Lecture 4 - Inflammatory Mediators I Flashcards
What do inflammatory mediators do? (4 things)
- activate cells
- localize process
- communicate between cells
- activate inflammation
List some cell responses that are activated (4):
- Expression of adhesion molecules
- Contraction of cytoskeleton (endothelial contraction, chemotaxis)
- Synthesis of arachidonic acid (aa) mediators
- Gene transcription (NFk-B, cell division)
Inflammation is largely local. Exceptions?
IL-1, IL-6, TNF are systemic
5 steps of evolution of inflammation:
- Vasodilation and increased vascular permeability
- Chemotaxis and cellular activation
- Phagocytosis
- Activation of immune processes
- Resolution and regeneration
The 4 types of mediators?
- Pre-formed (minutes)
- Plasma-derived (min-hours)
- aa-derived and chemokines (hrs-days)
- Cytokines and GFs (days-weeks)
Preformed mediators initiate inflammation in minutes. They are:
Histamine, serotonin, lysozymes
Plasma-derived mediators augment inflammation. They are:
Complement, kinins, coagulation factors
Arachidonic acid metabolites maintain inflammation, chemotaxis. They are:
Prostaglandins, leukotrienes, PAF (platelet activating factor)
Cytokines and chemokines primarily activate cells and intercellular signaling. They include:
Cytokines, interleukins, chemokines
yeah, ik this card kind of sucks.
Growth factors influence cell division and tissue regeneration. They include:
Colony-stimulating factors, growth factors (…)
Why are histamine and serotonin fast-acting?
Small (from single amino acid), diffuse rapidly, metabolize rapidly
Histamine comes from __________ and is derived from _______.
Mast cells and basophils; histidine
Serotonin comes from ______ and is derived from _______.
Platelets; tryptophan
What causes histamine release?
- Trauma, cold
- Cross-linking of IgE
- C3a, C5a complement receptors
- Factors from neutrophils, monocytes, platelets
- IL-1
What do histamine’s 4 receptors do?
H1: mediate inflammatory rxns and increase vascular permeability
H2: increase GI secretion
H3: CNS
H4: bone marrow and white blood cells
Why can anti-histamines make you drowsy?
Most block H1; cross-reactivity with H3 receptor (CNS)
List inflammatory responses to histamine (4):
- Vasodilation
- Increased venous vascular permeability (local tissue swelling)
- Stimulate pain, itching
- Contraction of smooth muscle (asthma - bronchial)
List some plasma-derived mediators (4):
minutes-hours (just a reminder)
- Coagulation proteins (Hageman/Factor XII)
- Complement (C3a, C5a, C3b)
- Fibrinolytic peptides (activation of plasmin)
- Kinins
What activates Hageman factor?
Local signals
- Negatively charged surfaces - basement membranes, collagen (like in a torn vessel)
- Bacterial LPS
- Enzymes (trypsin, plasmin)
What are general goals of plasma-derived proteins?
- Augment/maintain histamine response
- Coordinate coagulation, endothelial activation, leukocyte adhesion/migration, phagocytosis
Hageman factors is central to activating: (4 things)
- Coagulation
- Fibrinolytic pathways
- Kinin
- Complement pathways
What does plasmin do?
- Cleave fibrin, augment vascular permeability in skin and lung
- Generate C3a and C5a (also increase vascular permeability)
Also activate Hageman factor, kininogens, itself…response amplification.
What does the kallikrein/kinin system do?
Increase vascular permeability, smooth muscle contraction, dilate blood vessels, pain
What is thought to inactivate bradykinin?
ACE
Bradykinin levels increase with ACE-inhibitors (dry cough in ACE-inhibitor therapy)
What are anaphylatoxins?
C3a, C4a, C5a
- Mast cell, basophil degranulation
- Smooth muscle contraction
- Increased vascular permeability
Besides its role as an anaphylatoxin, what else does C5a do?
Chemotactic for PMNs
- Neutrophil degranulation
- Superoxide production
What is C3b good for?
Opsonization!
In inflammation, newly-synthesized products are either from _____ or _____.
- Lipids; membrane-released fatty acids (hours-days)
- New proteins (days to weeks)
New synthesis of cytokines begins…
18-72 hours
What produce cytokines?
Endothelial cells, monocytes (macrophages), lymphocytes, fibroblasts
Membrane fatty acids will yield:
Prostaglandins, leukotrienes, and platelet-activating factor
short-acting, local, metabolized quickly
What are the eicosanoids?
Prostaglandins, leukotrienes, thromboxanes
What are the two mechanisms for release of arachidonic acid?
- Direct action by phospholipase A2
- Phopholipase C, then diacylglycerol lipase
Cyclooxygenases transform aa to:
Prostaglandins and thromboxanes
Lipoxygenases transform aa to:
Leukotriene A…then further to LTB4 or LTC/LTD/LTE
Arachidonic Acid Derivatives in Inflammation
From macrophage:
PGE, PGF, PGD
Vasodilation, increased vascular permeability, enhance pain
Arachidonic Acid Derivatives in Inflammation
From neutrophil:
LTB4
Chemotaxis of neutrophils
Arachidonic Acid Derivatives in Inflammation
From mast cell:
LTC, LTD, LTE
Bronchoconstriction (asthma), vascular leakage
aka SRS-A’s
Arachidonic Acid Derivatives in Inflammation
From platelets:
Thromboxanes (TXA2)
Platelet aggregation, blood clotting
Arachidonic Acid Derivatives in Inflammation
From endothelial cells:
Prostacyclin (PGI2)
Anti-thrombotic
What is lipoxin (another aa derivative)?
Anti-inflammatory, late in inflammmation
Block LTC/LTD/LTE activity
Lipoxins can be formed from leukotriene precursors, or as product of ________
acetylated cyclooxygenase (aspirin therapy)
Aspirin inhibits prostaglandin synthesis and promotes lipoxin synthesis
What is PAF?
Platelet-activating factor
- acetylated lysophospholipid
- from mast cells, basophils, neutrophils, macrophages
What does PAF do?
Platelet aggregation/degranulation, histamine and serotonin release, increased vascular permeability, leukocyte adhesion, chemotaxis
