5_Cell Injury Flashcards
1
Q
what determines altered cellular homeostasis?
A
- type of AFFECTED CELL
- type of ALTERATION
- degree of ALTERATION
- REVERSIBILITY/IRREVERSIBILITY of injury
2
Q
list the mechanisms by which WATER causes
cellular injuries
A
Hydrolytic DNA damages by:
- Depurination
- Depyrimidination
-
Deamination of: cytosine –> uracil;
- adenine –> hypoxanthine
- 5-methyl-cytosine to thymine
- can yield transition mutations (esp at CpG hot spots)
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
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
5
Q
how are DNA, proteins, and membranes modified by oxygen (Free radical damage)?
A
Modifications of DNA by Hydroxy radicals –>
-
Hydroxylate bases (base damages):
- e.g. 8-hydroxyguanine, thymine glycol, 5-hydroxymethyluracil, urea, and very many others
- Single strand breaks
- Double strand breaks
Proteins: production of cross-linking
Membranes: peroxidation of lipids –> rearrangement of molecular structures –> Ca2+ entry into cell –> cascade of rxns
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)
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)
- NAD is source of ADP-ribose (nicotinamide adenine dinucleotide)
- PARP binds to DNA strand breaks during repair
- Abundant DNA damace can be lethal bc NAD can be depleted or consumed in ADP ribosylation
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
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
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
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)
12
Q
what are 3 major mechanisms of defense against free radicals and how do they work?
A
- SUPEROXIDE DISMUTASE: eliminate superoxide ion avail. for Haber-Weiss rxn
- CATALASE/ PEROXIDASE: eliminate hydrogen peroxide availability for Haber-Weiss rxn
-
ANTIOXIDANTS
- act in liquid, aqueous, and plasma
13
Q
what is the MECHANISM (steps) of free radical damages?
A
- INITIATION: abstraction of hydrogens b/w double bonds of polyunsaturated fatty acids –> rearranges molecular structure
- PROPAGATION OF RXN: spread of rxn to other polyunsaturated fatty acids; breakup of chains w/ generation of malonaldehyde
- TERMINATION: can end when all fatty acids are polymerized, termination by scavenger molecules provides cellular protection
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
15
Q
describe the direct and indirect ways that chemical agents can cause cellular injury
A
-
DIRECT-ACTING:
- mercury: binds sulfhydryl groups (Minamata disease)
- lead: protein cross-linking; substituion for Ca2+ in bone
- various diverse metal and chemicals
- INDIRECT: chemical agent may be INACTIVE until metabolized to a reactive form –>then causes trouble
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
what are the key **_mechanisms_** of **cell injury/necrosis?**
* **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
what are the key **_markers_** of **cell injury/necrosis**?
* 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
**apoptosis:**
## Footnote
*define*
* programmed suicide; induction of programmed cell suicide (i.e. apoptosis) by release of cytochrome C *(from the mitochondria)*
28
how does **hypoxia and ischemia** injure the cells?
* **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
**morphology changes**: cellular injury
| (accumulations and cholesterols)
* **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
**lipofuscin:** (cellular injury morphology)
## Footnote
*define;*
* **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
how does **_iron_ cause cellular injury?**
* **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
**hemochromatosis**:
## Footnote
*define, primary, secondary*
* **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
**bilirubin:**
*how does this cause cellular injury?*
* **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
**carbon:**
how does this cause cellular injury?
* 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
**calcium deposits:**
*how does this cause cellular injury?*
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
coronary artery calcifications
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
**homeostasis:**
*define*
* homeostasis can be reversible or irreversible
