Acute Inflammation 3: Lecture 9 Flashcards
What are the actions of soluble mediators
Conductors of the AI cycle are?
Conductors of the AI cycle:
Switches➡ turn inflammatory response on and off eg leukocyte activation
Messengers:
-control the actions of cells eg chemoattractants
-blood vessel responses- arteriolar constriction, vasodilation, vascular permeability
-stimulate pain
Usually endogenous (Endogenous substances are those that originate from within an organism, tissue, or cell).
- released from cells in the area (preformed or synthesized)
- activation of circulating substances
Describe the acute inflammation cycle on slide 6
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Plasma Protein cascade:
What is the 3 interrelated protease cascades involved in protein cascade? And their function?
Activated Hageman Factor is the Key, what is it and what activates it?
Activated Hageman Factor initiates four systems: what are they?
What is the main link between the coagulation system and inflammation?
What is the link between the Kinin cascade, clotting cascade and complement cascade?
Slide 9
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Kinin cascade, coagulation cascade, complement cascade. They are 3 plasma proteins (enzymes) that circulate in their inactive state and need to be activated. When they are they:
- activate nflammatory cells
- recruit other soluble mediators
- amplify the AI system,
Coagulation factor 12 (Hageman factor) is a plasma protein and forms part of the coagulation cascade.
It is activated by vessel damage, bacterial toxins, -Ve charge surfaces (collagen) and soluble mediators eg plasmin.
Activated Hageman Factor initiates four systems:
1. Kinine cascade
2. Clotting system
3. Fibrinolytic system
4. Complement system
Thrombin is the main link between the coagulation system and inflammation
- fibrinogen➡ fibrin
- major coagulation protease
What is the link between the Kinin cascade, clotting cascade and complement cascade? Factor 12
Slide 10
Plasma Proteins: The Kinin Cascade
Need to know bradykinin and its role in blood vessels and pain?
Kinin system:
- Generates vasoactive peptides from plasma proteins (kininogens) by the action of specific proteases (kallikreins)
- Activation of the Kinin system ➡ bradykinin➡ short lived ➡inactivated by kininase
- increases vascular permeability
- contraction of smooth muscle
- dilation of blood vessels
- pain - Kinin system is activated by Hageman factor 12 and kallikrein itself is a potent activator of Hageman factor
Bradykinin is a peptide that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to lower.
Has been correlated to the production of pain
Plasma proteins: Clotting Cascade
What’s the function of fibrin in the system?
And fibrin degradation products?
Fibrin:
- ⬆wbc adhesion
- scaffold for white blood cells
- “glue” to trap foreign agents
- fibroblast proliferation
- collagen production
Fibrin degradation products:
- ⬆vascular permeability
- ⬆leukocytes in Exudates
- ⬆chemotaxis (esp. Neutrophils)
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Plasma proteins: Complement Cascade
Biologic functions of the complement system (cell lysis by MAC or the effects of proteolytic fragments of C)
- Vascular phenomena
- anaphylatoxins= C3a, C5a, C4a
- C5a activates the lipoxygenasevpathway of AA in neutrophils and monocytes - Leukocyte adhesion, chemotactic agent for neutrophils, monocytes, eosinophils, basophils
- Phagocytosis
- C3b and its cleavage product iC3b act as opsonins when fixed to the bacterial cell wall
C5a, C3a: Inflammation
-recruitment and activation of leukocytes ➡ destruction of microbes by leukocytes
C3b: Phagocytosis
-recognition of bound C3b by phagocyte C3b receptor ➡Phagocytosis of microbe
MAC: lysis of microb (membrane attack complex)
Cell derived Soluble Mediators:
Vasoactive Amines
What are the preformed mediators in secretory granules and their function?
Histamine is released by mast cells when?
Histamine and serotonin
- arteriolar dilation
- extra-vascular sm contraction
- ⬆ venule permeability via rounding up of endothelial cells
- pain (serotonin)
- chemoattractants for eosinophils (histamine)
- rapidly degraded
- Neuropeptides
- similar role to these vasoactive amines
- small peptides within the CNS and PNS
Histamine is released by mast cells when?
- Physical injury (trauma, heat, cold)
- Immune reactions (binding of Ab)
- Fragments of complement (anaphylatoxins)
- Histamine-releasing proteins derived from leukocytes
- Neuropeptides (substance P)
- Cytokines (IL-1, IL-8) (small proteins important for cell signalling)
Histamine is released when C3a C5a diffuse to mast cells, bind, then granules within mast cells fuse with cell membrane releasing inflammatory mediators like Histamine.
Arachidonic acid metabolites (Eicosanoids)
Lipoxins=
- inhibit leukocyte recruitment
- inhibit neutrophil chemotaxis
- inhibit neutrophil adhesion
- negative regulators of LTs
Resolvins=
- inhibit leukocyte recruitment
- inhibit leukocyte activation
Cytokines
Major cytokines that mediate inflammation:
What’s their most important actions?
•Large family of small molecular weight protein messengers
•Can activate leukocytes and are produced by leukocytes after activation
•Can act locally or at long distances
•Major cytokines that mediate inflammation:
–IL-1, IL-6, TNFa
–produced by activated MØ
–stimulated by bacterial endotoxin, immune complexes,
–physical injury, other soluble inflammatory stimuli
•Most important actions
–1. endothelial activation
–2. leukocyte activation
–3. fibroblast recruitment
–5. priming of neutrophils
•Induce the systemic acute-phase responses
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The acute phase response
Slide 17
Pattern recognition receptors
•Sensors of microbial infection (bacteria, virus, parasites)
•Recognise conserved molecular patterns of microbes
–e.g. cell membrane LPS, DNA, RNA
•PRR activation:
• inflammatory mediators
•TNF, IL-1, IL-6, IL-8, COX-2
• phagocytosis (macs., neuts.)
•bacteria
• Th1 lymphocyte response
•viruses
– chemokine receptors and chemoattractants
•Toll-like receptors (TLR)
–The first PRR to be described
–TLR 4 is the classic example; binds LPS
- Why are soluble mediators important in AI?
- Describe the plasma protein cascades & their roles in AI
- Name 3 products of the complement cascade and describe their roles in AI.
- What are the main eicosanoids & how do NSAIDs & corticosteroids inhibit this system?
- What are the functions of 2 major vasoactive amines and where do they come from?
- What is the acute phase response and what cytokines are involved?
- What are pattern recognition receptors and why are they important in AI? Give an example
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