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Inflammatory response and immune Rxns
Lecture 2
30
Pharmacology
Professional
08/23/2012

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Term
What are the 4 components of inflammation?
Definition
- Inducers - initiate the response. PAMPs and DAMPs
- Sensors - receptors for inducers
- Mediators - produced by sensors
- Target tissues
Term
What is the difference between PAMPs and DAMPs?
What recognizes PAMPs and DAMPs?
Definition
PAMPs are pathogen associated, which DAMPs are damage associated and come from endogenous material. DAMPs are NOT released from cells undergoing apoptosis
Toll-like receptors - recognize PAMP and DAMP, activate NFkB in response.
Term
What is the difference between acute and chronic inflammation?
Definition
- acute - short duration, emigration of neutrophils. Increase in vascular permeability is the hallmark --> swelling/pain
- Chronic - longer duration, emigration of lymphocytes, plasma cells, and macrophages. Tissue destruction is a major hallmark.
Term
What are the responses to mediators in acute inflammation?
Definition
- vascular - vasodilation, increase in vascular permeability
- Cellular - neutrophil emigration
- Phagocytosis
- Killing/degradation
Remember --> Stimulus (inducer) --> bind to receptor --> release of mediators
Term
How do you calculate whether a vessel has edema?
Definition
(HPc - HPif) - (OPc - OPif). Arterial and venous end, positive = edema
Term
What is extravasation?
Definition
Movement of leukocytes from plasma to site of inflammation. Leukocytes recruited in the postcapillary venule.
Adhesion molecules completely necessary:
- Selectins used for rolling
- Integrins used for firm adhesion
Term
What are different kinds of adhesion molecules?
Definition
- Selections - upregulated by cytokines, L-selectin on leukocyte and E & P-selectin on endothelium. Initiates rolling.
- Integrins - on leukocytes, used in firm adhesion to endothelium. Binds to ICAM/VCAM receptor (upregulated by cytokines). PECAM receptor - trans-migration.
- Immunoglobulin-like - ICAM/VCAM and PECAM
- Mucin-like
Term
What is a chemotactic factor are what are some major chemotactic factors?
Definition
Chemotaxis - locomotion along a chemical gradient. Chemokines allow binding to integrins
- Leukotrienes - in pulmonary (LTB4)
- Complement C3a and C5a
- Cytokines that stimulate movement - IL8
Term
What are the three steps involved in phagocytosis?
Definition
- Recognition/attachment - opsonins. Neutrophils early, macrophages late. Fc allows antibody/antigen complex to attach, also C3b
- Engulfment - phagosome merges with a lysosome = phagolysosome
- Killing/degradation - goal is the killing of engulfed material
Term
What are mechanisms inside the phagolysosome?
Why is this a problem?
Definition
- Superoxides and myeloperoxidase
- cytotoxic enzymes
- Regurgitation of these substances or bursting due to urate crystals (gout)
- Colchicine prevents formation of the phagolysosome
Term
What is required to be considered a mediator?
Definition
- produce inflammation alone
- increase in levels at site of inflammation
- drugs that inhibit the mediator activity reduce inflammation
Term
What are the different types of mediators?
Definition
- Plasma derived - complement c3a, c5a, c3b. Bradykinin. Thrombin, fibrinopeptides, plasmin
- Cellular:
- Preformed - histamine, serotonin, lysosomal enzymes, Substance P
- De Novo/synthesized - prostaglandins, leukotrienes, PAF, nitric oxide, cytokines
Term
What are the two pathways are complement, and how are they related to inflammation?
Definition
- Classical - all 9 steps activated eventually leading to cell lysis
- Alternative - C3b acts as an opsonin
- C3a/C5a are both inflammatory, C5a much more powerful. Chemotactic agents that increase affinity of integrins
Term
How is bradykinin related to inflammation?
Definition
Produces all the cardinal signals of inflammation. Much more powerful than histamine.
B2 receptors cause vasodilation and increase in vascular permeability
B1 receptors are upregulated by IL-1 and TNF and contract bronchial tissue, release PGs and cytokines.
Term
How is the clotting system involved in inflammation?
Definition
The Hageman factor (12) is activated when coming to contact with a negatively charged surface. Activates a cascade leading to thrombin
- Thrombin - inflammatory, produces fibrinopeptides (increases vascular permeability) and adhesion molecules
- Kallikrein cleaves C5 to C5a - inflammatory complement protein
- plasmin cleaves C3 to C3a - inflammatory complement protein
- Xa - inflammatory
- fibrinolytic - complement activation
Term
How is histamine released?
Where does it bind?
Definition
Mast cell degranulation - allergen binds to IgE antibodies, granules released. Also found in basophils.
H1 receptors - vasodilation of arterioles, vascular permeability in post-capillary venules
H2 - vasodilation, effects in the gut in gastric acid
Term
What is the triple response?
Definition
Inflammatory effects of histamine:
- Redness
- Wheal/edema
- Flare
- release of prostaglandins, expression of adhesion molecules/P-selectins
Term
What is substance P and what targets it?
Definition
A neuropeptide synthesized by cell body of a sensory neuron.
- released from type C fibers to transmit pain signal
- released from sensory nerves as an inflammatory effect
Capsaicin acts on substance P
- all the typical responses of inflammation
Term
What are eicosanoids?
Definition
Autocoids - do not act systemically
- Prostaglandins - PgI2 on endothelium, TxA2 on platelets. IL-1 produces fever.
- Leukotrienes - in pulmonary
Formed from phospholipase A2 --> arachidonic acid
Term
What is the difference between COX-1 and COX-2?
Definition
- Cox1 - constitutively expressed, do not want to inhibit. Used in the GI, renal, platelet, BV. Protective in the stomach, increase filtration in the kidney, TxA in the platelet.
- Cox-2 - induced, want to inhibit. Induced by TNF, Il-1. vasodilation of BVs. No role in the stomach.
Term
How are leukotrienes synthesized?
Definition
5-LO is only active in the presence of FLAP - 5-LO/FLAP complex necessary for leukotriene synthesis
LTB is chemotactic, upregulates adhesion molecules while..
LTC/LTC/LTE bind to CtsLT1 receptor in lung - eosinophil migration, asthma
Term
Which drugs are CysLT1 receptor antagonists?
Definition
Singulair - Montelukast
Accolate - Zafirlukast
Zyflo - Zileuton
Term
What role does platelet activating factor play in inflammation?
Definition
Released from basophils, activates platelets
Greater vasodilation ability than histamine. Chemotactic agent.
Term
What role does nitric oxide play in inflammation?
Definition
iNOS - inducible in macrophages, activates by cytokines and IL-1
Produces free radicals that damage tissues, and L-citrulline is important in RA
- Induction of COX-2 and increase in cytokines. Can be highly toxic due to ATP depletion
Term
What are cytokines and what are their properies?
Definition
Small signalling molecules released during acute and chronic inflammation.
Usually affect a receptor
Can be pro or anti inflammatory. Beneficial at low levels, but cause harmful effects when out of balance.
Acute inflammation: TNF, IL-1, IL-6, IL-8
Anti-inflammation: Il-4, IL-10, IL-13
Term
What is the tumor necrosis factor and what role does it play?
Definition
Involved in disease early. Released in soluble form. Leads to increased formation of NFkB.
Increases formation of other cytokines (Il-1, etc), activates osteoclasts, destroys cartilage via chondrocytes/MMPs, accumulates leukocytes via chemokines.
Term
What is IL-1's significance?
Definition
IL-1 beta is circulating, similar to TNF. Also activates NFkB
Does everything TNF does plus induces fever.
Term
What is the importance of IL-6?
Definition
Activates B cells. Stimulated by IL-1 and TNF. Acts on liver to release CRP and fibrinogen
TNF, IL-1, and IL-6 are all drug targets.
Term
What is thought to be the mechanisms for resolution of inflammation?
Definition
Not passive!

Anti-inflammatory cytokines?
Soluble TNF receptors break off and prevent TNF from causing harmful effects
- Lipid Mediator class switching via LPO - arachidonic acid and omega 3's
- Cholinergic anti-inflammatory pathway - inhibit NFkB, no cytokines produced. Vagal stimulation interferes with NFkB --> nAcHR receptor
Term
What are the cardinal signs of inflammation?
Definition
rubor (redness), tumor (swelling), calor (heat), dolor (pain) and loss of function.
- Vasoconstriction initially followed by vasodilation - rubor and calor
- Increase in permeability - Tumor and dolor with leakage
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