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Immunology > Cell Injury Stress and Adaptations > Flashcards

Cell Injury Stress and Adaptations Flashcards

1
Q

Homeostasis

A

The healthy steady state of a cell/tissue/organ

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2
Q

Adaptation (give 2 examples)

A

Adaptation- reversible structural and functional responses, during which a new but altered steady state is achieved (ie hypertrophy or atrophy)

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3
Q

Cell Injury

A

reversible or irreversible sequence of events when the limits of adaptive responses are exceeded or cells are exposed to damaging insults, deprived of critical nutrients, or compromised by mutations.

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4
Q

What are the causes of cell Injury?

A

we R COPIING
Reperfusion
Oxygen deprivation (hypoxia)
- ischemia (↓ blood flow), inadequate blood oxygenation (ie cardiopulmonary failure),
decreased oxygen carrying capacity of blood (ie anemia, CO poisoning, etc)
Physical agents
- Mechanical trauma, electric shock, extreme temperatures, sudden Δ in pressure, radiation
Chemical Agents/Drugs
Infectious Agents
Immunologic Reactions
- Response to self-antigens (autoimmune diseases), immune response to external agents
Genetic abnormalities
Nutritional Imbalances
- vitamin deficiencies, protein deficiencies, obesity

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5
Q

How does Oxygen deprivation lead to Cell Injury?

A

Via ↓ oxidative respiration

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6
Q

What are 3 morphological characteristics of reversible cell injury.

A
  • Generalized Cell Swelling
  • Fatty change
  • Ultrastructural changes
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7
Q

What are some ultrastructural changes that occur in the cell?

A

PM blebbing, mito swelling and density accumulations, accumulation of “myelin figures,” dilation of ER, detachment of ribosomes, nuclear chromatin clumping

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8
Q

How does generalized cell swelling in reversible cell injury occur? What are the associated morphologies?

A

Reduced oxidative phosphorylation/mito damage -> ↓ [ATP] -> Na/K pump failure -> water influx
into cell -> generalized swelling,

pallor, increased turgor, increased weight of organ, increased vacuoles (detachments of ER)

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9
Q

What are the fatty changes that occur in reversibly injured cells and how do they occur?

A

Rapid accumulation of lipid vacuoles in cells involved in lipid synthesis as the result of disruption of
metabolic pathways

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10
Q

What are the causes of necrosis?

A 
Ischemia, exposure to microbial toxins, burns/chemical/physical injury, leaking of proteases into
surrounding tissue (ie pancreatitis)
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11
Q

What are the general characteristics of necrosis?

A

pathologic, “accidental” process resulting from severe injury
-Denaturation of cellular proteins
- Leakage of cellular contents through the damaged PM (this is the basis for blood tests that detect
tissue-specific cell injury)
- Local inflammation
- Enzymatic digestion of lethally injured cell
- karyolysis (nuclear disolution)

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12
Q

What are three determinants of “irreversibility?”

A
  • inability to reverse mitochondrial damage, loss of DNA and chromosomal integrity, and profound disturbances in PM fxn
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13
Q

What is apoptosis?

A

Regulated cell death that selectively eliminates damaged cells, without damaging surrounding cells

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14
Q

What is a hallmark of apoptosis and what mediates it?

A

Cellular shrinkage -> blebbing of PM and cellular fragmentation, followed by phagocytosis of apoptotic
cells
Mediated by caspases; can occur via intrinsic (mitochondrial) or extrinsic (death receptor) pathways

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15
Q

What is necroptosis?

A

Hybrid of apoptosis and necrosis

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16
Q

What does necroptosis morphologically resemble? What is it’s most studied pathway?

A

Necrosis. Triggered via cellular signaling pathways like apoptosis (not caspase)
Most studied pathway: TNF binds TNFR1 -> RIPK1/RIPK3 activation -> phosphorylation of MLKL ->
formation of MLKL oligomers -> PM disruption via MLKL translocation to PM

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17
Q

What is Pyroptosis, and what mediates it?

A

Apoptosis that is accompanied by release of IL-1, a cytokine that induces fever
Mediated by activation of the inflammasome and caspase 1

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18
Q

What is Ferroptosis?

A

Cell death triggered by excessive intracellular Fe, which leads to loss of PM permeability

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19
Q

What are 3 general feature of necrosis?

A

1- ↑ Eosinophilia due to loss of cytoplasmic RNA
2- Replacement of cells by myelin figures
3- Nuclear changes: ↓ chromatin basophilia, pyknosis (nuclear shrinkage and ↑ basophilia), karyorrhexis
(fragmentation of nucleus)

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20
Q

What are the 6 types of Necrosis?

A

Fat, Fibrinoid, Gangrenous, Caseous, Coagulative, Liquefactive
Fat Fools Go Chase Cool Leopards

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21
Q

Describe coagulative necrosis. Include what often causes it.

A

a. Localized area of coagulative necrosis: infarct (except in brain)
b. Characterized by preservation of architecture of dead tissue; results in firm texture of dead tissue
c. Mediated by coagulation of proteins
d. Nucleus not visible or extracellular
e. Area of infarcted tissue is often pale and wedge shaped (may become red-infarct if blood re-enters loosely organized tissue)
f. Often caused by ischemia -> hypoxia

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22
Q

Describe liquefactive necrosis. Include what diseases it is often characteristic of.

A

a. Enzymatic lysis of dead cells, resulting in liquefication of tissue -> pus (creamy yellow fluid; yellow is due to
presence of leukocytes)
b. Characteristic of: brain infarction, abscesses, pancreatitis

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23
Q

Describe gangrenous necrosis. When does wet gangrene occur?

A

a. Coagulative necrosis that resembles mummified tissue; not a specific pattern of necrosis, but broadly
applied to necrosis of lower limbs/GI tract
b. Wet gangrene occurs when a bacterial infection is superimposed upon the already dead tissue

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24
Q

Describe caseous necrosis. Where does it occur? What is it a result of?

A

a. Occurs in foci of TB infections -> formation of granuloma

b. Friable white appearance; combo of coagulative/liquefactive necrosis

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25
Q

Describe fat necrosis. What is it a result of and when does it classically occur?

A

a. Focal areas of fat destruction, resulting from trauma to fat
b. Classically occurs in breast (trauma to breast tissue) or pancreas (release of pancreatic lipases into
peritoneal cavity (pancreatitis))
c. Grossly visible chalky-white areas with saponification (due to calcium deposits)

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26
Q

Describe fibrinoid necrosis. How does it look on H&E stain?

A

Vascular damage due to deposition of antibodies/antigens on blood vessels
Bright pink and amorphous appearance on H&E stain

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27
Q

What is autophagy? What mediates it? What are some general features?

A

cell “eats” its own contents to derive nutrients, mediated by delivery of cytoplasmic material to lysosomes

Formation of phagophore and engulfment of contents -> formation of autophagosome -> maturation of
autophagosome via fusion with lysosome + degradation of contents

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28
Q

What has autophagy been implicated in and what is one cell type it is prominent in? What can happen when autophagy is inadequate to cope with stress?

A
  • Implicated in exercise and aging, and other situations where there is a lack of nutrients
  • Prominent in cells undergoing atrophy
  • Can trigger cell death independent of apoptosis or
    necrosis
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29
Q

Where has autophagy been implicated in disease?

A

Cancer, neurodegenerative disorders, infectious diseases, IBD

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30
Q

What are the determinants of cell response to injury? What are the consequences of response?

A

Determinants: nature, duration, and severity of injury and (characteristics of injured cell)
Consequences: type, state, and adaptability of cell

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31
Q

What are the major mechanisms of cell injury?

A

mitochondrial damage, membrane (PM and organelle) damage, DNA damage, and oxidative stress (free radicals and ROS)

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32
Q

What are causes and effects of mitochondrial damage?

What are the impacts of ATP depletion?

A

Causes: Increased [Ca2+], ROS, hypoxia, chemical agents, defects in mitochondrial proteins (genetic
mitochondrial diseases)
Effects: 1) ATP depletion
a) ↓ O2 -> ↓ oxidative phosphorylation -> ↓ ATP
b) Impact of ↓ [ATP]
i) Failure of Na+/K+ ATPase -> influx of Na+-> osmotic influx of water and cell swelling
ii) ↑ [cAMP] -> ↑ phosphorylase/phosphofructokinase activity -> ↑ glycogenolysis/glycolysis -> rapid ↓ [glycogen]
iii) Detachment of ribosomes from RER-> ↓ protein synthesis and ↑ misfolded proteins
2) Formation of ROS
3) Leakage of mitochondrial proteins -> initial step in intrinsic pathway of apoptosis -> cell death

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33
Q

What are the causes and effects of membrane damage? For effects, do mito, PM, and lysosomal?

A

Causes: 1) ROS
2) ↓ phospholipid synthesis accompanied by ↑ phospholipid breakdown
3) Cytoskeletal abnormalities
a) Example: ↑ [Ca2+] -> activation of proteases that target cytoskeleton -> cytoskeletal
breakdown, detachment of PM from cytoskeleton -> PM rupture/stretching
Effects:
1) Mitochondrial membrane damage -> release of mitochondrial proteins
2) PM damage -> disruption of osmotic balance -> swelling of cells and loss of cell contents
3) Lysosomal membrane damage -> leakage of lysosomal enzymes -> diffuse lysis of cell
components

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34
Q

What are the causes and effects of DNA damage?

A

Causes: Exposure to radiation, chemotherapy, ROS, spontaneous (esp due to aging)
Effects: p53 activation-> apoptosis

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35
Q

What are free radicals and ROS?

A

Free radicals: chemical species w/a single unpaired electron in an outer orbit
ROS: an oxygen-derived free radical

36
Q

How are free radical generated?

A

1) Redox reactions during normal metabolic processes, esp normal respiration
2) Absorption of radiant energy (UV, x-rays)
3) ROS generation by leukocytes during inflammation
4) Enzymatic metabolism of exogenous chemicals or drugs
5) Catalyzation of free radical formation by transition metals (ie Fe and Cu)
6) NO can act as a free radical

37
Q

How are free radicals removed? What are effects of free radicals?

A

1) Antioxidants block free radical formation or inactivate free radicals (ie vitamin E, A, ascorbic acid)
2) Sequestration of Fe and Cu by transport and storage proteins
3) Enzymatic free radical scavengers: catalase, superoxidase dismutases, glutathione peroxidase
Effects: can lead to either necrosis or apoptosis
1) Lipid peroxidation in membranes -> membrane damage
2) Oxidative modification of proteins -> formation of covalent cross-links, damage to active sites,
disruption of conformation, ↑ proteasomal degradation
3) Formation of DNA lesions

38
Q

How is calcium distributed in normal cells?

A

Intracellular Ca2+ is much lower than extracellular, and is sequestered in mito + ER

39
Q

What can cause release of intracellular Ca2+ stores and influx of extracellular Ca2+?

A

Ischemia and toxins

40
Q

What are some effects of Ca2+ damage

A

They are not well understood, but potentially activation of metabolic enzymes in cytoplasm and mito

41
Q

What are causes and effects of ER stress?

A

Causes: 1) Accumulation of misfolded proteins in ER
2) May be result of genetic abnormality in folding protein, viral infection that hacks protein synthesis machinery

Effects: Unfolded protein response: ↑ chaperones, ↑ proteasome activity, reduced rate of protein
translation
2) ER stress: If above efforts are not enough to cope, activation of caspases -> apoptosis

42
Q

What are mechanisms of ischemic cell injury? Describe difference between hypoxia and ischemia and what this means for a cell.

A

Ischemia is caused by hypoxia induced by reduced blood flow, most often caused by mechanical arterial
obstruction
i. There is no loss of blood flow in hypoxia, so anaerobic glycolysis can continue; in ischemia the loss of
blood flow prevents any energy-producing metabolism (due to lack of nutrients), resulting in more rapid and severe cell/tissue damage

43
Q

What does ischemia result in? How does the cell respond?

A
  • Briefly, ischemia results in decreased ATP production and the subsequent effects (under mito
    damage)
  • Cell response: TF hypoxia-inducible factor-1 (HIF-1) -> angiogenesis, activation of cell survival pathways, ↑
    glycolysis
44
Q

What is Ischemia-Reperfusion Injury?

A

Restoration of blood flow to ischemic tissue can lead to injury

45
Q

What are some proposed mechanisms for how I/R injury causes injury?

A

i. Oxidative stress due to increased ROS and nitrogen species, resulting from leukocytes and damaged
endothelial/parenchymal cells
ii. Increased intracellular Ca2+ due to influx of Ca2+ through the damaged PM from the now perfused
tissue
iii. Inflammation due to release of “danger signals” by dead cells, cytokine release from resident
macrophages, increased expression of adhesion molecules
iv. Complement activation; IgM antibodies bind ischemic tissue -> complement binding upon reperfusion

46
Q

What is hypertrophy?

A

increased size of cells –> increased size of organs

47
Q

What are physiologic and pathologic hypertrophy? Just give examples.

What is the increase in size a result of for the pathologic example?

A

Physiologic: growth of uterus during pregnancy (due mainly to growth of smooth muscle cells)

Pathologic: skeletal and cardiac muscle hypertrophy as a response to increased metabolic or mechanical demands, due to their limited capacity for regeneration –> ^^ in size of cells result of ^^ed protein synthesis and #of myofilaments

48
Q

What are mechanisms of hypertrophy?

A

Mechanical sensors in cell detects increased demands -> activation of downstream signaling
pathways -> ↑ growth factor synthesis and activation of TFs that stimulate muscle protein
transcription

49
Q

What is hyperplasia?

A

increased #of cells

50
Q

What is physiologic hyperplasia? Give an example.

A

mediated by hormones and growth factors; occurs when there is a need to ^^fx capacity of hormone sensitive organs or there is need for compensatory increase after damage or resection
Ex. Proliferation of glandular epithelia in female breast during puberty/pregnancy, liver regeneration after donation, bone marrow

51
Q

What is pathologic hyperplasia? Give an example.

A

Often result of excessive/inappropriate actions of growth factors/hormones

2) Ex: BPH, inappropriate hyperplasia of endometrium following menstruation
3) Although pathologic hyperplasia increases risk of cancer and is often a characteristic, it is a distinct process

52
Q

What are mechanisms of hyperplasia?

A

Growth-factor driven proliferation of mature cells

53
Q

What is atrophy?

A

reduction in size of organ/tissue due to a decrease in cell size and/or number

54
Q

When does physiologic atrophy normally occur? Where in the body does it normally occur?

A

Occurs commonly during normal development; atrophy of notochord and thryoglossal duct
during embryogenesis

55
Q

How can pathologic atrophy arise?

A

1) Disuse atrophy- due to decreased workload (ie skeletal muscle atrophy following
immobilization of a limb in a cast)
2) Denervation atrophy- due to a loss of innervation in muscle cells
3) Diminished blood supply (ie brain atrophy in old age due to reduced blood supply secondary to
atherosclerosis)
4) Inadequate nutrition- profound malnutrition results in use of skeletal muscle as source of
nutrients
5) Loss of endocrine stimulation- many hormone-dependent organs will atrophy upon loss of
endocrine stimulation
6) Pressure- compression of a tissue

56
Q

What are some mechanisms of atrophy and what often accompanies atrophy?

A

Decreased protein synthesis and increased protein degradation (via ubiquitin-proteasome pathway); autophagy

57
Q

What is metaplasia?

A

reversible change of one differentiated cell type to another

58
Q

Where do columnar epithelium to squamous epithelium metaplasia occur and what does this do?

A

Occurs in respiratory tract in response to chronic irritation (ie smoking)
Increases durability of epithelium, but decreases capacity to clear debris due to loss of cilia

59
Q

Where do squamous epithelium to columnar epithelium metaplasia occur and what is it influenced by?

A

Barrett esophagus, induced by refluxed gastric acid

60
Q

Where does connective tissue metaplasia occur?

A

Formation of mesenchymal tissue in tissue that does not normally contain these cell types

61
Q

What are mechanisms of metaplasia?

A
  • Re-programming of local tissue stem cells or colonization by adjacent, differentiated sites (does not result from change in phenotype of terminally differentiated cells)
  • Induced by signals from cytokines, growth factors, ECM proteins
62
Q

What are 4 mechanisms of intracellular accumulations?

A

i. Inadequate removal of molecules secondary to defects in transport
ii. Accumulation of molecules as a result of abnormal folding, packaging, transport, or secretion
iii. Failure to degrade a metabolite as a result of lysosomal abnormalities
iv. Deposition of abnormal exogenous substances within cell

63
Q

What is steatosis?

A

abnormal accumulation of triglycerides in parenchymal cells (ie fatty liver)

64
Q

What are 4 pathologies that arise from intracellular accumulations of cholesterol and cholesterol esters?

A

Atherosclerosis, xanthomas, cholesterolosis, and Niemann Pick disease

65
Q

Atherosclerosis

A

formation of cholesterol-containing lipid-vacuoles in smooth muscle cells of
aorta and large arteries

66
Q

xanthomas

A

intracellular accumulations of cholesterol in macrophages

67
Q

cholesterolosis

A

accumulation of cholesterol-laden macrophages in gallbladder

68
Q

Niemann Pick Disease

A

lysosomal disease involving protein involved in cholesterol trafficking

69
Q

How do proteins appear in protein accumulation?

A

rounded, eosinophilic droplets, vacuoles,

or aggregates

70
Q

What are 4 mechanisms of protein accumulation?

A

1) Reabsorption droplets in proximal renal tubules
2) Russell bodies- accumulation of normal cellular proteins that are overly synthesized, resulting
in distended RER that creates large eosinophilic inclusions
3) Accumulation of cytoskeletal proteins (ie neurofibrillary tangles in Alzheimer’s)
4) Aggregation of abnormal proteins

71
Q

Hyaline change

A

alteration w/in cells or ECM that gives homogenous, glassy pink appearance of tissue section–> result of accumulation of IC and EC hyaline

72
Q

How does glycogen accumulation appear, and how can it occur?

A

Formation of clear vacuoles in cytoplasm filled w/glycogen; Diabetes mellitus or glycogen storage disorders

73
Q

What types of pigments can accumulate and what is an(are) example(s)?

A

exogenous and endogenous; exogenous: Carbon as an air pollutant can accumulate in alveoli
Endogenous: 1) Lipofuscin- yellow-brown, finely granular pigment in cytoplasm; seen in cells undergoing slow,
regressive changes
2) Melanin- brown-black pigment formed by oxidation of tyrosine to dihydroxyphenylalanine by
tyrosinase
3) Hemosiderin- golden yellow-to-brown, granular, crystalline pigment in cytoplasm; storage of Fe

74
Q

What is pathologic calcification?

A

abnormal tissue deposition of calcium salts, as a result of hypercalcemia

75
Q

What are causes of hypercalcemia?

A

i. ↑ PTH secretion
ii. Resorption of bone tissue
iii. Vitamin-D related disorders
iv. Renal failure

76
Q

What are 2 types of calcification?

A

Dystrophic and metastatic

77
Q

What is dystrophic calcification? Where does it occur?

A

Calcification of locally dying tissues; occurs in areas of necrosis (independent of type)

78
Q

Where does metastatic calcification occur?

A

normal tissues in the presence of hypercalcemia

79
Q

Etiology

A

what caused the disease - either genetic or environmental

Ex. Cystic fibrosis is a genetic disease

80
Q

Pathogenesis

A

sequence of molecular, biochemical, and cellular events that lead to the development of disease; explains how etiologies give rise to symptoms.
Ex. a transporter defect in CF leads to accumulation of mucus in the lungs and other places

81
Q

Morphological changes

A

Ex. CF affected cells will look different

82
Q

Clinical manifestations

A

“trouble breathing” for the CF patient etc.

83
Q

What are potential early indicators for cell injury/death?

A

Loss of function, biochemical changes, and release of cytoplasmic enzymes

84
Q

How do you know when a cell is injured or has died?

A
85
Q

Disease

A

• Healthcare’s Perspective of this issue
“Disease … is a pathological process, most often
physical… some deviation from a biological norm.
There is an objectivity about disease which doctors
are able to see, touch, measure, smell. Diseases
are valued as the central facts in the medical
view…

86
Q

Illness

A

Individual Patient’s Perspective
“Illness … is a feeling, an experience of unhealth
which is entirely personal, interior to the person of
the patient. Often it accompanies disease, but…
Sometimes illness exists where no disease can be
found…”

Immunology (3 decks)

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