Robin Chapter 3 Flashcards
What are NOD-like receptor (NLR)?
A cytosolic receptor that detect molecules that are liberated as a consequenence of cell dammage, which are:
uric acid, ATP, reduced K+, DNA etc. Activates inflammasome, which induces the producion of IL1
What are the 5 R of inflammatory response steps?
Repair, Regulation, REmovl of the agent, Recruitement, REcognition
How does histamine (and bradykinin, leucotrienes, etc) cause vascular permeability of postcpillary veinules?
Contraction of endothelial cells. It is short-lived (15-30 min) except in some forms or mild injury like burns, UV, toxins where leakage begins after 2-12 hours and last for hours of days (endothelial injury)
What is the role of those proteins in migration of leucocytes through the capillaries?
- selectin
- chemokins (usually bound to proteoglycans)
- integrins
- CD31
- selectin: rolling
- chemokins/proteoglycans: acivating neutrophils to increase avidity of integrins
- integrin: firm adhesion
- CD31 (PECAM-1): transmigration
P-selectin is expressed on…. (2)
endohelium and platelet
Chemotactic agents (cytokines, complement (C5a), archidonic acid metabolites like LTB4) bind to which receptor on the leucocyte?
seven-transmembrane G protein-coupled receptors
Release of leucocytes from the bone marrow is caused by cytokines that include ___ and ___
TNF and IL-1.
These are released in huge number during sepsis
which comes first: vasodilatation or permeability?
Vasodilatation, then permeability (think becomes red b4 swelling). Both caused by histamine. increased permeability also caused by other kinins
Give their roles in leucocytes recruitment:
Selectins:
Chemokins:
integrins:
CD31 (PECAM-1):
ICAM-1:
IL-1:
TNF:
VCAM-1
selectins: rolling
chemokins: acivating neutrophils to increase avidity of integrins
Integrins: firm adhesion
PECAM-1: transmigration
ICAM-1 (binds to LFA-1): integrin ligand (on the endothelium)
IL-1 and TNF : activate endothelium (increase adhesion molecules), and promote the release of cytokines for chemotactic gradient
VCAM-1 (binds to VLA-4): intergrin ligand on endothelium
P selectin is expressed on:
platelet AND endothelium
Which is the most common exogenous factor causing chemotaxis? (Starts with N)
peptides with N-formylmethionine terminal (bacterial product)
Name the 3 phagocytic receptors
mannose receptor, scavenger receptor (binds the LDL) and opsonin receptor (C3b, plasma lectins, IgG)
On top of being involved in microbial killing, NO does soemthing else:
vasodilatation
eNOS: endothelial
nNOS: neutronal
iNOS: inducible (involved in microbial killing
difference between acid protease and neutral protease (granules in neutrophiles
acid protease: degrades bacteria and debris with phagolysosomes
neutral protease: destruction of extracellular components -> tissue desctruction that accompany inflammation
Two types of granules in neutrophils: what are their main difference?
specific (secondary granules), constituted of ex: collagenase and primary azurophil granules
what are alpha1 antitrypsin and alpha2-macroglobulin
antiproteases
What are NET
extracellular fibrillar network that concentate antimicrobial substances at site of infection and trap microbes, preventing their spread. It is composed of nuclear chromatin
lipoxins are pro or antiinflammatory
anti
MEdiators are either secreted by _____ or generated from _____
cells (sequestered in cells, rapidly secreted), plasma proteins (liver, exemple complement)
2 major vasoactive amines:
histamine, serotonin
Histamine is secreted secondary to binding of IgE antibodies OR (2 answers)
- cold, heat, physical injury
- anaphylatoxins, which are products of complement, C3a and C5a
- Neuropeptides like P substance and IL1 and IL8 can also trigger release of histamine
Serotonin is a preformed vasoactive mediator present in which cells? (2)
platelets and neuroendrocrine cells
TxA2 2 roles (thromboxane A2)
vasoconstriction and platelet agreggating
Prostacyclin role (PGI2)
vasodilation and inhibition of platelet agreggation (so contrary of thromboxane)
+ increase of vascular permeability and chemotactic effect of other mediators
this molecule of the aracidonic acid metabolites is involved in pain
prostaglndin (PGE2)
Also involved in fever
Which is more potent for causing bronchospasm and increasing vascular permeability: leucotriene or histamine?
leucotriene (C4, D4 E4)h
which two cell population are required for synhesis of lipoxins?
neutrophils and platelets
Name 3 cytokins that cause fever AND leucocyes production in the bone marrow
IL1, IL6, TNF
Name 2 cytokins that cause that increase acture phase proteins
IL1, IL6
What does IL8 does
chemotaxis and activation of neutrophils
chemokines binds o which receptor type?
G protein coupled receptor
chemokines are important in acute inflammation AND
maintenance of tissue architecture (ex: spleen and lymph node)
complement: innate, adaptive or both?
both
which is the critical step in the complement activation? and which are the 3 pathways?
cleavage of C3
pathway 1: classic (antibodies)
pathway 2:Alternative (endotoxin, LPS, venom, etc)
pathway 3: lectin pathway (mannose binding lectin binds to carbs on microbes)
Name the 3 complement proteins that are anaphylatoxins
C3a, C5a, (C4a)
Which complement protein activates the lipoxyfgenase pathway of AA metabolism?
C5a. It is also a chemotaxis agent for many leucocytes
what can platelet activating factor do on top of platelet aggregation?
vasoconstriction, bronchoconstriction. At low concentration: vasodilataiton and increased vascular permeability
Bradykinin has effects similar to which chemical?
Histamine. Bradykinin also cause pain. action is short lived
Substance P role in inflammation (2)
pain and vascular permeability
3 sites of production of macrophages
bone marrow in pos natal life-> blood monocyte and skin and intestine macrophages
yolk sac and liver-> resident macrophages
2 major pathways of macrophage activation, and what they are:
classical and alternative
classical:main role is to destroy microbes and promote the inflammatory response.
Alternative: terminate inflammation and promote tissue repair. induced by cytokines other than IFN gamma, such as iL4, IL13
pathogenesis of fever
exogenous pyrogens ex LPS-> stimulate lymphocytes to release IL1 and TNF (acute phase response, as well as IL6) -> induce production of prostaglandin (PGE2) in hypothalamus
Name the 3 most important acute phase protein (synthesised in liver)
SAA (serum amyloid A), fibfinogen, C reactive protein (CRP)
which cell is the most important source of growth factor when a tissue is injured?
macrophages
proliferation of hepatocytes following partial hepatectomy steps
- TNF simulates Kupffer cells to release IL6
- HGF and TGF, produced by many cells type, acted on primed hepatocytes (by IL6) to stimulate cell metabolism and make them enter the cell cycle
- replication of nonprenchymal cells
- return to quiescence
When does liver regenerate from progenitor cells?
chronic liver injury and inflammation (proliferative cpacity impared). Some of the progenitor cells are in canal of Herring
What is the name of the pathway that regulates the sprouting and branching of new vessels?
Notch pathway.
VEGF stimulates the expression of notch ligands which binds to the notch receptor on endothelial cell
ECM proteins prticipate inn the process of vessel sprouting in angiogenesis largely through interactions with ___________ receptors in endothelial cells
integrins
Which is the most important cytokin for the synthesis and deposition of connective tissue proteins
TGF-beta.
PRoduced by most cells in granulation tissue
TGF beta increase or decrease metalloproteases
decrease (inhibit), which decrease DEGRADATION of ECM
What are TIMPs?
tissue inhibitors of metalloproteinase
cellular receptors for microbes are in the cytosol, plasma membrane and ________
endosomes
Give 3 things NOD like receptors can detect
uric acid, ATP released from damaged mitochondria
reduced K+ concentration
DNA hanging around in the cytosol
What does NOD like receptors activate
an inflammasome, which produces IL-1, which recrutes leucocytes
vasodilatation starts with arterioles or capillaries?
arterioles
Which leucocyte produces growth factor that aid in repair of tissues?
macrophages
Histamin does vasodilatation, increased permeability or both?
both
Which cytokines (2) act on endothelial cells of post capillary veinules to express adhesion molecules and endothelial ligand like VCAM-1 and ICAM-1?
TNF and IL1
In which kind of blood vessels does transmigration occurs?
postcapillary veinules
does actin gets polymerized at the leading edge of cells or at the back?
Leading edge. Myosin filaments are at the back
Which leucocyte attaches better to the adhesion molecules of endothelium?
neutrophils
Activated leucocytes have more ____ (element) in their cytosol
calcium
Name 3 antioxydants other than glutathione peroxydase and superoxyde dysmutase
catalase, ceruloplasmine, iron free fraction of plasma transferrin
What is the name of the primary neutrophil grnaules? what are the secondary granules for?
primary granules: azurophils
secondary granules: they are more specific
Difference between acid protease and neutral protease in what they do
acid protease degrade bacteria and debris in the phagolysosome
neutral protease degrade extracellular components (collagen, fibrin…) resulting in tissue destruction
What do NET do?
They are neutrophil extracellular traps, they are fibrillar networks that concentrate antibicrobial substances at the sites of infection and traps microbes, helping to prevent their spread
Movement of cells/phagocytosis: myosin filaments is in the back or front? Polymerisation of actin?
Myosin: back
Polymerisation: back
Which one produces more cytokines, neutros or macrophages? And secretion of lysosomal enzymes?
Macrophages, neutrophils
Which receptor doesnt have as a functional outcome to kill microbes: G protein coupled receptor, toll like receptor, phagocytic receptor
G protein coupled receptor
Platelet activating factor (PAF) commes from which cells ?
Leucocytes, mast cells
Leukotrienes vasodilate or vasoconstrict?
Vasoconstricts
In the Arachidonic acid metabolites, which 2 do chemotaxis?
5-HETE and leucotriene B4 (and PGD2 for neutrophils)
Which cytokines activate classically activated macrophages (M1) vs alternatively activated macrophages (M2)?
IFN gamma= M1, IL13, IL4 = M2
To note that microbial products also activates M1
what is a tertiary lymphoid organ?
lymphoid organogenesis seen in chronic inflammation (formation of lymphoid follicule)
What does PCSK9 do? (hint: cholesterol metabolism)
Inhibits recyling of LDL receptorsn (reduces the amount of LDL receptors, therefore increase levels of blood cholesterol
How does a secondary storage problem differs from primary storage problem in lysosomal disease?
secondary storage: happens when there is no autophagy of mitochondria -> accumulation of aberrant mitochondria -> free radicals -> intrinsic apoptosis triggered
