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Pathological Basis of Disease I > 4-22 Cell Injury > Flashcards

4-22 Cell Injury Flashcards

1
Q

What are 2 reasonable answers to any question in PBD?

A

Sarcoidosis

Amyloidosis

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2
Q

Difference between necrosis and apoptosis?

A

Necrosis is always abnormal

Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with cell injury

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3
Q

What are adaptations in regards to cell growth and development?

A

Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment

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4
Q

What is hypertrophy? How is it achieved?

A

Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ

Hypertrophy is achieved by increasing the synthesis of cellular proteins.

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5
Q

What are some causes for hypertrophy?

A
  1. Mechanical stretch - major
  2. Agonists - pathologic state
  3. Growth factors - pathologic state
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6
Q

What is hyperplasia?

A

Hyperplasia is defined as an increase in the number of cells in an organ or tissue in response to a stimulus

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7
Q

What is physiologic hyperplasia?

A

Physiologic hyperplasia due to the action of hormones or growth factors occurs in several circumstances: when there is a need to increase functional capacity of hormone sensitive organs; when there is need for compensatory increase after damage or resection

For example: BPH

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8
Q

What is atrophy?

A

Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number

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9
Q

What are 7 causes of pathologic atrophy?

A

Decreased workload (atrophy of disuse)

Loss of innervation (denervation atrophy)

Diminished blood supply

Inadequate nutrition

This results in marked muscle wasting (cachexia)

Loss of endocrine stimulation

Pressure

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10
Q

What is metaplasia?

A

Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type

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11
Q

Columnar epithelium can frequently metastasize to what?

A

Squamous cell type

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12
Q

What is the sequence of events for morphologic alterations in cells after irreversible injury?

A

Biochemical alterations

Ultrastructural changes

Light microscopic changes

Gross morphological changes

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13
Q

What 2 features of reversible cell damage can be recognized under light microscopy?

A

cellular swelling

fatty change

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14
Q

What is the biochemical mechanism for myocardial hypertrophy?

A

Increased mechanical stretch

Possible input by agonists and growth factors - ANG, IGF-1

Signal transduction pathways are activated

Trx factors made

Induction of embryonic/fetal genes - i.e. ANF

Increased synthesis of contractile proteins

Increased production of growth factors, which continues the process

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15
Q

What causes cell injury?

A

If limits of the cell’s adaptive responses are exceeded or if cell are exposed to injurious agents or stress, deprived of essential nutrients, or become compromised by mutations that affect essential cellular constituents, a sequence of events follows that is termed cell injury.

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16
Q

What is physiologic hypertrophy?

A

Some cells have a limited ability to divide - i.e. striated muscle in heart or skeletal muscles. Increased functional or metabolic demands, or stimulation by growth factors or hormones will frequently cause these cells to hypertrophy.

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17
Q

What is the physical stimulus for myocardiocyte hypertrophy?

A

Increased chronic hemodynamic overload, from HTN or faulty valves

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18
Q

What is a common cause for pathological hyperplasia?

A

Often caused by excessive or inappropriate actions of hormones or growth factors acting on target mature cells.

Hyperplasia can also result if new tissue grows from stem cells. (Robbins is unclear if this process is necessarily pathologic - example is growth of new liver tissue aft transplant or liver infection.)

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19
Q

What are some examples of pathologic hyperplasia that were discussed in class? How are these different from cancer?

A

Endometrial hyperplasia - failure of the endometrium to regress due to high levels of estrogen

Benign Prostatic Hyperplasia - growth of the prostate gland under the continued influence of testosterone

Both of these processes will involute if hormone is removed. In cancer, the drive towards growth is unchecked.

Hyperplasia is distinct from cancer, but pathologic hyperplasias are fertile ground for eventual cancerous proliferations.

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20
Q

What is atrophy?

A

Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number

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21
Q

What are 6 causes of pathologic atrophy?

A

Decreased workload (atrophy of disuse)

Loss of innervation (denervation atrophy)

Diminished blood supply

Inadequate nutrition

This results in marked muscle wasting (cachexia)

Loss of endocrine stimulation

Pressure

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22
Q

What can result from decreased workload/atrophy of disuse?

A

Initial decrease in myocyte size is reversed when activity is resumed

With prolonged disuse, skeletal mm fibers decrease in size and number

Bone resorption is increased, osteoporosis of disuse can occur

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23
Q

What happens during denervation atrophy?

A

Normal metabolism and function of mm cells is dependent on nerve supply, damage to nerve results in atrophy of affected mm.

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24
Q

What happens during atrophy from diminished blood supply?

A

Blood supply can gradually decrease due to arterial occlusive diseases

  • brain undergoing atrophy due to atherosclerosis, called senile atrophy
  • can see widened sulci and narrowed gyri on gross brain, globally
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25
Q

What happens in atrophy due to inadequate nutrition?

A

Marasmus (profound protein-aclorie malnutrition) causes utilization of skeletal mm protein as a source of energy after adipose stores have been depleted.

Muscle wasting that results is called cachexia.

Also seen in chronic inflammatory disease and cancers.

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26
Q

What happens in atrophy due to loss of endocrine stimulation?

A

Hormone sensitive tissue is dependent on endocrine stimulation for normal metabolism and function.

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27
Q

What happens with pressure atrophy?

A

Tissue compressing for any length of time can cause atrophy.

Can happen due to tissues adjacent to an enlarging benign tumor getting compressed.

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28
Q

What is the idea behind atrophy? Is it the same for all types of atrophy?

A

Mechanism is the same for all types of atrophy

Decrease in cell size and organelles, resulting in decreased metabolic demands. Metabolism will be in sync with blood and nutrition supply. Early atrophic cells have diminished function, but cell death is minimal.

Gradual loss of blood supply can result in apoptosis.

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29
Q

What is the cellular mechanism of atrophy?

A

Atrophy results from decreased protein synthesis and increased protein degradation in cells.

Degradation of proteins occurs mostly though ubiquitin-proteosome pathway.

  • nutrient deficiency and disuse activates ubiquitin ligases
  • U(ubiquitin) ligases attach U’s to cellular proteins and target them to proteasome for degradation

Often accompanied by autophagy, with autophagic vacuoles and resulting residual bodies.

  • lipofuscin granules can result, staining tissues brown and creating brown atrophy
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30
Q

What is metaplasia?

A

Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type

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31
Q

What is a common reason for metaplasia to occur? What is the result?

A

Metaplasia is often an adaptive response where one cell type that is sensitive to a stress is replaced by another that can better withstand the environment.

Commonly see columnar → squamous epithelium change

  • seen in respiratory tract of smokers
  • excretory ducts of salivary glands, pancreas, or bile ducts with stones

Can also see squamous → columnar

  • Barrett’s esophagus

Can also result due to injury, not as an adaptive response

-i.e bone formation in muscle after a hemorrhage

32
Q

If metaplasia is an adaptive response, why is it concerning?

A

Can result in loss of protective mechanisms of original tissue

  • i.e. loss of ciliated respiratory epithelium to ward off infection and crud

Influences that predispose to metaplasia, if persistent, can initiate malignant transformation in metaplastic epithelium.

33
Q

What is the mechanism of metaplasia?

A

Metaplasia doesn’t result from a change in the phenotype of an already differentiated cell type, instead is the result of a reprogramming of stem cells that known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue.

Precursor cells differentiate along a new pathway, brought about by signals generated by cytokines, growth factors, and extracellular matrix components. All promote gene expression to a certain pathway.

Dysregulation of trx factors results in metaplasia - i.e. retinoic acid, vitamin A.

34
Q

What are 7 causes of cell injury?

A

Oxygen Deprivation

Chemical Agents and Drugs

Immunologic Reactions

Nutritional Imbalances

Genetic Derangements

Infectious Agents

Physical Agents

35
Q

What is hypoxia? What are 3 causes for it? Is it always fatal for cells?

A

Hypoxia is deficiency of O2, with resulting cell injury due to reduced aerobic oxidative respiration

Causes include:

reduced blood flow (ischemia)

inadequate oxygenation of blood due to cardioresp failure

decreased O2 carrying capacity of blood (anemia, CO poisoning, severe blood loss)

Cells can potentially adapt or atrophy if hypoxia is gradual, but sudden hypoxia will result in injury and death

36
Q

What 4 cellular changes happen with cellular injury? What do these changes cause?

A

Swelling of cell and organelles

blebbing of plasma membrane

detachment of ribosomes from plasma ER

clumping of nuclear chromatin

All cause:

decreased generation of ATP

loss of cell membrane integrity

defects in protein synthesis

cytoskeletal damage

DNA damage

37
Q

What happens with cell death?

A

Same sequence that happens with injury, but with continued noxious stimulus or new stress

38
Q

What changes of reversible cell injury can be seen under light microscope?

A

Cellular swelling - very common, due to breakdown of ATP-dependent ion pumps

Fatty change - happens in cells dependent on fat metabolism - heart and liver

39
Q

What 4 ultrastructural cell changes occur as a result of reversible cell injury?

A
  1. Plasma membrane alterations
    - blebbing, blunting, loss of microvilli
  2. Mitochondrial changes
    - swelling and appearance of small amorphous densities
  3. Dilation of ER
    - detachment of polysomes, intracytoplasmic myelin figures may appear
  4. Nuclear alterations
    - disaggregation of granular and fibillar elements
40
Q

Why does necrosis happen?

A

Result of denaturation of intracellular proteins and enzymatic digestion of lethally injured cell.

  • lack of membrane integrity = contents of cell leaks out, causing inflammation
41
Q

The enzymes that digest necrotic cells come from where?

A

Leaked lysosomes from dying cell

from leukocytes that are trying to clean up and incite inflammation

This process can take 2-12 hours to fully develop

42
Q

What is a clinical correlation to the timeframe of necrosis?

A

After an MI, necrosis will take hours to manifest gross changes to the heart

Cardiac troponin and other cardiac enzymes will be leaking into bloodstream as early as ~2 hours after MI. Levels can be checked to determine if injury to cardiac tissue has happened.

43
Q

Why are necrotic cells eosinophilic?

A

Loss of cytoplasmic RNA that would normally bind blue dye

Increase in proteins in cytoplasm, which binds pink eosin dye

Necrotic cells will appear chaotic in tissue organization, with mottled pink appearance and many cells lacking defining characteristics or nuclei

44
Q

What 6 mechanisms of necrosis did we learn about?

A
  1. Coagulative necrosis
  2. Liquifaction necrosis
  3. Gangrenous necrosis
  4. Caseous necrosis
  5. Fibrinoid necrosis
  6. Fat necrosis
45
Q

What causes coagulative necrosis? What is it associated with?

A

Necrosis due to sudden loss of blood supply

  • small local area is called an infarct
  • happens in kidney, heart

Often, ultrastructure of tissue/organ is left behind for a few days, and affected tissue has a firm texture. Proteolysis is blocked and dead cells may remain for weeks.

46
Q

What is liquifactive necrosis? What is it associated with?

A

Necrosis with digestion of cells, resulting in tissue turning into liquid

  • necrotic material is yellow, called pus

Hypoxic death of cells in CNS results in liquifactive necrosis

47
Q

What is gangrenous necrosis?

A

Typically applies to limb that has lost blood supply and is undergoing (coagulative) necrosis in several tissue planes

With addition of a bacterial infection, it turns into liquifactive necrosis due to the degradative enzymes in bacteria = wet necrosis

48
Q

What is caseous necrosis? What is it associated with?

A

Center of necrotic cells with granulomatous/inflammatory border

  • this type of structure often called a granuloma

This IS tuberculosis (TB).

49
Q

What is fat necrosis?

A

Refers to focal areas of fat destruction

  • frequently a result of acute pancreatitis - pancreatic enzymes leak from acinar cells into abdomen and cause saponification of fat cells, and form chalky white blebs with Ca++ on the mesentary
50
Q

What is fibrinoid necrosis? What is it associated with?

A

Necrosis in blood vessels that occurs after complexes of antigens and antibodies are deposited in vessel walls

Fibrin leaks out of vessels

Stains bright pink, results in immunologically-mediated vasculitis syndromes

51
Q

What does the cellular response to injurious stimuli depend on?

A

Nature of the injury

Duration

Severity

52
Q

What do the consequences of cell injury depend on?

A

Type, state and adaptability of injured cell

Depends on nutritional, hormonal, and metabolic status of cell

is cell vulnerable to insult?

genetic polymorphisms

53
Q

What sites in a cell are damaged as a result of cell injury? What happens?

A

Mitochondria

  • decreased ATP
  • increased ROS

Entry of Ca++

  • increased mitochondrial permeability
  • activation of multiple cellular enzymes

Membrane damage

  • plasma membrane - loss of cellular components
  • lysosomal membrane - enzymatic digestion of cellular components

Protein misfolding and DNA damage

  • activation of pro-apoptotic proteins
54
Q

What is the fundamental cause of necrotic cell death? What are the major reasons why this occurs?

A

Fundamental cause is depletion of ATP/decreased ATP synthesis

Causes:

reduced supply of O2 and nutrients

mitochondrial damage

actions of some toxins - i.e. CN

55
Q

Ischemia has happened. What is the sequence of events that follows?

A

Activity of plasma membrane energy-dependent sodium pump is reduced

  • net gain of Na+, loss of K+
  • cell swelling, blebbing, loss of microvilli follows

Cellular energy metabolism is reduced

  • decrease in ox phos
  • decrease in ATP levels
  • increased anaerobic glycolysis, loss of glycogen stores
  • increased lactate
  • decreased pH → clumping of nuclear chromatin

Influx of Ca++ due to failure of Ca++ pump

Detachment of ribosomes from rough ER

  • reduction in protein synthesis

No O2 or glucose results in misfolded proteins

  • misfolded proteins clump in ER and trigger misfolding response
56
Q

What are the 3 major consequences of mitochondrial damage?

A
  1. Formation of high conductance channel in mitochondrial membrane
    - called mitochondrial permeability transition pore
    - leads to loss of membrane potential
    - loss of ox phos and ATP
    - targeted by cyclophilin drugs to prevent graft rejection
  2. Abnormal ox phos leads to formation of ROS’s
  3. Leakage of cytochome c from membranes
    - activates caspases and starts apoptosis
57
Q

What are 3 major consequences of Ca++ influx and loss of Ca++ homeostasis?

A
  1. Accumulation of Ca++ in mitochondria opens mitochondrial permeability transition pore and failure of ATP generation
  2. Increased cytosolic Ca++ activates phospholipases, proteases, endonucleases, and ATPases
    - all hasten cell breakdown
  3. Increased intracellular Ca++ activates caspases and increases mitochondrial permeability
58
Q

What is oxidative stress?

A

Accumulation of oxygen-derived free radicals

59
Q

Cell injury, as a result of ROS damage, results from what pathological conditions?

A

Chemical and radiation injury

ischemia-reperfusion injury - restoration of blood flow in ischemic tissues

cellular aging

microbial killing by phagocytes

60
Q

How does oxidative stress occur?

A

ROS are produced as a byproduct of normal respiration and energy production

  • systems in place to scavenge them

Loss of ROS scavengers or overproduction of ROS leads to oxidative stress

61
Q

What diseases is oxidative stress implicated in?

A

Cancer

aging

degenerative diseases like Alzheimer’s

62
Q

How are free radicals generated?

A

Normal metabolic processes

  • RedOx rxns

Absorption of radiant energy (ionizing radiation)

Inflammation

  • made by leukocytes during inflammatory processes

Enzymatic metabolism of exogenous chemicals or drugs

Transition metals

NO, or ONOO-

63
Q

How are free radicals removed?

A

Antioxidants

Binding of transition metals - Fe, Cu - to carrier proteins

Enzymes that scavenge free radicals

Lipid peroxidation in membranes

Oxidative modification of proteins

(oxidation of side chains, formation of disulfide bonds, oxidation of protein)

Lesions in DNA

64
Q

What are the enzymes that scavenge free radicals/ROS?

A

SOD

Catalase

Glutathione peroxidase

(intracellular balance of reduced versus oxidized glutathione is an indicator of oxidative stress)

65
Q

Are free radicals always pathologic? Do they cause cell injury and death by necrosis?

A

Not always pathologic, do not directly cause necrosis

  • frequently a prelude to necrosis, not causative
  • free radicals can trigger apoptosis

Signalling via superoxide triggers production of degradative enzymes

66
Q

What are some mechanisms of membrane damage?

A

ROS - via lipid peroxidation

Decreased phospholipid synthesis

Increased phospholipid breakdown - due to Ca++ dependent phospholipases

Cytoskeletal abnormalities - loss of microfilaments that anchor membrane, making membrane susceptible to shearing and stretching

67
Q

What are some consequences of membrane damage?

A

Mitochondrial membrane damage

Plasma membrane damage

Injury to lysosomal membranes

68
Q

What 2 things characterize irreversible cell injury?

A

Inability to revere mitochondrial disfunction

Profound disturbances in membrane function

69
Q

What is the most common type of cell injury in clinical medicine? What does it result from?

A

Ischemia

Results from hypoxia induced by reduced blood flow

  • most commonly due to mechanical arterial obstruction
70
Q

What happens with a reperfusion injury?

A

Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured

  • but -

can also exacerbate the injury and cause cell death

71
Q

How does reperfusion injury occur?

A

Oxidative stress

  • reduced antioxidant systems, and increased ROS reduction by damaged mitochondria, or increased oxidase production by endothelials, leukocytes, or parenchymal cells

Intracellular Ca++ overload

Inflammation

Activation of complement system

-IgM Ab tend to deposit in ischemic tissues, and complement cascade occurs when perfusion resumes

72
Q

What type of cell injury is a major limitation to drug therapy?

A

Chemical/toxic injury

  • many drugs are metabolized in the liver, and the drugs themselves or their metabolites can wreak havoc
73
Q

How is direct toxicity induced?

A

Injury via chemicals combining to critical molecular components

Injury is usually to cells that use, absorb, excrete, or concentrate the chemicals

74
Q

What are some examples of chemicals that induce direct toxicity?

A

Mercuric chloride

  • binds sulfhydryl groups of cell membrane proteins
  • increased membrane permeability and inhibition of ion transport

Cyanide

  • poisons mitochondrial cytochrome oxidases
  • stops ox phos

Antineoplastic chemotherapeutics, antibiotics

  • directly cytotoxic
75
Q

How is indirect toxicity induced?

A

Via conversion to toxic metabolites

Chemicals have to converted to toxic metabolites before having their effect on targets

  • conversion frequently mediated by cytochrome p450, in liver and other organs
  • damage frequently caused by conversion to a free radical
76
Q

What are some examples of chemicals that are indirectly toxic?

A

CCl4

  • converted by cytocrhome p450 to highly reactive CCl3-
  • causes lipid peroxidation and damages many cellular structures

Acetaminophen

  • creates many toxic metabolite when broken down by liver
77
Q
A

Pathological Basis of Disease I (11 decks)

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