L13: Inflammatory Response Flashcards
(50 cards)
Hallmarks of the inflammatory response
rubor (redness)
tumor (swelling)
calor (heat at tissue site)
dolor (pain)
functio laesa (loss of function)
Inflammation is caused by ______.
vascular changes:
- endothelium leaks
- edema
- positive feedback loop of cell signaling
- further changes in cell adhesion molecules on both cells and endothelium.
Giving blood is associated with _____ (as are statins, aspirin and fish oils, all of which are anti-inflammatory and all of which tend to increase bleeding).
lower heart disease
generally used to describe a variety of molecules used to identify pathogens. The first group identifies was the toll-like receptors, but many more types.
-PAMPS (pattern-associated molecular proteins)
-molecules that are normal cell components but should be inside
– cytoplasmic or nuclear proteins of membrane proteins belonging in the inner leaflet.
DAMPS (death or damage-associated molecular proteins)
Response to PAMPS and DAMPS =
- Activate complement, which in turn releases inflammatory signals (anaphylatoxins)
- Attracts neutrophils, macrophages and mast cells.
- Smallish (90 to 130 amino acids), with conserved cysteines
- Receptors are seven-span membrane proteins.
- Binding activates G-proteins
Inflammatory Chemokines
Cross reception common: a given chemokine may bind more than one receptor and a specific receptor may bind more than one chemokine
G-proteins kick of several internal cascades:
- hydrolyzes membrane phospholipids to IP3 and DAG -lets Ca2+ loose in the cytoplasm, polymerizing actin and promoting movement
- kicks off Ras cascade that leads to activation of transcription factors.
The High-endothelial Venules are found __
at the end of capillaries in lymph nodes, Peyr’s patches, and tonsils (not spleen).
In the HEV rhe endothelial lining here is composed of cells that ___
do not look like flattened paving stones, but are thicker.
Most lymph cells that extravasate attach to these specific cells in the ____
HEV
The HEVs specifically attract ____ and do NOT attract neutrophils
lymphocytes
The HEV develops in response to _____.
foreign antigen exposure
-you don’t see this in mice raised in a germ-free environment and you don’t see this in tissues that have the circulation to them blocked to that antigen does not enter.
The unique morphology of the HEV is associated with ___
the induced expression of specific selectins, mucin-like, and Ig CAMs, and they specifically allow different classes of lymphocytes to home to different organs and regions of the body.
Cell adhesion molecules involved in extravasation:
Selectins, mucins, I-CAM, integrins
- membrane glycoprotein with lectin at amino terminus that binds carbohydrates. Compare with complement lectin pathway
- specific for sialic acid (mucins have a lot of these)
- comes is L (Leukocyte), E and P (endothelium) versions
- initiate initial sticking of leukocytes to the endothelial wall
Selectin family
- protein part rich in serine and threonine (OH-containing R groups)
- LOTS of carbohydrate linked to these OHs.
- Carbohydrates have lots of sialic acid, interact with selectins
Mucin-like family
-The mucin-like versions of the endothelium interact with the selectins on the leukocytes and vice-versa.
- endothelium has several versions
- mucosa has another, which also has a mucin-like domain
- bind to integrin on leukocytes
- inflammation increases their expression
I-CAM- Ig superfamily
- Heterodimer (α and β chains)
- Expressed in leukocytes -Different integrins bind to different immunoglobulin CAMs (cell specificity)
- Can also bind to fibronectin
- Cytoplasmic portion can interact with cytoskeleton and signaling proteins such as the tyrosine kinases, Fyn and Lck.
Integrin family
4 steps of extravasation
- rolling
- activation
- arrest and adhesion
- transendothelial migration
Rolling
- attachment by low affinity P selectins (yellow) on the endothelium to mucin-like molecules on the neutrophil (purple).
- Because the connections are loose, they tend to break and the neutrophils kind of roll along, attaching to one endothelial cell after the next as it is swept along by the flow of blood.
Activation
- the “stick and release” from the rolling response along the endothelium triggers chemokine (IL-8) release by the endothelium.
- The neutrophils activate G-protein cytoplasmic pathways via the 7-span receptor.
Steps of arrest and adhesion
1) The chemokine binds to a 7-span chemokine receptor.
2) This receptor activates a G protein and sets off an internal signaling cascade.
3) The integrins change conformation, enter the lipid rafts, deploy and stick Ig tightly to the Ig CAMs of the endothelium
4) Some of the first proteins affected are those that associated with the inner side of the plasma membrane and connect to the cytoskeleton
Transendothelial migration
- the arrested neutrophil then finds the gap between two adjacent endothelial cells and squeezes through it.
- The cytoskeletal changes lead to the neutrophils changing shape and moving by amoeboid motion.
- The neutrophil forms a leading wedge and ootches through a gap between the endothelial cells (recall that inflammation makes the endothelium somewhat leaky).
