Flashcards in More acute inflammation Deck (20):
what are the phases of acute inflammation?
fluid phase, neutrophil phase (24 hrs), macrophage phase (2-3 days)
Phases of neutrophil arrival and action
1. vasodilation: blood vessel is wider. particles that were running in the center, now go to the sides: margination
2. rolling: neutrophils hit selectins
4. transmigration and chemotaxis
6. destruction of phagocytosed material
What is margination?
vasodilation slows blood flow in the postcapillary venules cells migrate from the center to the periphery
What is rolling? what molecs are important?
selectin spped bumps are upregulated on endothelial cells.
P selectin is released from Weibel Palade bodies; are mediated by histamine.
E-selectin is induced by TNF and IL-1
selectins bind sialyl Lewis X on leukocytes. allows for neutrophil rolling. Interaction results in rolling of leukocytes along the vessel wall.
What happens during adhesion?
cellular adhesion molecs are upregulated on endothelium by TNF and IL-1. (aka CAMs)
CAMs bind integrin. Integrins are upregulated ON leukocytes by C5a and LTB4 (which we know attract neutrophils).
What is leukocyte adhesion deficiency? Pathophysiology and clinical features)
autosomal recessive defect of integrins (CD18 subunit). without integrin, neutrophils can't adhere to the endothelium).
1. delayed separation of the umbilical cord: tissue is supposed to undergo necrosis, and then inflammation is supposed to come in. These babies' neutrophils can't come in, so the umbilical cord doesn't separate when it should.
2. Incr. circulating neutrophils: neutrophils in blood represent 50% of neutrophils. the rest are hanging out stuck to the blood vessels in the lung (marginated pool): these are basically reserve troops. In this disease, the neutrophils can't hang on, so there is more in the blood.
3. recurrent bacterial infections that LACK pus (dead neutrophils) formation.
What do I need to know about transmigration and chemotaxisz?
leukcytes transmigrate across the endothelium of post-cap venules
move toward chemical attractants. move toward C5a, bacterial products, leukotriene B4, IL-8
What should I know about phagocytosis?
consumpttion of pathogens and necrotic tissue
enhanced by opsonins (like IgG and C3b).
How does phagocytosis occur?
pseudopods (little fingers) from leukocytes extend to form phagosomes (vesicles of eaten material). these are internalized and merged with lysosomes to form phagolysosomes. lysosomes have degradative enzymes necessary to destroy things
What is Chediak Higashi syndrome?
this is a protein trafficking defect. autosomal recessive.
remember that phagosomes must be moved toward the lysosome to make the phagolysosome along microtubules in the normal cell. these pts can't move phagosomes to lysosomes b/c of the defect.
features: incr. risk of pyogenic infections, neutropenia (protein trafficing is important for neturophil cell division and development), giant granules in leukocytes (they pile up near the golgi where the are made, since they can't be distributed throughout the cell), defective primary hemostasis (platelets are important for hemostasis and depend on proper distribution of granules), albinism (pigmenting occurs via melanocytes. melanocytes make pigment, but can't transfer it to the keritinocytes), and peripheral neuropathy (can't move stuff from nucleus all the way to the end of the nerve cell)
How does destruction of phagocytosed material occur?
1. O2 dependent killing:
and O2 independent killing.
Describe O2 dependent killing. Include biochemistry.
most effective mechanism.
O2 converted to superoxide by NADPH oxidase (oxidative burst)
superoxide taken by superoxide dysmutase to make H2O2. H2O2 converted by myeloperoxidase to HOCl.
HOCl (bleach) is generated by oxidative burst in phagolysosomes and destroys phagocytosed microbes.
What is Chronic granulomatous disease?
poor O2 dependent killing d/t NADPH oxidase defect. This may be X-linked or autosomal recessive.
they get chronic granulomas. as a result.
patients get infections, ESPECIALLY with catalase positive organisms.
H2O2 can also be generated from bacteria themselves. Then, myeloperoxidase (which is OK in this disease) can come in convert the H2O2 to bleach to destroy the bacteria. CGD patients are ok with an bacteria that has intrinsic H2O2. However, some bacteria also produce catalase, which destroys their intrinsic H2O2. So patients have problems with catalase positive organisms.
What are the catalase positive organisms?
S aureus, Pseudomonas cepacia (important for chronic granulomatous disease)
(also S marcescens, Nocardia, and aspergillus)
What is the nitroblue tetrazolium test?
screens for chronic granulomatous disease
asks if conversion to O2 to supraoxide is intact
turns blue if NADPH oxidase can convert O2 to O2- (supraoxide)
remains colorless if NADPH oxidase is defective
MPO converts H2O2 to HOCl. If patient has an MPO defect, they are usually asymptomatic, though they may have an incr. risk of candida infections.
Note that NBT test will be normal with MPO deficiency
What is MPO deficiency?
results in defective conversion of H2O2 to HOCldot.
incr. risk for candida infections; however, most pts are asymptomatic.
NBT test is normal
What is O2 independent killing?
occurs via enzymes present in leukocyte secondary granules (lysozyme and major basic protein).
What happens during the resolution phase of acute inflammation?
neutrophils undergo apoptosis. neutrophils disappear within 24 hrs after resolution of the inflammatory stimulus.
What is the macrophage phase of acute inflammation?
predominates after neutrophils and peaks 2-3 days after inflammation begins
macrophages are derived from monocytes in the blood. they arrive just like neutrophil: margination, rolling, adhesion, transmigration, ingest via phagocytosis and destroy phagocytosed material using enzymes in the secondary granules, esp. lysozyme (unlike neutrophils, which mostly use the oxygen dependent pathway).