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Y1 - Pathology > 5_Cell Injury > Flashcards

5_Cell Injury Flashcards

1
Q

what determines altered cellular homeostasis?

A
  1. type of AFFECTED CELL
  2. type of ALTERATION
  3. degree of ALTERATION
  4. REVERSIBILITY/IRREVERSIBILITY of injury
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2
Q

list the mechanisms by which WATER causes

cellular injuries

A

Hydrolytic DNA damages by:

  1. Depurination
  2. Depyrimidination
  3. Deamination of: cytosine –> uracil;
    • adenine –> hypoxanthine
    • 5-methyl-cytosine to thymine
    • can yield transition mutations (esp at CpG hot spots)
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3
Q

list the mechanisms by which OXYGEN causes

cellular injuries

A
  • free radical OH- is the mechanism
    • Isotope K40
  • cellular reducation of molecular oxygen – >water
  • external radiation can induce heterolytic cleavage of water –> producing OH- radical
    • e.g. x-rays, gamma-rays, cosmic rays, radon, nuclear medicine
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4
Q

how is OXYGEN reduced to WATER?

A

O2 –> superoxide anion –> hydrogen peroxide –> form hydroxyl radical, hydroxyl ion, and oxygen

hydroxyl radical is very reactive; and is most important free radical in biology; rxn w/ lipids, carbohydrates, proteins, and DNA

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5
Q

how are DNA, proteins, and membranes modified by oxygen (Free radical damage)?

A

Modifications of DNA by Hydroxy radicals –>

  1. Hydroxylate bases (base damages):
    • e.g. 8-hydroxyguanine, thymine glycol, 5-hydroxymethyluracil, urea, and very many others
  2. Single strand breaks
  3. Double strand breaks

Proteins: production of cross-linking

Membranes: peroxidation of lipids –> rearrangement of molecular structures –> Ca2+ entry into cell –> cascade of rxns

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6
Q

methylation:

donator, fxn/ effects

A
  • mechanism of cellular injury
  • donator: S-adenosyl-methionine
  • fxn:
    • methylation fo cytosine –> 5-methylcytosine –> effects on gene expression
    • promutagenic methylation of DNA bases (O-6-methylguanine etc)
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7
Q

if DNA damage is not repaired, what could happen?

A
  • mutations: can be lethal or procarcinogenic (transformation)
  • involvement of poly(ADP-ribose) polymerase (PARP)
    1. NAD is source of ADP-ribose (nicotinamide adenine dinucleotide)
    2. PARP binds to DNA strand breaks during repair
    3. Abundant DNA damace can be lethal bc NAD can be depleted or consumed in ADP ribosylation
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8
Q

list some external causes of free radical oxygen species?

A
  • excitotoxicity: glutamate in neurons –> induce oxygen species
  • ischemia/reperfusion injury
    • inflammatory cells –> neutrophils and macrophages can produce free radicals
    • aberrant clones creating light chains of immunoglobulins in myocardial cells
  • metabolism of drugs, toxins, chemicals –> free radicals
  • RAGE (receptor against glycosylated end products) stimulation in neurons and endothelial cells
  • RAGE stimulation in cultured neuroblasts by beta-amyloid
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9
Q

what drug induces P-450 system?

how does this affect toxicity of carbon tetrachloride?

how does partial hepatectomy affect toxicity?

A
  • BARBITUATES induce the P-450 system; so prior admin of phenobarbital INCREASES toxicity of carbon tetrachloride
  • partial hepatectomy results –> cell division and regeneration –> reducing toxicity of carbon tetrachloride
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10
Q

how does small dose of Carbon tetrachloride affect P-450?

A
  • Prior administration of a small dose of carbon tetrachloride is toxic –>
  • inhibits P-450 induction
  • SO prior small dose is protective
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11
Q

how does cytochrome P-450 play a role in cell injury and necrosis?

A
  • cytochrome P-450 activates many harmful chemicals into toxic forms (often free radicals)
  • (e.g. CCl4)
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12
Q

what are 3 major mechanisms of defense against free radicals and how do they work?

A
  1. SUPEROXIDE DISMUTASE: eliminate superoxide ion avail. for Haber-Weiss rxn
  2. CATALASE/ PEROXIDASE: eliminate hydrogen peroxide availability for Haber-Weiss rxn
  3. ANTIOXIDANTS
    • act in liquid, aqueous, and plasma
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13
Q

what is the MECHANISM (steps) of free radical damages?

A
  1. INITIATION: abstraction of hydrogens b/w double bonds of polyunsaturated fatty acids –> rearranges molecular structure
  2. PROPAGATION OF RXN: spread of rxn to other polyunsaturated fatty acids; breakup of chains w/ generation of malonaldehyde
  3. TERMINATION: can end when all fatty acids are polymerized, termination by scavenger molecules provides cellular protection
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14
Q

what are some external causes of cellular injury?

A
  • physical agents - trauma, radiation, extreme temps, electric shock
  • chemicals - drugs, metals, hormones, poisons
  • infectious agents - viruses, bacteria, fungi, protozoa, prions
  • inflammation - neutrophils/macrophages elaborate free radicals
  • auto-immune diseases
  • aging
  • nutritional imbalances - calories, proteins, vitamins, minerals
  • genetic diseases - mutations, chromosomal abnormalities
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15
Q

describe the direct and indirect ways that chemical agents can cause cellular injury

A
  • DIRECT-ACTING:
    1. mercury: binds sulfhydryl groups (Minamata disease)
    2. lead: protein cross-linking; substituion for Ca2+ in bone
    3. various diverse metal and chemicals
  • INDIRECT: chemical agent may be INACTIVE until metabolized to a reactive form –>then causes trouble
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16
Q

how does metabolism play a role in cell injury?

what’s an example of this?

A
  • **There is species specificity and gender preference in certain carcinogens (due to differences in metabolism)
  • ex: N-2-acetylaminofluorene: proposed as pesiticide; no issues in guinea pigs, but liver CA in rats (M>F); and cancer in humans
17
Q

describe the 2 phases of metabolism of n-2-acetylaminofluorine

A
  • 1st phase: oxidation to N-hydroxy-N-2-acetylaminofluorene
    • *present in rats & humans, but not in guinea pigs
  • 2nd phase: sulfation at hydroxy group –> carcinogenesis
18
Q

infectious agents:

define, mechanism, examples

A
  • def: causes cell death
  • mech (3 possible):
    • direct cell death by contact w/ cell
    • releases toxins –> can kill cell at a distance, or release enzymes that digest tissue components or damage BVs –> causing ischemic damage
    • induce host response to attack parasite–> cause tissue damage
  • ex:
    • prions
19
Q

prions:

define, mech, ex

A
  • def: infectious agent
  • mech: causes change in protein structure (alpha helix –> insoluble Beta-pleat) –> lethal intracellular accumulation
  • ex:
    • kuru (Acquired) - new guinea; Fore people due to cannibalistic religious practice
    • jacob-cruezfeld disease (congenital)
20
Q

how do auto-immune diseases cause cell injury?

A
  • loss of immune tolerance –> attack on normal cells by host immune system
  • may be mediated by T-lymphocytes or B-lymphocytes
21
Q

what are the mechanisms by which aging causes cell injury?

A
  • LOSS OF TELOMERES
  • accumulation of DNA damages
  • errors in replication due to infidelity of DNA polymerases
22
Q

Hypoxia vs. Ischemia

A
  • Hypoxia: reduced oxygenation
    • reduced oxygenation w/ normal blood flow <– caused by pulm disease, anemia, CO poisoning
  • Ischemia: hypoxia DUE TO REDUCED blood flow;
    • typically from blockage of BV;
    • results in myocardial infarct & stroke
23
Q

how does metabolic rate, viral receptors, and metabolism of inert compound affect cellular response?

A
  • metabolic rate: cells w/ high metabolic rates are MOST susceptible to hypoxia (e.g. neurons, cardiac myocytes)
  • viral receptors: presence of specific vectors (e.g. T-lymphocytes for HIV, hepatocytes for hepatitis)
  • metabolism: of an inert compound to toxic agent affects cellular response
24
Q

what other factors (of the host) might affect cellular response

A
  • nutritional state of the host
  • metabolic state of the host: species and sex specificity
  • idiosyncratic factors: individual susceptibility
25
Q

what are the key mechanisms of cell injury/necrosis?

A
  • ATP DEPLETION:
    • causes dec. phospholipid synthesis
    • accumulation of sodium adn water –> cell swelling
  • INCREASED CYTOSOLIC FREE CALCIUM:
    • damage to cell –> releases intracellular stores of calcium –> inc. calcium concentration
    • results in degradation of membranes by calcium-activated phospholipase A2 & proteases
  • LIPID PEROXIDATION BY FREE RADICALS:
  • DETACHMENT OF MEMBRANES FROM PROTEASE-DAMAGED CYTOSKELETON:
26
Q

what are the key markers of cell injury/necrosis?

A
  • release of proteolytic enzymes from lysosomes
  • leakage of cellular constituents into systemic circulation
    1. diagnosis of myocardial infarction by troponins or creatine kinase-MB isoform
    2. diagnosis of acute pancreatitis by elevated serum amylase and lipase
27
Q

apoptosis:

define

A
  • programmed suicide; induction of programmed cell suicide (i.e. apoptosis) by release of cytochrome C (from the mitochondria)
28
Q

how does hypoxia and ischemia injure the cells?

A
  • decreased oxygen causes reversible, non-lethal ATP depletion
    • can cause cell swelling
    • accumulation of intracytoplasmic triglycerides
    • massively enlarged liver (steatosis)
    • inc. in free fatty acid
    • dec. free fatty acid oxidation
    • dec. synthesis of lipoprotein
  • lethal injury – involves membrane damages
  • increased cytosolic Ca2+ mediates many morphologic changes
  • reperfusion of ischemic tissue may yield further injury from free radicals produced by neutrophils
29
Q

morphology changes: cellular injury

(accumulations and cholesterols)

A
  • intracellular accumulations:
    • results from inability to metabolize endogenous (normal or abnormal) substances or exogenous materials
  • cholesterol and cholesterol esters:
    • accumulate in macrophages and smooth muscle cells of atherosclerotic plaques
30
Q

lipofuscin: (cellular injury morphology)

define;

A
  • lipofuscin: polymers of phospholipids and lipids complexed w/ proteins derived from peroxidation of membrane lipids
    • found in hepatocytes, and cardiac myocytes in the aged w/o apparent impairment of cellular fxn
  • intracellular accumulations: results from inability to metabolize endogenous (normal or abnormal) substances or exogenous materials
31
Q

how does iron cause cellular injury?

A
  • hemosiderin: aggregates of ferritin molecules
    • accumulate in macrophages following red cell breakdown
  • hemosiderosis: systemic iron overload;
    • accumulation in liver, spleen, lymph nodes, and bone marrow macrophages;
    • accumulation in parenchymal cells of liver, pancreas, heart, adn other organs possible
  • hemochromatosis: hemosiderin accumulation in parenchymal cells
32
Q

hemochromatosis:

define, primary, secondary

A
  • define: hemosiderin accumulation in parenchymal cells resulting in organ dysfunction
    • iron causing cellular injury by changing morphology
  • primary: genetic disorder of iron metabolism
  • secondary: secondary acquired iron overload may be dietary or due to red cell breakdown
33
Q

bilirubin:

how does this cause cellular injury?

A
  • bilirubin accumulation in hepatocytes, kupffer cells, and hepatic sinusoids
    • present in tissues of severely jaundiced patients
    • obstructive jaundice due to biliary tract disease or carcinoma in the pancreas
    • heptaocellular jaundice
34
Q

carbon:

how does this cause cellular injury?

A
  • carbon is a ubiquitous air pollutant: deposited in macrophages (dust cells) and lymph nodes (anthracosis)
  • can be assoc. w/ severe and disabling pulmonary fibrosis in coal miners (coal worker’s pneumoconiasis); rarely seen now
    • histologically: dark spots on
35
Q

calcium deposits:

how does this cause cellular injury?

A

Either by DYSTROPHIC CALCIFICATION or by METASTATIC CALCIFICATION

  • DYSTROPHIC calcification: occurs in damaged or dead tissues in individuals w/ normal calcium metabolism; seen in necrotic tissues, fibrotic tissues, and heart valves and atherosclerotic plaques
  • METASTATIC calcification: result of hypercalcemia; results from hyperparathyroidism and bone malignancies
36
Q

coronary artery calcifications

A

buildup of calcium in the arteries, which can cause blood vessels to narrow and lead to the development of heart disease –>

forming an atherosclerotic plaque

37
Q

homeostasis:

define

A
  • homeostasis can be reversible or irreversible

Y1 - Pathology (14 decks)

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