Complement System, Chemical Mediators, Angiogenesis Flashcards
What functions do cleavage products of complement have? (3)
Increased vascular permeability
Chemotaxis
Opsonization
What is the critical step in complement activation?
Cleavage of C3
What triggers the classical pathway? Next steps
Binding of C1q to antibody bound to antigen; C1r cleaves C1s, form C3 convertase with C2 and C4
What triggers the alternative pathway? Next steps
Microbial surface molecules (no antibody!); Factor B and Factor D form C3 convertase with C3b
What triggers the lectin pathway? Next steps
Plasma mannose-binding lectin bound to carbs on microbes; MASP-2 cleaves C4 and C2 to activate pathway
End result of all three complement pathways; possible outcomes (3)
C3b deposited on microbe; C3a and C5a recruits and activates leukocytes, C3b on microbe is bound by phagocyte C3b receptor for phagocytosis, formation of MAC
What splits C3 into C3a and C3b?
C3 convertase
What makes up the MAC?
C5b+C6-C9
How do C3a and C5a cause inflammation?
Both stimulate histamine release (anaphylatoxin)
C5a chemotactic for leukocytes
C5a activates lipoxygenase pathway in leukocytes
Decay accelerative factor (DAF) MOA
Prevents formation of C3 convertase
CD59 MOA
Inhibits formation of MAC
Complement factor H MOA
Inhibits alternative pathway by promoting cleavage of C3b and turnover of C3 convertase
In classical complement, what binds the Fc portion of antibody? What protein cleaves what?
C1q; C1r cleaves C1s
What makes up C3 convertase?
C4bC2a
Other than microbial products, what can trigger the alternative pathway by cleaving C3?
Other plasma proteins- kallikrein, plasmin, activated factor XII
Loss of what is associated with SLE? Mechanism?
C1q; loss of CD8 T cell regulation by C1q
What two special roles does C1q have?
Opsonization of apoptotic cells for phagocytosis
Regulation of CD8 T cells (self-tolerance)
How does complement induce antibody production?
B cells have receptors for C3b and C4b
Which complement proteins induce cleanup by phagocytosis?
C1q, C3, C4
Two major vasoactive amines
Histamine and serotonin
Histamine effect on arterioles vs venules?
Vasodilation vs increased permeability
Major effect of serotonin
Vascular permeability
Where are each of the histamine receptors found?
H1- endothelial cells and leukocytes
H2- gastric mucosa
H3- nerve terminals
H4- leukocytes
What enzyme forms leukotrienes? What do they generally do? What is the exception?
5-lipoxygenase; increased vascular permeability, bronchospasm, vasoconstriction; LTB4 causes chemotaxis
What enzyme forms prostaglandins? What do they generally do? What is the exception?
Cyclooxygenase; vasodilation, increased permeability, inhibit platelet aggregation; TXA2 causes vasoconstriction, promotes platelet aggregation
Which prostaglandin is primarily synthesized by mast cells? Which one is more widely distributed
PGD2; PGE2
Which prostaglandin is hyperalgesic?
PGE2
What is the major prostaglandin produced by platelets?
Thromboxane A2
What is the major prostaglandin produced by endothelial cells?
Prostacyclin PGI2
What is unique about lipoxins?
Synthesized in neutrophils, activated in platelets
What class of chemokines is attractant for neutrophils? Specific one and its receptor
CXC
CXCL8 (IL-8) binds CXCR2
What class of chemokines attracts anything but neutrophils? Monocyte chemokine and receptor? Eosinophil? Macrophage?
CC
CCL2 (MCP-1) binds CCR2
CCL11 (eotaxin) binds CCR3
CCL3 (MIP-1alpha) binds CCR1
What class of chemokines attracts lymphocytes? Example and receptor?
C
XCL1 (lymphotactin) binds XCR1
What class of chemokines attracts monocytes and T cells? Example?
CX3C
CX3CL1 (fractalkine) binds CX3CR1
What type of receptor do chemokines use?
G protein coupled receptor
Functions of PAF
Platelet aggregation
Vasoconstriction
Bronchoconstriction
Role of PARs in inflammation?
Found on leukocytes, also activated by thrombin, link between coag and inflammation
What are kinins, where do they come from? What inactivates them?
Vasoactive peptides from kininogens (in plasma) that are cleaved by kallikreins (proteases); kininase
Primary example of kinin; function? Receptor in normal and inflamed tissue
Bradykinin; vascular permeability, dilation, pain (histamine-like); B1r in inflamed, B2r in normal
What is the main example of a neuropeptide? Where is it prominent?
Substance P; GI and lungs
Purpose of substance P
Pain signals
Vascular permeability
Activation of mast cells
Affect of histamine on substance P
Negative feedback via H3 receptors
How does angiogenesis start? What two mediators are involved?
NO causes vasodilation
VEGF causes increased permeability
What allows formation of a vessel sprout?
Separation of pericytes and breakdown of BM
What stimulates the production of VEGF?
HIF-1alpha (hypoxia)
PDGF
TGF alpha
What is FGF-2’s role in angiogenesis?
Stimulate proliferation of endothelial cells (along with VEGF), promote migration of macs and fibroblasts for healing
What is Ang 1 and Ang 2’s role?
Ang 1- Stage 2 proliferation
Ang 2- Vascular remodeling, maturation
What is PDGF’s role? TGF beta?
Recruits smooth muscle; suppresses endothelial proliferation and migration, ECM protein production (stabilizes new vessel)
What regulates the sprouting and branching of new vessels? How?
Notch pathway; VEGF-A binds VEGF-R2, stimulates tip to express Notch ligand DII4, which binds Notch receptors in stalk, causing stalk cells to reduce VEGF-R expression
What inhibits binding of Notch receptor by DII4
Jagged
What kind of receptor is the VEGF receptor?
Tyrosine kinase receptor
What stimulates MMP release? What inhibits MMP release? What activates MMPs? What inhibits activated MMPs?
GFs and cytokines; steroids, TGF-beta; plasmin; TIMPs
What ligand and receptor mediate migration of endothelial cells?
alpha5beta3 integrin on endothelial cells bind fibrin/fibronectin in ECM
What ligand and receptor mediate second stage of proliferation (periendothelial cell recruitment)
ANG-1 binds Tie-2
What ligand and receptor mediate remodeling of the vessel?
Ephrin B2 binds EphB4
Which growth factor stimulates granulation tissue formation?
EGF
Which GFs stimulate hepatocyte and epithelial proliferation
TGF alpha and EGF (related)
HGF (scatter factor)
Which GF (2) is produced by fibroblasts?
Hepatocyte Growth Factor (scatter factor)
Keratinocyte Growth Factor aka FGF 7
Which GF is only produced by mesenchymal cells?
VEGF
Which GF is chemotactic for neutrophils and many other cells?
PDGF
What does FGF-10 do?
Epithelial call differentiation in wound repair
What is different about TGF-beta receptors?
They are serine-threonine kinase receptors that induce phosphorylation of Smad transcription factors
Main effects of TGF beta
Stimulate production of collagen and matrix proteins
Decrease MMPs, increase TIMPs
Drives fibrosis in chronic inflammation
Antiinflammatory cytokine
