Term
| What are the 4 components of inflammation? |
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Definition
- Inducers - initiate the response. PAMPs and DAMPs
- Sensors - receptors for inducers
- Mediators - produced by sensors
- Target tissues |
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Term
What is the difference between PAMPs and DAMPs?
What recognizes PAMPs and DAMPs? |
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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. |
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Term
| What is the difference between acute and chronic inflammation? |
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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. |
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Term
| What are the responses to mediators in acute inflammation? |
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Definition
- vascular - vasodilation, increase in vascular permeability
- Cellular - neutrophil emigration
- Phagocytosis
- Killing/degradation
Remember --> Stimulus (inducer) --> bind to receptor --> release of mediators |
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Term
| How do you calculate whether a vessel has edema? |
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Definition
| (HPc - HPif) - (OPc - OPif). Arterial and venous end, positive = edema |
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Term
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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 |
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Term
| What are different kinds of adhesion molecules? |
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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 |
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Term
| What is a chemotactic factor are what are some major chemotactic factors? |
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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 |
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Term
| What are the three steps involved in phagocytosis? |
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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 |
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Term
What are mechanisms inside the phagolysosome?
Why is this a problem? |
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Definition
- Superoxides and myeloperoxidase
- cytotoxic enzymes
- Regurgitation of these substances or bursting due to urate crystals (gout)
- Colchicine prevents formation of the phagolysosome |
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Term
| What is required to be considered a mediator? |
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Definition
- produce inflammation alone
- increase in levels at site of inflammation
- drugs that inhibit the mediator activity reduce inflammation |
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Term
| What are the different types of mediators? |
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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 |
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Term
| What are the two pathways are complement, and how are they related to inflammation? |
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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 |
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Term
| How is bradykinin related to inflammation? |
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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. |
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Term
| How is the clotting system involved in inflammation? |
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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 |
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Term
How is histamine released?
Where does it bind? |
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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 |
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Term
| What is the triple response? |
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Definition
Inflammatory effects of histamine:
- Redness
- Wheal/edema
- Flare
- release of prostaglandins, expression of adhesion molecules/P-selectins |
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Term
| What is substance P and what targets it? |
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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 |
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Term
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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 |
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Term
| What is the difference between COX-1 and COX-2? |
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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. |
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Term
| How are leukotrienes synthesized? |
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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 |
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Term
| Which drugs are CysLT1 receptor antagonists? |
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Definition
Singulair - Montelukast
Accolate - Zafirlukast
Zyflo - Zileuton |
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Term
| What role does platelet activating factor play in inflammation? |
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Definition
Released from basophils, activates platelets
Greater vasodilation ability than histamine. Chemotactic agent. |
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Term
| What role does nitric oxide play in inflammation? |
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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 |
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Term
| What are cytokines and what are their properies? |
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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 |
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Term
| What is the tumor necrosis factor and what role does it play? |
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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. |
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Term
| What is IL-1's significance? |
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Definition
IL-1 beta is circulating, similar to TNF. Also activates NFkB
Does everything TNF does plus induces fever. |
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Term
| What is the importance of IL-6? |
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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. |
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Term
| What is thought to be the mechanisms for resolution of inflammation? |
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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 |
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Term
| What are the cardinal signs of inflammation? |
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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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