Term
|
Definition
| inadequate oxygen at the level of the tissue |
|
|
Term
| what are the components that determine blood oxygen levels |
|
Definition
| saturation of heme, ammount of heme, oxygen dissolved in plasma / partial pressure of oxygen |
|
|
Term
|
Definition
| decreased blood flow to and from a tissue |
|
|
Term
|
Definition
| decreased oxygen in plasma / partial pressure of oxygen |
|
|
Term
| what are sources of cell stress (10) |
|
Definition
hypoxia
ischemia
hypoxemia
chemical agents
physical agents
infectious agents
immunologic agents
genetic defects
nutritional imbalances
aging |
|
|
Term
|
Definition
metabolism redox reactions
incomplete reduction of oxygen in ETC
absorption of radiant injury
enzyme metabolism of exogenous chemicals (CCl4)
inflammation via leukocytes
release from NO
free transition metals |
|
|
Term
| what can ROS do to cells / what can happen to ROS once created(7) |
|
Definition
degraded or removed by cell defence
autocatlytic reactions to make more ROS
attack lipids --> dysrupt membrane
degrade nucleic acids
protein misfolding and cross linking |
|
|
Term
| what can happen if nucleic acids are degraded (4) |
|
Definition
mutated DNA
silencing genes
signaling of apoptosis
protein mis/inactivity |
|
|
Term
| what are ways cell stressors can degrade nucleic acids (4) |
|
Definition
oxidative stress
toxins
ionizing radiation
increased Ca turning on nucleases |
|
|
Term
| what are the consequences of protein misfolding or cross linking (3) |
|
Definition
protein degradation
protein mis/inactivity
impaired protein degredation / build up
proteins tagged with ubiquitin and targeted for degration, if too many build up like this it gets clogged and proteins cannot be removed |
|
|
Term
| what sources of cell injury can cause protein misfolding / cross linking (2) |
|
Definition
ROS
decrease in active transport (due to decreased ATP) |
|
|
Term
| what sources of cell injury can cause plasma membrane damage (3) |
|
Definition
microbe or other toxins
ischemia
lytic complements |
|
|
Term
| what can plasma membrane damage cause to happen in a cell |
|
Definition
decrease cell contents and ions
decrease metabolites and thus ATP
damage the lysosome (degrading enzymes leak into cytoplasm)
increase intracellular Ca (turn on enzymes that we dont want on) |
|
|
Term
| what can cause mitochondrial damage (2) |
|
Definition
|
|
Term
| what are the results of mitochondrial damage in the cell (2) |
|
Definition
decreased ATP synthesis
leaking of cytochrome C -> apoptosis |
|
|
Term
| what are the causes of decreased ATP synthesis due to damage (4) |
|
Definition
mitochondrial damage (Ca increase, ROS)
decreased oxygen
decrease in metabolites (due to membrane damage) |
|
|
Term
| what are the results of decreased ATP synthesis in the cell (3) |
|
Definition
misfolded proteins
decreased metabolic pathways needing energy
decrease in active transport |
|
|
Term
| what are the results of proteins not being folded due to no ATP (2) |
|
Definition
go into cytosol and be useless
accumulate in ER and make it swell signaling apoptosis |
|
|
Term
| when active transport is decreased in a cell, due to no ATP, what are the results (5) |
|
Definition
increase in intracellular Na -> swelling
protein misfolding and cross linking
increase in Ca -> bad enzymes turn on
ribosome detachement -> no proteins made
no ETC -> anaerobic glycolysis -> lactic acid -> decreased pH -> decreased enzyme function |
|
|
Term
| what damagers can cause an increase in cellular Ca (3) |
|
Definition
plasma membrane damage
cyanide kicks it out of cellular reserves
decreased active transport makes it stuck in cell (due to no ATP) |
|
|
Term
| what does cyanide do to the cell (2) |
|
Definition
cause Ca to leak from reserves -> not wanted enzymes turn on
causes cytochrome C release from mitochondria -> apoptosis |
|
|
Term
| CO poisoning: what does it do to the tissue, what is the MOA |
|
Definition
hypoxia
CO fills up heme decreasing oxygen saturation |
|
|
Term
| anemia: what does it do to the tissue, what is the MOA |
|
Definition
hypoxia
heme is dysfunctional so heme levels are decreased and oxygen cannot get to tissue |
|
|
Term
| what are issues that would cause hypoxemia |
|
Definition
decreased alveoli function
change in avilable oxygen: altitude, drowning |
|
|
Term
| what are the causes of hypoxia |
|
Definition
decreased saturation of heme
decreased heme
ischemia
hypoxemia |
|
|
Term
| define reperfusion injury |
|
Definition
| after ischemia, when blood is restored, there is more cell death and neutrophils come despite lack of infection |
|
|
Term
| why is hydrogen peroxida dangerous |
|
Definition
forms free radicals with Fe catalyzed reactions (fenton reactions)
diffuses easily |
|
|
Term
| how is hydrogen peroxide naturally broken down |
|
Definition
| catalase turns it into water and oxygen |
|
|
Term
| how does superoxide anion form, why is it dangerous |
|
Definition
forms from leaks in ETC
helps make other ROS, does not diffuse |
|
|
Term
| how is superoxide anion naturally broken down |
|
Definition
| superoxide dismutase breaks it into hydrogen peroxide then catalase turns it into water and oxygen |
|
|
Term
| how are hydroxyl radicals made, why are they scary |
|
Definition
comes from peroxide iron reaction (fenton rxn)
attacks macromolecules: membrane and protein damage |
|
|
Term
| how are hydroxyl radicals naturally broken down |
|
Definition
| glutathione peroxidase breaks it into hydrogen peroxide, catalyse breaks peroxide into water and oxygen |
|
|
Term
| what does cellular response to stress depend on (4) |
|
Definition
the injury: type, duration, severty
cell type: energy stores, enzymes in cell
cell status: is this a good time for the cell to take on stress
cell adaptability: different cells can metabolize different toxins |
|
|
Term
| hypertrophy: definition, what types of cells is it in, what situations |
|
Definition
increase in cell size
occurs in cells unable to divide
physiologic and pathologic |
|
|
Term
| hyperplasia: definition, what cells is it in, what situations |
|
Definition
increase in cell number
occurs in cells with mitotic potential
physiologic, pathologic, and compensatory |
|
|
Term
| give an example of the common occurance of hypertrophy and hyperplasia occuring together |
|
Definition
| gravid cells in pregnacy become both and take time to return to normal |
|
|
Term
| give an example of physiologic hyperplasia |
|
Definition
| endometrium, breast tissue in pregnacy |
|
|
Term
| why is pathologic hyperplasia usually milignant |
|
Definition
| every time DNA divides there is a chance for mutation. more cells means more divisions |
|
|
Term
| give an example of pathologic benign hyperplasia, is this common |
|
Definition
it is more common for hyperplasia to be milignant
benign prostatic hyperplasia |
|
|
Term
| explain compensatory hyperplasia |
|
Definition
| removal of tissue triggers increase in cells in remaining tissue, not recessairly to replace the removed part but in general in the tissue |
|
|
Term
|
Definition
| reduction in cell size and decrease in tissue size |
|
|
Term
| what are the results of atrophy (5) |
|
Definition
diminished function/decreased workload
loss of innervation
diminshed blood supply
inadequate nutrition
decreased hormonal stimulation |
|
|
Term
| give some ways atrophy is caused (3) |
|
Definition
decreased protein synthesis
increased proteasomal degradation
autophagy |
|
|
Term
|
Definition
| broken organells are put in vacolues, digested, and exocytosed |
|
|
Term
|
Definition
| repalcing one cell type with another that can handle the stress via changes in gene expression. reversible when stimuli removed |
|
|
Term
| give an example of metaplasia, how does it affect the tissue |
|
Definition
smoker: bronchial tissue changed from columnar to squamous
increased protection to smoke, toxins, and abrasions
decreased protection to illness due to decreased mucous and cillia |
|
|
Term
|
Definition
| undifferentiated cells are reprogrammed to grow up into new tissue, old differentiated cells stay the same and are over time replaced |
|
|
Term
| what are the results of metaplasia (3) |
|
Definition
loss of origional function of tissue
loss of protective mechanisms
predisposition of milignancy (lots of cell division, lots of DNA division --> mutations) |
|
|
Term
| list a bunch of reversable cell injuries (9) |
|
Definition
clumping of chromatin
lipid vacolues in cytoplasm (mostly in cells of fat catabolism)
mitochondrial calcification
aggregrated cytoskeleton
protein accumulations
cellular swelling/bleb
ribosomal detachment
mitochondrial swelling
ER swelling |
|
|
Term
| why would proteins accumulate in a stressed cell |
|
Definition
| ATP stops pumps and anaerobic glycolysis kicks in causing acidity, enzymes stop working, ROS made |
|
|
Term
| why do cells swell when stressed |
|
Definition
|
|
Term
| what are some irreversible cell injuries |
|
Definition
necrosis
nuclear changes
protein digestion
activation of lysosomal enzymes |
|
|
Term
| fatty accumulations: where, asociated with |
|
Definition
liver, heart, skeletal muscle, kidney
alcohol abuse, obseity, toxins, protein malnutrition, diabetes mellidus |
|
|
Term
| how do fatty accumulations come about, 3 ways |
|
Definition
excess TG due to defecits in FA entry lead to export of lipoproteins then FA are oxidated by toxins
increased mobilization of FA during starvation
prolonged hypoxia in the heart > reduced oxidation of fatty acids |
|
|
Term
| explain the morphology of fatty accumulations in parenchymal cells, liver, and heart. what do they stain with |
|
Definition
parenchymal: clear vacuoles. stain waith sudan IV or oil red O
liver: large pale to yellow
heart: focal deposits |
|
|
Term
| cholesterol accumulations: found in, associated with |
|
Definition
in macrophages
atherosclerosis, hyperlipidemia |
|
|
Term
| cholesterol accumulations: MOA |
|
Definition
lipid overload
oxidixed low density lipoproteins targeted by macrophages |
|
|
Term
| cholesterol accumulations morphology (3) |
|
Definition
yellow atherosclerotic plaques
xanthomas: clusters of macrophages in skin and tendons
cholesterol crystals |
|
|
Term
| protein accumulations: location (3), associated conditions (5) |
|
Definition
kidney, liver, brain
nephrotic syndrome (proteins leak into urine)
alpha 1 - antitrupsin deficiency
variety of brain diseases like alzheimers, picks, huntingtons |
|
|
Term
| protein accumulations: MOA (3), and morphology |
|
Definition
excess production
increased delivery
reduced degradation (due to misfolding)
morphology: eosinophillic inclusions |
|
|
Term
| glycogen accumulations: locations (6), associated conditions (2) |
|
Definition
lysosomes, liver, muscle, kidneys, heart, pancreas
glycogen storage diseases, diabetes mellidus |
|
|
Term
| glycogen accumulations: MOA |
|
Definition
| defect in enzymes for converting glycogen to glucose |
|
|
Term
| glycogen accumulations: morphology (4) and staining |
|
Definition
intracytoplasmic accumulation of glycogen: stain with periodic acid schiff (PAS)
hepatomeagealy
renomeaglu
cardiomeagaly |
|
|
Term
| carbon accumulation: location, associated diseases |
|
Definition
|
|
Term
| carbon accumulation: MOA, morphology |
|
Definition
phagocytosed carbon
blacened lymph nodes in lung |
|
|
Term
| lipofuscin accumulation: location, associated diseases |
|
Definition
heart, liver, brain
marker of age or atrophy |
|
|
Term
| lipofuschin accumulation: MOA and morphology |
|
Definition
peroxidation of membranes
brownish yellow granules (like ear wax) |
|
|
Term
| hemosidern accumulation: location, associated conditions |
|
Definition
liver, spleen, marrow
vascular congestion, hemosiderosis |
|
|
Term
| hemosidern accumulation: MOA and morphology |
|
Definition
released by RBC breakdown
golden yellow to brown granules |
|
|
Term
| what is the cause of a reprofusion injury, 2 ways |
|
Definition
damaged mitochondria > ROS > antioxidants compormized
antibodies accumulate > complement activated > inflammation and ROS (from leukocytes) made |
|
|
Term
| explain carbon tetrachloride poisoning |
|
Definition
cytochrome P450 turns CCl4 into a free radical in the liver, the free radical causes autocataltic phosphlipid peroxidation which causes two things...
1. er degredation > hepatocytes cannot make apoprotein > TG cannot get out of the liver > fatty liver
2. membrane damege > mito injury > cell death |
|
|
Term
| explain acetaminophen hepatotoxicity MOA |
|
Definition
some is detox in the liver and some is converted by cytochrome P450 into toxic metabolite NAPQI
NAPQI is neutralized by gutathione but if there is too much it cannot keep up |
|
|
Term
| what are the negative results of acetaminophen hepatotoxicity (3) |
|
Definition
covalenly bind DNA and proteins
increase other oxidative damage because glutathione cannot help
liver necrosis in 3-5 days |
|
|
Term
| what are the causes of dystrophic calcifications (3) |
|
Definition
dead or dying dissue
hypercalcemia not needed, but worsens it
cancer/dysfunctional tissue |
|
|
Term
| what are the symptoms of dystrophic calcification (4) |
|
Definition
| atherosclerotic plaques, aortic stenosis, gritty deposits (fine white granules or clumps), basophillic deposits |
|
|
Term
| what is the MOA of dystrophic calcification intracellularly and extracellularly |
|
Definition
extracellular: ca phosphate forms in matrix vesicles
intracellular: initiation occurs in mitochondria due to calcium influx |
|
|
Term
| what are examples of dystrophic calcification |
|
Definition
| it is what we look for in a mammogram |
|
|
Term
| metastic calcification caused by |
|
Definition
|
|
Term
| what causes hypercalcemia (4) |
|
Definition
increased parathyroid hormone
bone destruction
vitamin D
renal failure |
|
|
Term
| what causes increased PTH (2) |
|
Definition
| paraneoplastic syndrome (PTH like proteins made in tumor), Parathyroid tumor |
|
|
Term
| what causes bone destruction (5) |
|
Definition
| paget diseae (elevated turn over), skeletal metasteses, immobilization, multiple myeloma, leukemia |
|
|
Term
| how does vitamin D cause hypercalcemia (2) |
|
Definition
| intoxication via vit D, sarcidosis |
|
|
Term
| what causes renal failure |
|
Definition
| phosphate retention causes hyperparatyroidism which causes failure |
|
|
Term
| what are the symptoms of a metatastic calcification (7) |
|
Definition
affects vessels, kidneys, lungs, and gastric mucosa
shows on x-ray
can cause respiratory deficits
nephrocalcinosis: deposits that can cause kidney damage |
|
|
Term
| what is metastic calcification morphology |
|
Definition
|
|
Term
| where does inflammation occur, why, what does it involve, what regulates it |
|
Definition
vascularized CT responds to noxious stimuli. involves plasma, circulating cells, vessels and CT
mediated by chemicals from plasma and cells |
|
|
Term
| what are causes of inflammation (6) |
|
Definition
toxins from microbes of enivornment
physical factors like heat or trauma
microbes
necrotic tissue
foreign bodies
immune response: hypersensitive, autoimmune, immune complex |
|
|
Term
| what are the function os fhte 1ummune response (4) |
|
Definition
protect healthy tissue by localising the isolating injured tissue
inactivate toxins made by humoral factors and enzymes
destories or limits growth of infectous agents
prepares area for wound healing |
|
|
Term
| what are the down sides to inflammation, give an example (4) |
|
Definition
organ damage: myocarditis
excessive scar formation: keloids, contractures
fistula formation: chrons disease
infiltration and inflammation of healthy tissue: glomerulonephritis, arthritis, allergic reactions |
|
|
Term
| what are the reaction of vessels to infammation (7) |
|
Definition
accumulation of fluid
leukocyte recruitment
rubor: erythema
calor: heat
tumor: swelling
dolor: pain
loss of function: function laesa |
|
|
Term
| what is the time length of chronic vs acute inflammation |
|
Definition
chronic is days to years
acute is minutes to days |
|
|
Term
| what are the 2 main characteristics of chronic and accute inflammation |
|
Definition
chronice: vascular perforationa and scaring, lymphocytes and macrophages
acute: fluid and plasm aprotein edudates
neutrophillic leukocyte accumulation |
|
|
Term
| what is the general MOA of acute inflammation |
|
Definition
Vasoactive mediators (histamine from mast cells, leukotrienes) cause endothelial contraction
Contraction (vasodilation) opens space between cells allowing substances through that are bigger than normal and increases blood flow
This immediate transient response lasts for 15-30 min
Neutrophils arrive and recruit macrophages via cytokines (or endothelium changes)
Macrophages sustain the inflammation and vessel contraction
New vessel formation persists until intracellular junctions form |
|
|
Term
|
Definition
| fluid filled tumor/swelling due to new vessels because they are leaky and allow the plasma out. Could spread sutures apart. |
|
|
Term
| what are normal changes for a vessel |
|
Definition
| hydrostatic pressure and colloid osmotic pressure are in check not allowing protein leakage |
|
|
Term
| transudate: what is it, what qualifies it, what are the results of it |
|
Definition
o Fluid with low protein concentration and specific gravity of <1.012
o Secondary to hydrostatic imbalance
o Fluid leaks from vessels into ECF due to: Decreased protein synthesis decreases colloid osmotic pressure. Increased hydrostatic pressure due to venous outflow obstruction |
|
|
Term
| edudate; what is it a sign on, what qualifies it, what is the reuslt of it |
|
Definition
o Big sign of inflammation
o Inflammatory extravascular fluid has a high protein concentration, cellular debris, and specific gravity >1.020
o Secondary to alteration of vascular permeability
o Fluid and proteins leak out due to: Vasodilation and stasis due to inflammation. Increased endothelial spaces due to inflammation |
|
|
Term
| edema: what is it, where does it come from, what activates it |
|
Definition
Big sign of inflammation
Inflammatory extravascular fluid has a high protein concentration, cellular debris, and specific gravity >1.020
Secondary to alteration of vascular permeability
Fluid and proteins leak out due to
Vasodilation and stasis due to inflammation
Increased endothelial spaces due to inflammation |
|
|
Term
|
Definition
o Vasodilation in arterioles then capillary beds
o Slowing of circulation secondary to increased permeability of microvasculature resulting in outpour of protein into ECF
o Stasis allowing leukocytes to stick to endothelium and migrate across vessel wall into interstitial tissue |
|
|
Term
|
Definition
| • Purulent inflammatory exudate rich in leukocytes, debris of dead cells and microbes |
|
|
Term
| what is rolling, adhesion, and transmigration dependent on |
|
Definition
|
|
Term
| why do neutrophils come first to an inflammatory site |
|
Definition
| rolling, adhesion, and transmigration are required on the arriving cell. neutrophils dont have to do this |
|
|
Term
| selectin: what is it, where is it, what locations, what types |
|
Definition
o Sugars on cells that bind sialylated forms of oligosaccharides
o Stored on weibel-palade bodies. Histamine stimulates movement to cell border to be used.
endoderm E-selectin, P selecting
platelets P selectin
leukocytes L sekectin |
|
|
Term
| what are endothelial adhesion molecules, what do they do |
|
Definition
o Act as ligans for integrins like CAMs (on surface of cells)
o Immunoglobin family
o Major protein mediating transmigration (PECAM-1)
o Help WBC bind other cells |
|
|
Term
| integrans: what ate they, where are they, how are they acivated, where do they go |
|
Definition
o Transmembrane glycoproteins
o Mostly on WBC with its ligand on the endothelium
o They are always on WBC surface and not sequestered but don’t have a high binding affinity unless activated by histamine or thrombin
o Bind ligands on endothelial cells, other leukocytes, and ECM |
|
|
Term
| what does rolling adhesion |
|
Definition
| neutrophils, monocytes, eosinophils, lymphocytes |
|
|
Term
| transmigration: aka, function, MOA |
|
Definition
•Adhesion molecules help WBC get between cells. proteases (ex: collagenases) secreted to digest the basement membrane and let the cell get through
diapedisis |
|
|
Term
| activation of rolling or transmigration by leukocytes |
|
Definition
• Leukocytes respond with oxidative burse to…
o Destroy invading microbes
o Degranulate to release digestive enzymes that help clear dead tissue and microbes
o Elaborate arachidonic acid metabolites to recruit other cells involved in inflammation repair |
|
|
Term
| what is the most common type of activation in transmigration, exmples too |
|
Definition
o G-protein signals the release of Ca from the cell stores signaling
Arachadonic acid
Degranulation
Opsin release serum proteins that bind targets for phagocytosis
• IgG can also serve as this tag |
|
|
Term
| what helps phagocyte recognize particles, what is it made of, give examples |
|
Definition
opsonin, serum protein
Ig Fc region, C3b fragment of complement, collectins bind microbe wall sugar |
|
|
Term
| how do phagocytes kills stuff |
|
Definition
A. vacuole with microbe (phagosome) fills with lysosomal granules
B. oxidative burse stimulated via NADPH oxidase
C. NADPH oxidase converts oxygen to superoxide
D. superoxide converts to hydrogen peroxide
E. hydrogen peroxide converts to a hydroxyl radical
F. asurophilic granules of neutrophils myeloperoxidase uses halides (Cl ) to make hypochlororous radical (bleach)
G. HOCl- does most microbe killing |
|
|
Term
| what are other ways of killing other than phagocytes |
|
Definition
o Neutrophil extracellular traps (NETs): chromatin and anti-microbial granule proteins
o Bactericidial permeability increasing protein: activates phospholipase
o Lysosome: decrades bacteria oligosaccharides
o Major basic protein: in eosinophils, kills invasive parasites
o Defensins: forms pores in microbial membranes |
|
|
Term
| resident cells: functions, what are they |
|
Definition
initiate acute inflammation
mast cells and macriphages |
|
|
Term
| mast cells, what to they react to, what do they do |
|
Definition
o React to physical trauma, complement products, microbes, neuropeptides
o Release histamine, leukotrienes, enzymes, cytokines (TNF, IL-1, chemokines) |
|
|
Term
| macrophages what do the recognize what do they do |
|
Definition
| o Recognize microbes and secrete cytokines causing inflammation |
|
|
Term
| how is the inflammatry response terminated |
|
Definition
| Due to short half-life of chemical mediators of inflammation and switch to production of anti-inflammatory mediators |
|
|
Term
| where do cell derived mediators come from |
|
Definition
o Locally made by cells at inflammation site
From platelets, neutrophils, monocytes, macrophages, mast cells
o Derived from circulating inactive precursors
Made in the liver
Ex: complement, kinins |
|
|
Term
| how are cell derived mediators produced |
|
Definition
o Sequestered in intracellular granules and stored until used
Ex: histamine in mas cell granules
o Made upon request
Ex: prostaglandins, cytokines |
|
|
Term
| how do cell derived mediators work |
|
Definition
o Can act on one or a few cell types with different actions in each cell
o Can have direct enzymatic or toxic activity without required binding to receptor first |
|
|
Term
| how are cell derived mediators regulated |
|
Definition
| o Quickly decay, are inactivated by enzymes, are eliminated, or are inhibited |
|
|
Term
| what are the vasoactive amines |
|
Definition
cell derived mediators
histamine and serotonin |
|
|
Term
| where is histamine made, what does it do |
|
Definition
o Made resident mast cells (and basophils and platelets which circulate)
vasodilation and permeability increase
Venular endothelial contraction and formation of interendothelial gaps |
|
|
Term
| what is histamine activated and inactivated by |
|
Definition
Physical injury, trauma, or heat
Immune reactions binding IgE to Fc receptor on mast cell
C3a and C5a anaphylatoxins
Leukocyte derived histamine releasing proteins
Neuropeptides (substance P)
Cytokines IL1 and IL8
Physical injury, trauma, or heat
Immune reactions binding IgE to Fc receptor on mast cell
C3a and C5a anaphylatoxins
Leukocyte derived histamine releasing proteins
Neuropeptides (substance P)
Cytokines IL1 and IL8
Inactivated by histaminase |
|
|
Term
| where is serotonin made what does it do |
|
Definition
o In platelet granules released during aggregation
Induces vasoconstriction during clotting (notes say vasodilation and increased permeability)
o Made in some neurons and enterochromaffin cells
Neurotransmitter that regulates intestinal motility |
|
|
Term
| ecosanoids: what are they, what do they do, where do they come from, how are they regulated |
|
Definition
o AA metabolite cell mediators
o Initiate and inhibit inflammation
o Increases synthesis at sites of inflammation
o Released from leukocytes, mast cells, endothelial cells, and platelets
o Decay spontaneously or are enzymatically destroyed |
|
|
Term
| explain the process of ecosanoid formation up until the splitting point |
|
Definition
• Phospholipases are activated by physical, chemical, or inflammatory mediator stimuli
o Inhibited by steroids
• Phospholipases release membrane phospholipid arachadonic acid (derived from linoleic acid)
• Arachadonic acid is converted to
o Cyclooxygenase and 5-lipooxygenase |
|
|
Term
| explain the path of cycloogygenase until its three terminal pathways and their functions |
|
Definition
Cyclooxygenase is converted to prostaglandin G2 then prostaglandin H2
Prostaglandin H2 is turned into different products
• Prostacyclin GI2 via prostacyclin synthase in endothelial cells
o Vasodilation, inhibits platelet aggregation
• Thromboxane A2 via thromboxane synthase in platelets
o vasoconstriction, platelet aggregation
• Prostacyclin GD2 + GE2 in mast cells (notes say macrophages, endothelium, and platelets)
o vasodilation, increase vascular permeability, pain, fever |
|
|
Term
| explain the pathway of lipooxygenase until its terminal products and their functions |
|
Definition
Is converted to 5-HPETE in leukocytes which is converted to
• 12-lipooxygenase which is converted to
o Lipotoxin A4 +B4 in platelets and neutrophils
inhibit neutrophil adhesion and chemotaxis
platelets need neutrophils to do final activation
• Leukotriene A4 which is converted to
o Leukotriene B4 in neutrophils
causes chemotaxis to recruit neutrophils
o Leukotriene C4-E4 in mast cells
bronchospasm, increased vascular permeability, vasoconstriction |
|
|
Term
| where is platelet activating factor made, how |
|
Definition
• generated from membrane phospholipids of neutrophils, monocytes, basophils, endothelial cells, and platelets
• phospholipase A2 releases PAF from the membrane |
|
|
Term
| what does platelet activating factor do |
|
Definition
o Platelet activation
o causes bronchioconstriction (more than histamine)
o vascular effects
low levels: vasodilation, increased permeability
high levels: vasoconstriction, bronchoconstriction
o stimulates synthesis of other mediators
o enhances leukocyte adhesion, chemotaxis, leukocyte degranulation, and respiratory burst |
|
|
Term
| what cytokines are major players in acute inflammation |
|
Definition
| TNF, IL-1, IL-6, IL-17, chemokines |
|
|
Term
| what cytokines are major players in chronic inflammation |
|
Definition
|
|
Term
| INF and IL1: what stimulates production, what makes them |
|
Definition
o Produced by activated macrophages, mast cells, endothelial cells
o Secreted via stimulation by microbial products, immune complexes
IL-1 is also released from the imflammasome (see above) |
|
|
Term
| enothelial effects of TNF and IL-1 |
|
Definition
• Leukocyte adherence
• Prostaglandin GI2 synthesis
• Coagulation activation, anticoagulant decrease (via TNF)
• IL-1, IL-8, IL-6, PDGF increase |
|
|
Term
| systemic effects of TNF and IL-1, include any helper mediators too |
|
Definition
• Fever, lethargy, decreased appetite (IL-1, IL-6, TNF)
• Increased acute phase protein in liver (IL-1, IL-6)
• Hemodynamic effects: shock
• decreased BP (TNF)
• Cachexia: metabolic wasting
• Neutrophilia
• Insulin release in skeletal muscle (TNF, IL-1) |
|
|
Term
| fibroblast affects of IL-1 |
|
Definition
• Proliferation
• Collagenase and collagen increase
• Protease increase
• PGE synthesis |
|
|
Term
| leukocyte effects of TNF and IL1 |
|
Definition
• Activation (TNF, IL-1)
• stimulate marrow precursors to produce more leukocytes to replace the ones consumed in inflammation (TNF, IL-1, IL-6)
• Stimulate expression of adhesion molecules on endothelial cells
• Increase IL-6 and IL-6 |
|
|
Term
| how do chemokines work, what types are there |
|
Definition
Bind to G protein receptor (CXCr4 or CCR5) on target cell
CXC and CC |
|
|
Term
| CXC: what does it act on, what makes it, what stimuli |
|
Definition
• Act mostly on neutrophils
• Produced by macrophages, endothelial cells, mast cells, and fibroblasts in response to IL-1 and TNF |
|
|
Term
| CC chemokine: 3 functions and their MOA |
|
Definition
• Monocyte chemoattractant
o Include monocyte chemoattractant protein-1 and macrophage inflammatory protein-1a
• Memory CD4 chemo attractant
o RANTES: Regulated on activation normal T cell expressed and secreted
• Eosinophil chemoattractant
o Via eotaxin |
|
|
Term
| functions of both types of chemokines |
|
Definition
Chemoattractants for leukocytes
Activate leukocytes
Control development of T vs B lymphocytes in nodes and spleen |
|
|
Term
| what enzymes makes ROS, where, what stimuli |
|
Definition
• made with NADPH oxidase (phagocyte oxidase) in lysosome
• released from neutrophils and macrophages via stimulifrom microbes, immune complexes, cytokines |
|
|
Term
| what are the functions of high and low levels of ROS |
|
Definition
o Low levels: increase chemokine, cytokine, adhesion molecule expression
o High levels: injury
Endothelial damage via thrombosis and increased permeability
Protease activation and antiprotease activation breaks down ECM
Direct cell injury |
|
|
Term
| what are the functions of NO |
|
Definition
o Regulates neurotransmitter release and blood flow in CNS
o Used in macrophages as (microbocidal) cytotoxic agent
o Relaxes smooth muscle in endothelial cells causing vasodilation
o Antagonize platelet adhesion, aggregation, and degranulation
o Reduce leukocyte recruitment |
|
|
Term
|
Definition
| o Made on demant from L-arginine + O2 + NADPH + nitric oxide synthase (NOS) |
|
|
Term
| function of complement C1-9 |
|
Definition
o Activated by proteolysis
o Cause MAC attack: lysis of microbe |
|
|
Term
| C3 is activated by three pathways, explain them |
|
Definition
Classic complement pathway: triggered when C1 encounters antigen-antibody complex
Alternate plathway: triggered when bacterial product encounters properdin and Factors B and D
Lectin pathway: triggered when plasma lectin binds to mannose on microbe which starts the classic pathway |
|
|
Term
| once activated, C3 goes to microbe surface then what |
|
Definition
C3 convertase which cleaves it into C3a and C3b
C5 convertase which cleaves it into C5a and C5b |
|
|
Term
| vascular effects of complements |
|
Definition
(C3a and C5a)
• Induce mast cells to release histamine increasing permeability with vasodilation
• Can cause symptoms like anaphylaxis
• C5a activates lipooxygenase pathway which makes more inflammatory mediators |
|
|
Term
| laukocyte effects of complements |
|
Definition
(C5a, C3a, C4a)
• Activate leukocytes
• Increase adhesion to endothelium
• Chemoattractant to neutrophils, monocytes, eosinophils, and basophils |
|
|
Term
| phagocyte effects of complements |
|
Definition
| • C3b acts as opsonin which makes phagocytosis easier for neutrophils and macrophages |
|
|
Term
| MAC effects of complements |
|
Definition
(C9)
• Needs C6-8 to activate it
• Kills bacteria by making pores and disrupting osmotic balance |
|
|
Term
| hageman factor: where is it made, what does it do |
|
Definition
o Made in liver and circulates inactive until it finds collagen, BM, or activated platelets
o Initiates kinin system and clotting system, fibrinolytic system, complement system |
|
|
Term
|
Definition
Bradykinin is formed from its precursor (HMW kininogen)
Bradykinin causes increased vascular permeability, arteriolar dilation, bronchial contraction
Kallikerin is intermediate is made and activates Hageman factor to create a loop
Bradykinin is degraded by kinases quickly |
|
|
Term
| explain the clotting system |
|
Definition
Thrombin
• cleaves fibrinogen which makes fibrin clots
• binds to platelets, endothelial cells and enhances leukocyte adhesion
• generates fibrinopeptides during fibrinogen cleavage that increase vascular permeability
• cleaves C5 to C5a
Factor Xa
• causes increased vascular permeability and leukocyte emigration |
|
|
Term
| explain the fibrinolytic system |
|
Definition
Plasminogen activator is released from endothelium, leukocytes and tissues
Activated by kallikerin
Cleaves fibrin and lyses clots
Cleaves C3 into C3a causing vasodilation and increase permeavility |
|
|
Term
| what are the antiinflammatory cell mediators. what do they do |
|
Definition
• Lipoxins: see arachidonic derived mediators
• IL-10: down regulate response of macrophages
• TGF-B: helps in fibrosis tissue repair after inflammation |
|
|
Term
| what cells or molecules are involved in acute respiratory distress syndrom |
|
Definition
|
|
Term
| what cells or molecules are involved in acute transplant rejection |
|
Definition
| lymphocytes, andibodies, complement |
|
|
Term
| what cells or molecules are involved in asthma |
|
Definition
|
|
Term
| what cells or molecules are involved in glomerulnopheritis |
|
Definition
| antibodies, complement, neutrophils, monocytes |
|
|
Term
| what cells or molecules are involved in septic shock |
|
Definition
|
|
Term
| what cells or molecules are involved in athlerosclerosis |
|
Definition
| macrophages and lymphocytes |
|
|
Term
| what cells or molecules are involved in primary fibrosis |
|
Definition
| macrophages and fibroblasts |
|
|
Term
| what cells or molecules are involved in chronic transplate rejection |
|
Definition
| lymphocytes, macrophages, cytokines |
|
|
Term
| what cells or molecules are involved in RA |
|
Definition
| lymphocytes, macrophages, antibodies |
|
|
Term
| chrnic inflammation: length, three characteristics |
|
Definition
• Infiltration with mononuclear cells
o macrophages, lymphocytes, plasma cells
• Tissue destruction
o Due to inflammatory products
• Repair
o new vessel proliferation (angiogenesis)
o fibrosis |
|
|
Term
| what does chronic inflammation happen |
|
Definition
persistant infection
immune mediated inflammatory diseases
prolonged exposure to toxic agents |
|
|
Term
| give examples of persistant infections that cause chronic inflammation |
|
Definition
o Mycobacterium tuberculosis, treponema pallidum (syphilis), some viruses and fungi
o T lymphocyte mediated delayed type hypersensitivity |
|
|
Term
| give examples of immune inflammatory disease that cause chronic inflammation |
|
Definition
o Autoimmune reactions
Rheumatoid arthritis, IBS, psoriasis
o Allergic diseases
Bronchial asthma
Mixed acute and chronic symptoms |
|
|
Term
| what is the dominant cell of chronic inflammation |
|
Definition
|
|
Term
| what is the mononuclear phagocyte / reticular endothelial system |
|
Definition
Macrophages usually hang out in CT of spleen, liver, and lymphnodes
There are also some around the tissues to clean up particulates and kill microbes |
|
|
Term
| explain macrophage production |
|
Definition
Come from precursors in marrow that release monocytes into blood
Arrive at site of injury in 24-48 hours and mature into macrophages |
|
|
Term
| how are macrophages classically activated, what do they do |
|
Definition
• Stimulated by endotoxin, T cell signals, INF-γ, particulates
• Production of products for microbe digestion
o lysosomal enzymes, NO, ROS
• Secrete eicosanoids, cytokines and complements to stimulate inflammation
• Display T antigens to T cells and respond to their signsls |
|
|
Term
| how are macrophages alternativly activated what do they do |
|
Definition
• Stimulated by InF-γ, IL-4, IL-3, T cells, mast cells, and eosinophils
• Secrete growth factors for angiogenesis
• Activate fibroblasts to stimulate collage synthesis
• Classic activation can turn into alternate later |
|
|
Term
| how do lymphocytes sustain chronic inflammation |
|
Definition
Macrophages display antigens stimulate T cell
T cell produces INF-γ to activate macrophage |
|
|
Term
| what are plasma cells, what do they do |
|
Definition
o Terminally differentiated T cells
o Produce antibodies against antigens in inflammatory site |
|
|
Term
| eosinophils: location, function |
|
Definition
o Usually around parasitic infections or IgE mediated allergic reactions
o Travel on adhesion molecules and towards eotaxn chemokines
o Granules have major basic protein
Charged cationic protein
Parasite toxin
Causes epithelial cell necrosis |
|
|
Term
| mast cells: location, function |
|
Definition
o Distributed in CT
o Participate in acute and chronic inflammatory response
o Produce inflammatory cytokines
o Has IgE antibody for environmental antigens
when IgE encouters mast cell it releases histamine and causes acute inflammation
too much of this can cause anaphylactic shock |
|
|
Term
| what are the morphological patterns of inflammation |
|
Definition
| serous, fibrinous, suppurative, ulceration, granulomatous |
|
|
Term
| serous inflammation: characterized by, develops intp, morphology |
|
Definition
• Serous cavity is filled with protein poor
• from either serum or mesothelial cell secretions
• increased vascular permeability
• skin blister |
|
|
Term
| fibrinous inflammation: characterized by, develops intp, morphology |
|
Definition
• fibrin can be seen in the ECF
• seen on meningies, pericardium, and pleura
• greater vascular permeability that allows fibrinogen to escape
• fibrinous pericarditis
• may lead to dangerous adhesions that restrict organ function |
|
|
Term
| suppurative inflammation: characterized by, develops intp, morphology |
|
Definition
• large amounts of purulent exudate (pus) containing neutrophils, necrotic cells, and edema fluid
• abscess = focal collection of pus
• pyogenic organisms (e.g., S. aureus)
• skin abscess
• scaring in the future |
|
|
Term
| ulcerative inflammation: characterized by, develops intp, morphology, example |
|
Definition
• epithelial surface becomes necrotic and eroded
• sloughing of necrosed and inflammatory tissue near the surface
• peptic ulcer
• stasis ulcers (diabetics) |
|
|
Term
| granulomatous inflammation: characterized by, develops intp, example |
|
Definition
• aggregates of activated macrophages that assume an epithelioid appearance (are flat like squamous cells)
• macrophages may fuse to form multinucleate giant cells
• persistent T-cell response to microbes and foreign bodies (attempting to “wall off” invader)
• persistent T-cell response to microbes and foreign bodies (attempting to “wall off” invader) |
|
|
Term
| what cytokines have a role in the acute phase reaction, what is their role |
|
Definition
TNF and IL-1 have similar functions
IL-6 stimulates hepatic synthesis of plasma proteins |
|
|
Term
| explain how a fever is produced |
|
Definition
o Bacterial products (like LPS layer) release IL-1 and TNF (endogenous pyrogens)
o IL-1 and TNF increase cyclooxygenases which convert AA into prostaglandins
o PGE2 stimulates neurotransmitters that increase the temp set point in the hypothalamus
o Fever helps fight off the organisms |
|
|
Term
| what are the acute phase proteins, what are the released by, from where |
|
Definition
IL-6 in hepatocytes
o C-Reactive protein
o Fibrinogen
o Serum amyloid A |
|
|
Term
| c reactive protein: function, interpertation |
|
Definition
Measure of inflammation
Marker for necrosis and disease activity
Elevation indicates increased risk for MI or stroke |
|
|
Term
| fibrinogen: function, interpertation |
|
Definition
Increased during inflammation
Binds to RBC and causes them to stack (rouleaux) and sediment
Basis of erythrocyte sedimentation rate lab test (higher in women) |
|
|
Term
| serum amyloid A: function, staining |
|
Definition
Replaces apolipoprotein to help target lipids to macrophages for energy source
Stained with congo red. Shows green in polarized light |
|
|
Term
| what are normal, infectous, and super nigh WBC counts |
|
Definition
Normal 4,000 – 11,000 cells/uL
Normal infection levels 15,000 – 20,000 cells/mL
Extraordinary levels 40,000 – 100,000 cells/mL |
|
|
Term
| what is a super high WBC count called, why |
|
Definition
| • Leukemoid reactions: levels of leukocytes seen in leukemia because the cancer is WBC reproducing at high rates |
|
|
Term
| what are the causes of leukocytosis/neutropenia |
|
Definition
Accelerated release of cells (due to cytokines and increased colony stimulating factors (CSFs)) from the marrow post-mitotic pool
Increased lymphocytes are associated with viral infections
Increased neutrophils are associated with bacterial infection and acute inflammation |
|
|
Term
| what does shift left mean |
|
Definition
| presence of immature cells |
|
|
Term
| what is the concern about immature leukocytes in the blood |
|
Definition
Asurophilic granules arise when these immature leukocytes mature in the bood
Dhole bodies: Blue cytoplasmic inclusions that are remnents of the ER |
|
|
Term
|
Definition
o Can come from drug therapy
Catecholamines, lithium, corticosteroids
Inhibit adhesion molecules and release of neutrophils from migrating pools |
|
|
Term
|
Definition
| o Associated with type I and II hypersensitivity (allergic reaction, asthma) and parasite infections |
|
|
Term
| leukopenia: definition, cause |
|
Definition
o Decrease in WBC
o Associated with some viral infections, typhoid fever, rickettsiae, some protozoa |
|
|
Term
| what are other symptoms of acute phase reaction |
|
Definition
o Increase HR and BP
o Decreased swelling
o Shivering, Rigors, chills
o Anorexia, malaise
o Sepsis |
|
|
Term
| define etiology, what are the two types, how are they interconnected (give example situation) |
|
Definition
cause of disease
intrinsic and acquired
both types work together to cause disease: environmental factors add to risk and development of an intrinsic disease |
|
|
Term
| define intrinsic etiology |
|
Definition
| genetic causes (mutations) lead to malfunction proteins which lead to increased disease susceptability |
|
|
Term
| what are causes of acquired etiology |
|
Definition
| infections, environmental (smoking), nutrition |
|
|
Term
|
Definition
|
|
Term
| define morphologic changes |
|
Definition
| alteration in cell, tissue, or organs the lead to a pathology |
|
|
Term
| define clinical significance in three ways |
|
Definition
functional consequences of a disease
how morphological changes lead to dysfunction
manifestations of signs (objective) and symptoms (subjective) |
|
|
Term
| what is clinical significance altered / dependent on |
|
Definition
| severity of chenges influences course of prognosis of the disease |
|
|
Term
| use huntingtons disease as an example of the pathology core |
|
Definition
etiology: intrinsic
pathology: LMNA mutation
morphologic changes: causes changes in nuclear envelope
clinical significance: aging more quickly |
|
|
Term
| use celiac disease as an example of the pathology core |
|
Definition
etiology: intrinsic and extrinsic
pathology: genetic susceptibility, rotavirus causes susceptibility
morphologic changes: alteration in structure of intestine villi
clinical significance: gluten intolerance, failure to thrive |
|
|
Term
|
Definition
| functional changes as a result of a disease of injury |
|
|
Term
|
Definition
| MOA of pathologic changes |
|
|
Term
|
Definition
| cannot be measured objectively (counted, measured, tested) |
|
|
Term
|
Definition
| condition with defined etiologic agent/cause |
|
|
Term
| give and example of a disease and explain why it is called that |
|
Definition
| Cushing disease: caused by pituitary tumor (defined etiology) which increases ACTH and thus cortisol |
|
|
Term
|
Definition
undefined, multiple, or unknown etiology for a condition
collection of signs and symptoms frequently found together |
|
|
Term
| give and example of a syndrome and explain why it is called that |
|
Definition
cushing syndrome: can be due to adrenal gland, cancer, or medications
multiple causes |
|
|
Term
| give some examples of reversible cell damage |
|
Definition
cell swelling (due to ATP and pump failure)
fatty change: lipid vacolules in cytoplasm, phospholipid rich amorphous densities) |
|
|
Term
| what is the major pathway of cell death, give the 3 main causes of it |
|
Definition
necrosis
decreased ATP, membrane damage, always pathogenic |
|
|
Term
| what are the 6 cell changes that tell you there is necrosis |
|
Definition
eosinophillia and other immune cells
glassy homogenous appearance
vacoulated cytoplasm
zebra bodies
changes in nucleus and its staining
leaking cell |
|
|
Term
| what is eosinophillia, what process is it associated with, what does it do to the cell, how can we get evidence of it |
|
Definition
found in necrosis
increased binding of eosin to denature proteins
decreases nucleic acids
less blue, more pink in staining |
|
|
Term
| during necrosis, what appearnce does the cytoplasm take on, why (2 changes) |
|
Definition
glassy homogeneous due to increased glycogen
vacoulated due to loss of organells |
|
|
Term
| what are zebra bodies, when do they occur, how do they hurt the cell, aka |
|
Definition
aka myelin finers
phospholipids derived from damaged cell membrane that appear in necrosis
can be phagocytosed by other cells and made into FA residues which turn into calcification of the dead cell |
|
|
Term
| what are the 4 changes to the nucleus in a necrosis cell |
|
Definition
pyknsis: nuclear shrinkage and basophillia
karyorrhexis: pyknotic nucleus with fragmentation
karyolysis: fading due to DNAases digesting DNA. nuclei shrivvles and shows less pink or dissapears
after 1-2 days nucleus dissapears
endonucleases cut DNA into millions of pieces of different sizes |
|
|
Term
| what are the 7 patterns of necrosis |
|
Definition
| coagulative, liquefacitive, gangremous, caseous, fat/calcification, fibrinoid |
|
|
Term
| coagulative necrosis: morphology (4) |
|
Definition
| firm texture, tissue architecture maintained for several days, eosinophilic cells, anucleate cells |
|
|
Term
| coagulative necrosis: seen in what diseases (2) |
|
Definition
infarcts (except brain)
gangrene of organs |
|
|
Term
| liquefactive necrosis: morphology (4) |
|
Definition
| viscous mass, puss if acute, inflammatory cells, digestion of cells |
|
|
Term
| liquefactive necrosis: diseases (4) |
|
Definition
bacterial and fungal infections
brain infarcts
stroke |
|
|
Term
| gangrenous necrosis: morphology (4) |
|
Definition
| firm texture, may be modified by liquefication if infection superimposed, type of coagulative necrosis involving many tissue layers, bacteria may be visible |
|
|
Term
| gangrenous necrosis: diseases (2) |
|
Definition
loss of blood supply in limbs
wet gangrene if superimposed with bacterial infection |
|
|
Term
| caseous necrosis: morphology (3) |
|
Definition
loss of tissue architecture
enclosed with inflammatory border (granuloma: flattened monocytes walling it off)
cheese like |
|
|
Term
| caseous necrosis: diseases |
|
Definition
|
|
Term
| fat necrosis: morphology (5) |
|
Definition
focal areas of fat distribution
fat saponification (chalky white areas of Ca)
necrotic fat cells
basophillic calcium deposits
inflammatory reaction |
|
|
Term
| fat necrosis: diseases (2) |
|
Definition
acute pancreatitis
necrosis in breast tissue from trauma busting open fat cells that liberate FA to bind to Ca |
|
|
Term
| fibrnoid necrosis: morphology |
|
Definition
| immune complexes and fibrin create bright pink deposits |
|
|
Term
| fibrnoid necrosis; diseases |
|
Definition
| immunologic reactions in blood vessels |
|
|
Term
|
Definition
DNA or protein damage
normal function in development
sometimes pathologic
growth factor deprivation
accumulatedmis-folded proteins
self-reactive lymphocytes
cytotoxic T lymphocytes irritation |
|
|
Term
| what are the effects of apoptosis (4) |
|
Definition
cell directs its own destruction
cel dosent leak it makes apoptotic bodies, enzymes are contained
endonucleases chop DNA in an organized fashion
very esoinophillic cytoplasm
NO inflammation |
|
|
Term
| what are the two ways to regulate apoptosis |
|
Definition
mitochondrial intrinsic pathway
death receptor extrinsic pathway |
|
|
Term
| explain the mitochondrial pathway of apoptosis |
|
Definition
cell injuyr > apoptotic proteins > BCL-2 family sensors activated > BCL-2 family effectors (Bax, Bak) bind poorly to mitochondrial membrane causing...
A. cytochrome C initiates capsases adaptor protein Apaf-1, executioner capsases turned on and break down cytoskeleton and activate endonucleases
B. pro-apoptotic proteins turn on executioner capsases and break down cytoskeleton and activate endonucleases |
|
|
Term
| explain teh death receptor pathway |
|
Definition
| FAS/TNF/CD8 ligand interaction triggers death domain receptors activating adaptor proteins which turn on procapsases which turn on executioner capsases which break down the cytoskeleton and activate endonucleases |
|
|
Term
| explain how a capsase works |
|
Definition
| cysteine protease cleaves aspartic acid |
|
|
Term
| what are the 4 components of agine |
|
Definition
| telomeres, calories, oxygen utilization, insulin |
|
|
Term
| what is a telomere, how is it involved in aging |
|
Definition
self tandem repeates of G rich 2-26 bp
when they shorten they cause genetic instability leading to senesence and death |
|
|
Term
| why aernt telomeres shortened all the time |
|
Definition
| because proteins protect them, help them avoid DSB repair mechanisms, and prevent NHEJ |
|
|
Term
| why aernt telomeres making proteins |
|
Definition
| because in cells they are protected by proteins to stop erosion which also stopps genetic machines |
|
|
Term
| what conditions have been associated with telomere shortening |
|
Definition
coronary artery disease
premature MI
infection
insulin dependent diabetes
smokers
stress |
|
|
Term
| werner's syndrome: cause, results |
|
Definition
RecQ helicase mutation breaks telomere secondary structure shortening it early
causes genetic instability and increased aging, suseptability to cancer usually leads to death |
|
|
Term
| dyskeratosis congenita: how is it aquired, explain how this makes the disease process different |
|
Definition
x-linked: mutation in dyskerin which binds telomerase RNA template
autosomal dominant inheritance: telomerase RNA template mutation |
|
|
Term
| dyskeratosis congenita symptoms |
|
Definition
| premature gray hair, dental loss, bone marrow failure which often leads to infection and death, skin disorders |
|
|
Term
|
Definition
| mutation interrupts genetic stability leading to aging |
|
|
Term
| hutchinson-gilford: cause, results |
|
Definition
mutation in lamin A protein of the nuclear scaffolding
children die at ages 2-21 from athlerosclerosis |
|
|
Term
| how can calorie deprivation lead to aging |
|
Definition
enhances activity ot situins
prevents accumulation of methylglyoxal |
|
|
Term
| what is sirtuins, what does it do, how does this have to do with aging |
|
Definition
NAD dependent decaylator of proteins that activate DNA repair enzymes and mess up telomeres
feeding promotes NADH production and takes away NAD, calorie restriction increases NAD build up and thus telomere damage |
|
|
Term
| what is methylglyoxal, how is it made, what does it do |
|
Definition
glycating agent made from spontaneous decomposition of DHAP and G3P
results in advanced glycosulation end products
forms adducts with growth factor receptors
causes mito dysfunction and ROS |
|
|
Term
| what does increased oxygen utilization do to aging |
|
Definition
| supresses age related changes because it means mito is working good and no ROS are made and NADH are made so no NAD is buildig up |
|
|
Term
| how is insulin involved in aging |
|
Definition
| insulin receptors down signaling regulates sirtuins and autophagy (removing of damaged organells) |
|
|
Term
| common themes of wound healing (5) |
|
Definition
angiogenesis
fibroblast formation
deposition of ECM
formation of granular tissue
maturation and reorganization of the fibrous tissue |
|
|
Term
|
Definition
| generation of new vessels at periphery of injury |
|
|
Term
|
Definition
| fibroblast with a contractile phenotype to close wounds |
|
|
Term
| granular tissue: composition, function |
|
Definition
immature vessels, immature collagen, mycofibroblast, elastin, growth factors
fills in large wound deficit that mycofibroblasts cannot close |
|
|
Term
| how can you tell if collagen is mature |
|
Definition
| mature collagen stains with trichrome blue |
|
|
Term
| explain what happens in the phase where there is maturation and reorganiation of fibrous tissue in wound healing |
|
Definition
vessels regress, collagen remains
excess collagen forms scar (fibrosis) |
|
|
Term
| first 12-24 hours of wound repair (2) |
|
Definition
filled by clot
neutrophils invate and release growth factor and cytokines to initiate inflammatory response |
|
|
Term
|
Definition
| platelets interacting with collagen that was exposed via wounding |
|
|
Term
| what is nescessary for wound healing, in general |
|
Definition
|
|
Term
| next 3-7 days of wound healing (4) |
|
Definition
neutrophils have apoptosed
macrophages abudent
angiogenesis
fibroblasts come and form granular tissue |
|
|
Term
| last 1-2 weeks of wound repair (4) |
|
Definition
wound fills with granular tissue
fibroblasts form into myofibroblasts
myofibroblasts contact
collagen deposits |
|
|
Term
| define labile cell, give examples |
|
Definition
cells capiable of continous replication
epithelium. GI |
|
|
Term
| define permanent cell, give examples |
|
Definition
cells that don't have the capacity to re-renter the cell cycle
cardial muscle and neurons |
|
|
Term
| define quiescent cell, give examples |
|
Definition
cells that don't continously replicate but do have the abaility to be called back into the cell cycle on demand
kidney, hepatocytes |
|
|
Term
|
Definition
| replace cells with same type |
|
|
Term
|
Definition
| regenerating and replacement. fills with some of the origin cells and with granular tissue, collagen, ECM because the hole is too big |
|
|
Term
| what regulates the cell cycle, how do they work |
|
Definition
growth factors
and
cyclin dependent kinase is produced consistuiently (always expressed) but is inactive
cyclins turn on CDK with phosphorlyation. CDK can then go phosphorlyate things that manage the cell cycle |
|
|
Term
| how does CDK and cyclins manage the cell cycle |
|
Definition
shorten the cycle (enhance cell proliferation)
recruit resting cells into the cycle |
|
|
Term
| ECM mechanical functions(4) |
|
Definition
tensile and compressive strength and elasticity
turor in soft tissue
rigidity to bone
support for cell adhesion |
|
|
Term
| how does the ECM give rigidity to bone |
|
Definition
| it had the ability to sequester water |
|
|
Term
|
Definition
| buffers against extracellular changes and water rention |
|
|
Term
| how does the ECM function in organizing our tissues (5) |
|
Definition
control their behavior by holding onto growth factors and interacting with cell receptors
cell-cell communicationg
determine cell polarity
determination location of cell growth
contol cell differentiation |
|
|
Term
| what does it mean when said that the ECM is dynamic |
|
Definition
| it is constantly remodeling |
|
|
Term
| give 7 examples of how the ECM is specific |
|
Definition
plasma ECM is liquid
bone and tooth enamel is highly mineralized
tendon ECM is very elastic
coats for muscle and fat cells
forms glomerular filter in the kidney
wraps myelin sheath |
|
|
Term
| what are the two types of ECM |
|
Definition
basement membrane (basal lamina)
interstitial matrix |
|
|
Term
| give some examples of where a basement mebrane is located (3) |
|
Definition
beneath epithelial cells
under endothelium in vessels
around smooth muscle cells |
|
|
Term
| how is basement membrane made |
|
Definition
| made by epithelium and mysenchymal cells (fibrobroblasts, chrondrocytes, osteoblasts) |
|
|
Term
| what are the two main function of the basement membrane, what is its consistancy |
|
Definition
hold the cells down
integrity is crucial for tissue regeneration
gel like |
|
|
Term
| what are the components of the basement membrane(3) |
|
Definition
type 4 or 7 collagen
laminin |
|
|
Term
| type 4 collagen: where is it located, what is its classification, why would it not be in it is location |
|
Definition
located in ECM basement membrane
amorphpous non-fibullar collagen
sometime collagen 4 is replaced by collagen 7. this occurs when you call the basement membrane a basal lamina in the stratified squamous epithelium |
|
|
Term
|
Definition
an adhesive glycoprotein in the basemement membrane
can connect to other adhesive glycoproteins (like in the ECM to anchor cell) |
|
|
Term
| interstitial matrix: give 3 examples of its location |
|
Definition
| between cells in the CT, between epithelium, between smooth muscle cells |
|
|
Term
| what makes the interstitial matrix, what is its consistancy |
|
Definition
made by mesenchymal cells (fibrobolasts)
amorphous gel |
|
|
Term
| what are the compontents of the interstitial matrix (16) |
|
Definition
fibullar and non-fibullar collagen:1-4, 7, 9, 12
adhesive glycoproteins: fibronectin, nidogon
elastin
GAGs: hayluronan, chondrotin, dermatin, heparin, keratan
proteoglycans: herparin sulfate, syndecan, perlican
integrins |
|
|
Term
| collagen: general structure |
|
Definition
3 alpha chains in triple helix
GXY repeats (glycine-proline-hydroxy proline)
fibrullar and non-fibullar |
|
|
Term
|
Definition
|
|
Term
| collagen 2 location, function |
|
Definition
| tensile strength in tendons |
|
|
Term
|
Definition
| granulation tissue, embryonic tisssue, uterus, KELOIDS |
|
|
Term
| how is the structure of a fribullar collagen different from that of a non, which collagen are fribullar |
|
Definition
| collagen 1-3 form fibrils around the triple helix and laterally cross link the strands with covalent bonds made through lysyl oxidase and vitamin C |
|
|
Term
| collagen 9 and 12 function |
|
Definition
fibril associated collagen
link type 1 and 2 collagen together |
|
|
Term
| collagen 4 and 7 function |
|
Definition
form mesh networks
collagen 7 connects to basal lamina to epithelium |
|
|
Term
| frbronectin: what is it, what are the functions (7) |
|
Definition
adhesive glycoprotein
fibroblasts, monocytes, endothelium use it for adhesion
Attaches to the ECM with integrins with a specil motif
forms firbillar aggregates during wound healing so fibrin in cloths has scaffolding
binds heparin, collagen, cells, and self |
|
|
Term
| what is the morif that fibronectin uses to bind to the ECM, what is its importance |
|
Definition
tripeptide argining-glycine-aspartic acid motif
without the motif fibronectin cant tell where itself is and will apototose. this is a letheal mutation |
|
|
Term
| what adhesive glycoproteins are in the interstitial matrix |
|
Definition
|
|
Term
| elastin: functions, how is it made, what is its structure |
|
Definition
gives ability to reocil
is important in vessel walls, uterus, skin, and ligaments
secreted as a tropeleasin precursor that is cross linked like collagen and coated with firbillin microfibrils |
|
|
Term
| what component of elastin can be deficient, what disease is this, what is the symptom |
|
Definition
| fibrillin 1 is deficient in marfan's syndome and causes weak elastic tissue |
|
|
Term
| GAGs: composition, chemical significance |
|
Definition
unbranched repeated disaccharides
negative charge attracts ions, espially Na which attracts water and causes GAG to puff up like a gel and fill lots of space while remaining light |
|
|
Term
| hyaluronan: composition, function, how it is made |
|
Definition
large mucopolysaccharide with no protein core
binds water forming a gel matrix and fills up space
sun out from cell membrane
not sulfated or anchored to proteins
removed after cell migration is complete |
|
|
Term
| GAGs other than hyaluronan: how are they made, where are they located, list 4 of them |
|
Definition
made intracellular, secreted, sulfated
covalently bound to proteoglycans
chondroitin, dermatin, heparin, keratan |
|
|
Term
| proteoglcans: function (6), composition |
|
Definition
compressible gel for resiliance and lubrication
reservior for growth factors
some are integral membrane proteins with role in proliferation, migration, and adhesion of cells
glycosamine and mucopolysaccharides linked to a protein back bone |
|
|
Term
| heparin sulfate: what is it, what are its functions (3) |
|
Definition
proteoglycan
bind fibroblast growth factor in ECM and release it during injury
bind chemokines at inflammatory sites to prolong WBC chemotaxis
blind and block some proteases |
|
|
Term
| syndecan: what is it, what are its functions (2) |
|
Definition
transmembrane proteoglycan
interaction with FGF facilitating it with its receptors
important in epithelial sheath morphology via interaction with actin |
|
|
Term
| perlican: what is it, what is its structure |
|
Definition
main proteoglycan in the basal lamina
core protein with three heparin sulfates |
|
|
Term
| integrins: what are they, how do they work |
|
Definition
transmembrane adhesive membrane receptors
low affinity for their ligand but there are a lot of them
require Ca or Mg for lingand binding |
|
|
Term
|
Definition
link the ECM to fibronectin which is required for cell survival
helps leukocytes roll along vessels to get to inflammatory sites
involved in cell-cell attachments (hemidesmosomes and focal adhesions) |
|
|
Term
| why do cells apoptose when integrin isn't holding them to the ECM |
|
Definition
because failure to adhere can lead to metastasis
mutations can cause failure to apoptose leading to cancer |
|
|
Term
| what growth factors regulate wound healing (7) |
|
Definition
platelet derived growth factor
fibroblast growth factor
epidermal growth factor
vascular endothelial growth factor
insulin like growth factor I and II
transforming growth factor B |
|
|
Term
| platelet derived growth factor (PDGF): where does it come from, what is a drug that has it in it |
|
Definition
released from degranulating platelets upon injury
approved to treat skin ulcers |
|
|
Term
|
Definition
binds to transmembrane tyrosine kinase in epidermis, dermis, and granulation tissue
chemotactic: neutrophils, monocytes, fibroblasts
stimulates activation of fibroblasts |
|
|
Term
| what functions does PDGF tell fibroblasts to do (3) |
|
Definition
proliferate
produce ECM
contract collagen matrices (myofibroblasts) |
|
|
Term
| fibroblast growth factor (FGF): how does it work, where is it located |
|
Definition
sends signal through tyrosine kinase
sequestered in herparin sulfate proteogycans |
|
|
Term
| what is the benifit of FGF being sequestered in heparin sulfate (4) |
|
Definition
stabilizes it from thermal denaturization and proteolysis
limists diffusability
essential for receptor activation |
|
|
Term
|
Definition
stimulate proliferation of cells in ectoderm, mesoderm, and endoderm origins
cytosupportive: supports cells under stress
stimulates tissue repair |
|
|
Term
| epidermal growth factor (EGF): how does it work |
|
Definition
up-regulated early after injury
binds to high affinity receptors making dimers
EGF binds to EGFR (receptor) on tyrosine kinase on epithelial cells and fibroblasts |
|
|
Term
|
Definition
stimulate cell division
role in re-epithelialization |
|
|
Term
| vascular endothelial growth factor (VEGF): how does it work |
|
Definition
| binds to tyroskin kinase receptors on blood vessels and granulation tissues |
|
|
Term
|
Definition
| macrophages and keritnocytes |
|
|
Term
|
Definition
regulate vasculogenesis and angiogenesis development in wound healing
increase permeability of vessels increasing swelling
lymphangiogenesis: absence of lymph vessels in chronic wounds |
|
|
Term
| insulin like growth factor I and II (ILGF): where does it come from (3) |
|
Definition
| macrophages, epidermal cells, inflammatory cells |
|
|
Term
|
Definition
| mitogenic, promotes survival of cells, role in scaring, matrix deposition, re-epithelization, fibroplasia |
|
|
Term
| what does delayed expression of ILGF cause, where is this seen |
|
Definition
| in people with diabetes and glucocorticoid treatment it causes delayed wound healing |
|
|
Term
| transforming growth factor B (TGFb): how does it work, where does it come from |
|
Definition
released from platlets on woundiing
attaches to heterochromatic receptor complexes (serine-tyrosine kinase)
sequested in matrix in latent form allowing sustained release when proteolytic enzymes come along |
|
|
Term
|
Definition
development, homeostasis, disease and repair
chemoattractant for neutrophils, macrophages, fibroblasts
mitogenic for fibroblasts ***
inhibits proliferation of other cells**
stimulates ECM proteins and integrins**
implicated in the fibrosis elicted in chronic inflammatory states |
|
|
Term
| how has TGFb been used in wound treatment, what was the outcome |
|
Definition
treatment of wounds with B1 increases scaring
treatment of wounds with B1 and B2 reduces scaring |
|
|
Term
| what cytokines are used to regulate wound healing (9) |
|
Definition
| chemokines, TNFa, IL-1a, 1b, 6, 8, 10, lymphokines, interferons |
|
|
Term
| role of chemokines in wound healing |
|
Definition
| secreted proteins that stimulate chemotaxis and extravasion of leukocyes |
|
|
Term
| role of IL-8 in wound healing |
|
Definition
| chemoattractant for NEUTROPHILS in human blister in skin graft |
|
|
Term
| role of IL-6 in wound healing |
|
Definition
scaring
neutrophil chemoattractant
up-reglated in inflammatory phase
made by macrophages and neutrophils |
|
|
Term
| role of IL-1a, IL-1b, IL-6, TNFa in wound healing |
|
Definition
up-regulated in inflammatory phase
made by macrophages and neutrophils |
|
|
Term
| why don't fetuses get scars |
|
Definition
| they have different expression of IL-1a, 1b, 6, TNFa |
|
|
Term
| role of IL-10 in wound healing |
|
Definition
inhibits neutrophil and macrophage infiltration
inhibits scaring |
|
|
Term
|
Definition
| assembly of primitive vascular network from angioblasts in angeogenesis |
|
|
Term
| what are the supplies needed for angiogenesis |
|
Definition
endothelial progenitor cells
OR
pre-existing vessels |
|
|
Term
| what are the two ways angiogenesis can occur |
|
Definition
endothelial progenitor cells come from the marrow
OR
endothelial cells grow from pre-existing vessels |
|
|
Term
| explain the process of angiogenesis |
|
Definition
proteolysis of the ECM
migration and chemotaxis
proliferation
lumen formation, maturation, and inhibition of growth
increased permeability through gaps and transcytosis |
|
|
Term
| what stimulates the proliferation during angiogenesis |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
the more damage there is the more must be replaced with collagen and not the native tissue. collagen is reformed into a scar
basement membrane of the underlying ECM is not in tact |
|
|
Term
| what are some of the down sides of scar tissue (2) |
|
Definition
it is unable to perform the functions of the native tissue
it will never be more than 80% of the native tissue strength |
|
|
Term
| when does scar tissue begin to form |
|
Definition
| 24 hours after the injury |
|
|
Term
| explain the process of scar formation (5) |
|
Definition
endothelium and inflammatory cells (macrophages) release mediators to attract fibrobolasts
fibroblasts are stimulate to proliferate and deposit ECM and collagen
fibroblasts, deposited CT, and leukocytes make pink granular tissue
maturation and remodeling of fibrous tissue into collagen forms scar
scar is remodeled over time by matrix metalloproteins |
|
|
Term
| what mediators do macrophages use to call in fibroblasts (3) |
|
Definition
|
|
Term
| what mediators stimulate for fibroblasts to proliferate |
|
Definition
|
|
Term
| matrix metalloproteinases: what is their function, what makes them |
|
Definition
made by fibroblasts,epithelium, synovial joints.
break down protein (type III collagen) and replace it with type I collagen to reorganize the wound |
|
|
Term
| how do matrix metalloproteinases work, how do they stop working |
|
Definition
dependent on zinc
stored inactivated and are activated by plasmin (splits clots to limit size)
inactivated by tissue inhibitors of metalloproteinases (TIMPs) |
|
|
Term
| what are type types of matelloproteinases, what do they do |
|
Definition
stromelysins: break down proteoglycans, laminin, fibronectin
collagenases: break down collagen |
|
|
Term
| what are two types of abberations |
|
Definition
|
|
Term
| what is the cause of a kypertrophic scar |
|
Definition
normal wound healing progresses to excessive accumulation of type I collagen
PGDF may have a role |
|
|
Term
| what is the cause of a keloid |
|
Definition
scar tissue (type III collagen) grows beyond the boundries of a wound
keyloid fibroblasts have increased response to PDGF so this may be the cause |
|
|
Term
| what are the six steps in wound healing |
|
Definition
1. acute inflammation
2. parenchymal cell regeneration if possible
3. migration and proliferation of parenchymal cells and CT
4. synthesis of ECM
5. remodeling parenchymal elements to restore tissue function
6. remodeling of CT to achieve wound strength |
|
|
Term
| primary goals of wound healing |
|
Definition
heal focal disruption of epithelial cells
clean, disinfect
epithelial regeneration predominates over fibroblasts |
|
|
Term
| secondary goal of wound healing |
|
Definition
cell or tissue loss like ulcers, abscesses, or large wounds form granulation tissue
ECM accumulation and scaring |
|
|
Term
| what are the differences between the primary and secondary goals of wound healing |
|
Definition
secondary has
more intense inflammatory reactions: more necrosis, debris, exudate, fibrin
larger granulation tissue: fills gaps, provides framework
wound contraction: myofibrills contract and wound shrinks by 5-10% in 6 weeks |
|
|
Term
| first intention wound: aka, describe it, what are the main goals in healing this would |
|
Definition
primary union
the edges of the wound line up well and the primay goals of healing are to disingect, clean, and regenerate epithelium (rather than insert fibrous tissue) |
|
|
Term
| secondary intention wound: aka, describt it, what are the main goals of healing in this woumd |
|
Definition
secondary union
large gaps between wound edges
primary goal of healing is extension of granulation, ECM, scars, wound contraction |
|
|
Term
| in one week how strong is scar tissue? how long does it take for it to reach full strength, how strong is this? |
|
Definition
10% strength in a week
70-80% max strength in 3 mo |
|
|
Term
| how is scar tissue strengthed (3) |
|
Definition
collagen degredation and synthesis
switching from collagen III to collagen I
extracellular cross linking of collagen |
|
|
Term
|
Definition
| wound fails to heal in closed position |
|
|
Term
|
Definition
excessive tension on the wound leads to necrosis, decreased strength
electronic coagulation increases inflammatory response to necrotic tissue
removal of suturues to early
infection
trauma |
|
|
Term
| what are risk factors for wound dehisence (5) |
|
Definition
>65 yo
hypoalbumenia
tobacco
corticosteroids
systemic infection |
|
|
Term
| list some disorders that cause issues with inflammation and repair (5) and breifly describe them |
|
Definition
leukocyte adhesion deficiency: integrin deficiency causes problems with chemotaxis
chronic granulamatous disease: NADPH oxidase deficiency causes problem with killing bacteria and infection is the most important delay in wound healing
keloids: type III collagen overgrowth and no transformation to type I
vitamin C deficiency: hinders collagen synthesis
corticosteroids |
|
|
Term
| explain the role of fibrosis formation in chronic inflammation |
|
Definition
continous stimulus keeps activating macrophages and leukocytes to release growth factor and cytokines to increase collagen and decrease metaloproteinase activity which causes fibrosis
people who have chronic inflammation are often on seroids and this decreases metaloproteinase activity too |
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