q

all synthetic and degenerative processes require what

A

ATP, its depletion has widespread defects on many critical systems

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24
Q

example of membrane-bound pump malfunction

A
  • Na/K-ATPase –> cell swelling/ER dilation
  • CA++ pump –> influx of Ca+ = derangement of cellular process
  • stimulation of glycolytic pathway –> decrease pH ER detachment of ribosomes –> decreased protein synthesis
  • protein missfolding, mitochondrial, lysosomal, nuclear membrane damage = necrosis
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25
Q

what decreases ATP production

A

injury leads to formation of high-condunctance channel - the mitochondrial permeability transition pore –> decreased potential –> decreased ATP

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26
Q

activation of apoptosis occurs within

A

cytochrome c and caspases in the mitochondria

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27
Q

membrane injury and leakage of cytochrome c and caspases activates what pathway

A

apoptotic pathway

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28
Q

intracellular Ca 2+ levels

A

maintained at very low levels (~0.1 umol) in mitochondria and the ER

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29
Q

extracellular Ca 2+ levels

A

are high (1.3 mmil) therefore a loss of homeostasis can lead to massive Ca 2+ influx

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30
Q

massive Ca2+ influx leads to

A
  • activation of the mitochondrial permeability transition pore (mPTP)
  • activation of phospholipases, proteases, endonucleases
  • increased mitochondrial permeability and activation of caspases and procaspases which directly induce apoptosis
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31
Q

O2 derived free radicals are

A

species with an unstable single election on its outer orbit which easily reacts with many key components of the cell

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32
Q

free radicals initiate

A

autocatalytic reactions, converting molecules that they react with into free radicals, propagating the cellular damage

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33
Q

define physiologic generations

A

ROS are produced normally in cells but they are degraded and removed by cellular defense systems

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34
Q

loss of steady state (where ROS are transient and in low concentrations) results in

A

oxidative stress

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35
Q

during normal respiration, O2 is reduced to

A

2H2O2 by transfer of 4 electrons to )2

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36
Q

oxidative enzymes in the cell catalyze this rxn and produce

A

partially reduced intermediates (ROS) during the process (see slide 26)

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37
Q

radiation can break down water into

A

OH and H free radical

38
Q

inflammation leads to bursts of ROS which activate what

A

leukocytes which generate ROS via a redox rxn lead by NADPH oxidase in PM

39
Q

enzymatic drug metabolism CCL4 is converted to

A

toxic CCL3 in liver

40
Q

nitric oxide (NO) generated by many cells can react with

A

O2 and be converted to highly reactive peroxynitrite anion (ONOO-), NO2 and NO3-

41
Q

during reoxygenation of blood flow to ischemic viable tissue, what can occur

A
  • ROS generated (from damaged mitochondria, inflammatory cells, endothelial cells, parenchymal cells)
  • influx of plasma proteins and leukocytes
  • activation of complement system
  • cellular antioxidant defense mechanisms not normal
42
Q

spontaneous decay

A

Superoxide (O2.-) –> O2 and H2O2 in the presence of water

43
Q

what are the active mechanisms of cellular removal of ROS

A
  1. antioxidants

2. transferring, ferritin, lactoferrin and ceruloplasmin

44
Q

what are antioxidants

A

block initiation of free radical formation or inactive free radicals

45
Q

examples of antioxidants

A

Lipid-soluble vitamins E and A , ascorbic acid and glutathione in the cytosol

46
Q

what are transferrin, ferritin, lactoferrin and ceruloplasmin

A

-are transport and storage proteins that chelate iron and copper which can catalyze the formation of ROS

47
Q

what enzymes remove ROS cellularly

A
  1. catalase
  2. superoxide dismutases
  3. glutathione peroxidase

(see rxns on slide 34)

48
Q

name 4 membrane disruptions

A
  1. ROS
  2. Decreased phospholipid synthesis
  3. increased phospholipid breakdown
  4. protease activation
49
Q

ROS can cause

A

injury to cell membrane via lipid peroxidation

50
Q

decreased phospholipid synthesis

A

low ATP leads to decreased production of phospholipids affecting all cellular membranes

51
Q

increased phospholipid breakdown

A
  • Cell injury leads to activation of endogenous phospholipases and membrane breakdown
  • Lipid breakdown products have a detergent effect on membranes resulting in changes in permeability
52
Q

protease activation

A

increased intracellular calcium proteases that damage cytoskeleton

53
Q

what are the effects of membrane disruption

A
  1. mitochondrial membrane damage
  2. plasma membrane damage
  3. injury to lysosomal membranes
54
Q

mitochondrial membrane damage

A
  • Mt permeability transition pore

- decreased ATP, release of apoptotic proteins

55
Q

plasma membrane damage

A

loss of osmotic balance and influx of fluids and ions –>further decrease in ATP

56
Q

injury to lysosomal membrane

A
  • leakage of hydrolases into cytoplasm (RNases, DNases, proteases, phosphatases, glucosidases) and degradation of targets
  • Low intracellular pH allows for activation of hydrolases
57
Q

DNA damage can be caused by

A

toxic drugs, radiation, oxidative stress

58
Q

normal DNA repair mechanisms do what

A

correct damage and maintain the steady state

59
Q

If DNA damage is too extensive for repair and misfolded proteins accumulate, what happens to the cell

A

the cell initiates a self destructive program called apoptosis

60
Q

What are the mechanisms of Cell injury

A 
ATP Depletion
Mitochondrial Damage
Loss of Calcium Homeostasis
Oxidative Stress
Membrane Permeability Defects
DNA and Protein Damage
61
Q

what are reversible morphologic changes of cell injury

A

cellular swelling

62
Q

cellular swelling is the first response to

A

injury

-loss of energy disables ATP-dependent ion pumps and leads to loss of osmotic homeostasis

63
Q

what are the morphological manifestations of cellular swelling

A

Plasma membrane blebbing or loss of microvilli
Mitochondrial swelling
ER swelling with detachment of ribosomes
Nuclear chromatin clumping (see chunks of nuclear material)
Cytoplasm may contain myelin figures (phospholipid masses from damaged cell membranes)

64
Q

irreversible changes (necrosis)

A
  1. nuclear changes - breakdown of DNA
  2. severe mt damage - ATP depletion
  3. lysosome damage - autophagy
  4. cytoplasmic changes - increased eosinophilia, loss of glycogen particles, more prominent myelin figures
  5. membrane damage - leakage of cellular contents
65
Q

necrosis often leads to what

A

inflammation/injury of surrounding cells

66
Q

nuclear changes due to breakdown of DNA

A
  1. pyknosis
  2. karyorrhexis
  3. karyolysis
  4. loss of nuclei
67
Q

define pyknosis

A

Shrinkage and increased basophilia (blue) due to chromatin condensation (often seen in apoptosis)

68
Q

define karyorrhexis

A

Fragmentation of pyknotic nuclei

69
Q

define karyolysis

A

Decreased nuclear basophilia due to DNA degradation by nucleases

70
Q

loss of nuclei

A

With time necrotic nuclei disappear

71
Q

what are cytoplasmic changes of necrosis

A
  1. cytoplasmic eosinophilia
  2. glassy cytoplasm
  3. myelin figures
72
Q

cytoplasmic eosinophilia due to

A

decline in cytosolic mRNA, which is basophilic, and an increase in cytosolic concentration of denatured proteins

73
Q

glassy cytoplasm result of

A

loss of glycogen particles

74
Q

myelin figures formed by

A

broken cell membrane

75
Q

irreversible cell injury is characterized by what 2 main events

A
  1. mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury
  2. disturbances in membrane function
76
Q

lysosomal injury results in

A

the enzymatic degradation of the cell that is characteristic of necrosis

77
Q

leakage of intracellular proteins through the damaged cell membrane leads to

A

recruitment of inflammatory response also typical of necrosis

78
Q

patterns of tissue necrosis

A
  1. coagulative necrosis
  2. Liquefactive Necrosis
  3. Gangrenous Necrosis
  4. Caseous Necrosis
  5. Fat Necrosis
  6. Fibrinoid Necrosis
79
Q

what is coagulative necrosis

A
  • Overall architecture is preserved, individual cells have a ghostly appearance
  • Destruction of proteolytic enzymes hinders proteolysis of necrotic cell
  • Necrotic cells remain until phagocytosis by infiltrating leukocytes occurs
    (ex. ischemia –> infarction)
80
Q

what is liquefactive necrosis

A

Digestion of dead cells which gives tissue a liquid appearance

81
Q

liquefactive necrosis occurs in

A
  • abscess

- brain infarction

82
Q

define abscess

A

infectious process leads to recruitment of white cells which release proteolytic enzymes which digest the dead cells

83
Q

define brain infarction

A

Microglial monocytic cells produce proteolytic enzymes and liquefy brain tissue

84
Q

grossly, liquefactive necrosis often seen as

A

a circumscribed lesion filled with pus and cellular debris or as gelatinous tissue with cavity

85
Q

define gangrenous necrosis

A
  • More than a pattern of necrosis it is a clinical descriptor (often a combination of coagulative and liquefactive necrosis)
  • often used to describe limb necrosis secondary to loss of blood supply (coagulative necrosis) with superimposed bacterial infection (liquefactive necrosis)–> wet-gangrene
86
Q

caseous necrosis is commonly seen in

A

mycobacterial/fungal infections and refers to the cheese-like appearance of the necrotic tissue

87
Q

what is a granulomatous reaction

A
  • where there is an amorphous granular debris enclosed within an inflammatory border
  • tissue architecture is completely obliterated, unlike coagulative necrosis
88
Q

define fat necrosis

A
  • not a real pattern of necrosis

- refers to fat necrosis of pancreas and peritoneal cavity as seen in pancreatitis

89
Q

in acute pancreatitis, what happens to pancreatic enzymes

A
  • pancreatic enzymes leak into the peritoneum and liquefy surrounding fat cells releasing fatty acids
  • these fatty acids combine with calcium to form calcium salts (soap)
90
Q

define fibrinoid necrosis

A

necrosis caused by deposition of immune-complexes and fibrin within walls of blood vessels

Pathology (18 decks)

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