Assignment 11 - look at pictures too! Flashcards
what are the 5 hallmarks of inflammation
redness heat edema pain pus
how is redness and heat brought about
increased blood flow (vasodilation)
red cell extravasation (leaking out)
how is edema brought about?
caused by leakage of fluid from circulation into tissues (increased vascular permeability)
how is pain brought about?
result of stimulation of nerve endings by bradykinin
how is pus brought about?
accumulation of dead phagocytes and bacteria along with byproducts of tissue destruction
What does tissue damage, microbial infections, toxic agents induce inflammation activate?
o Complement system o Mast cell degranulation o Blood coagulation contact system = producing bradykinin o Macrophages, dendrites o T-cells/b-cells
what does the activation of the complement system, mast cell degranulation, blood coagulation contact system, macrophage, dendrites, T and B cells generally cause?
ALL increase vascular permeability & increase blood flow to infected site
what 4 proteins make up the coagulation pathway contact system?
Factor XII
Factor XI
prekallikrein
kininogen (high molec. weight)
collagen exposed in damaged tissue + platelet membranes serves as a target for what?
Factor XII
what does activated Factor XII do?
converts prekallikrein –> kallikrein
what does enzymatically active kallikrein do?
cleaves kininogen –> bradykinin
cleaves C5 –> C5a by hydrolysis
activates neutrophils
what is bradykinin
potent vasodilator and increases vascular permeability
what is the role of C5a?
anaphylatoxin that binds to receptors on basophils and mast cells inducing degranulation and histamine release
what is the stimulus for histamine release from mast cells
o Mast cells express FCeR
o FCeR binds to IgE antibodies with active Fc regions that have a bound antigen
o Antigens bind to FAB region of IgE via crosslinks to the FCeR
o triggering mast cells to release histamine
explain the role of histamine on the expression of P-selectin on the endothelial cels?
P-selectin is moved from the cytoplasm to the plasma membrane in the presence of histamine
describe the role of P-selectin in acute inflammation
expressed on plasma membranes – not on circulating cells
induces rolling of the leukocytes on the endothelium
describe the other effects of histamine on the endothelium and the role that this plays in acute inflammation?
When histamine is released it causes vasodilation of the precapillary arterioles = increased blood flow to capillary beds
there is then induced contraction of endothelial cells in the capillary beds and post cap venues = increased vascular permeability + edema
how is the alternative pathway activated and what are the consequences of activating the alternative pathway?
presence of infection - deposition of C3b
generates C5a/5b
these anaphylatoxins with their cognate receptors on mast cells cause mast cell degranulation and release histamine + others = enhance the effect mediated by kallikrein mediated hydrolysis of C5 and C5a fragment?
List the chemokines that macrophages secrete and describe the role of each. List the cytokines they secrete.
o Secrete cytokines (IL-1, IL-6, IL-12, TNF)
o Secrete chemokines (MCP-1, IL-8)
o Secrete matrix metalloprotieinases (degradation)
o Secrete tissue inhibitors of matrix metalloproteinases (regulation)
List the local effects of TNF and IL-1 on
monocyte/macrophages and vascular endothelium
Monocyte and macrophages
Enhance cytotoxicity of macrophages
Vascular endothelium
Expression of E-selectin on endothelium (cell rolling)
Expression of VCAM-1 and ICAM-1 on
endothelium (firm adhesion)
Induce secretion of IL-8 (CXCL8) and MCP1 (CCL2) by endothelial cells
Auto and paracrine activation of Mφ
list the systemic effects of IL-1 and TNF
o TNF and IL-1 stimulate endothelial cells to express adhesive molecules
- E-selectin
- VCAM-1
- Chemokines IL-8
- MCP-1
- Produce vasodilation
- Induce fever
explain how CRP increases in pts with Heart disease
o IL-6 induces secretion of acute phase proteins from the liver called CRP
o CRP serves as an opsonin for enhanced phagocytosis of bacteria
o People with heart failure will have higher levels of CRP
how are the first responders in mediating the clearance of necrotic tissue and/or invading organisms present at inflammatory sites?
macrophages (leukocytes)
the activation of macrophages leads to processes that recruit what to the site of inflammation?
neutrophils and monocytes (cells that mature to macrophages)
what are metalloproteinases?
proteins that degrade the BM to allow cell migration
what do macrophages secrete as a secondary even?
TIMPS (tissue inhibitors of matrix matalloproteinases) to downreg their activity
what is the stimulus for expression of p-selectin on the endothelium?
Induced by histamine
Lead to leukocyte rolling on endothelium
what is the stimulus for E-selectin expression on the endothelial cell surface?
Induced by TNF and IL-1
Lead to leukocyte rolling on endothelium
describe the effects of IL-1 and TNF on the vascular endothelium
Produces vasodilation –>contributes to low blood pressure
Induce fever –>modifies hypothalamus
list the integrins expressed on leukocytes
PSGL-1 –> p-selectin
Ligand:e-selectin –> eselectin
MAC-1 –> ICAM-1
LFA-1–> ICAM 1 or ICAM 2
name the counter molecules for VLA-4 and the effect of IL-1 and TNF on its expression
VLA-4–>VCAM 1
IL-1 and TNF will promote expression of VCAM-1 on endothelial cell surface
what are the members of the selectin family
P
E
L
where are L selectins expressed?
on circulting lymphocytes in a NON inflammatory state!
where are P and E selectin equally expressed?
activated endothelium
what activates p-selectin
histamine from mast cells because of C5a
what activates E selectin
TNF and IL-1
what are the functions of P and E selectin in inflammation
rolling
what is the important of cell rolling?
prolongs the duration of time to which leukocytes are exposed to chemoattractants and activators secreted into this inflammatory microenvironment
