Physiology of Inflammation Flashcards
What are the 3 phases of inflammation?
INITIATION:
- stimulus + recognition = local production of inflammatory mediators
PATENT INFLAMMATION PROCESS:
RESOLUTION:
- Local dilation of capillaries = increased blood flow
- Microvascular structural changes and plasma proteins escape from blood
- Leukocytes accumulate at injury site
RESOLUTION:
- Removal of stimulus
- Inhibitory feedbacks and counter-balanced cellular and humour response
- Repair and if adaptive immunity engaged we get memory development
What are the 2 ways inflammation is defined?
1- Morphological pattern
* Serous inflammation
* Fibrinous inflammation
* Haemorrhagic inflammation
* Suppurative (purulent) inflammation
*Necrotising (gangrenous) inflammation
* Ulcers
2- Classification of inflammation
* Acute – fast onset, prominent signs, mild outcomes and self-limited
* Chronic – slow onset, less prominent signs & severe outcomes and progressive disease
Describe the steps in the key inflammatory process. (8)
1- Stimulus occurrence
2- Stimulus recognition
3- Vasodilation
4- Vascular permeability changes
5- Cell recruitment
6- Cell activation
7- Cell extra-vasation
8- Repair/resolution
What are different ways in which non-self antigens can be indentified?
1- Humoral factors
* Complement system * Antibodies *Other proteins e.g. LBP
2- Innate cell recognition (mostly due to immune cells)
* PRRs
* complement and antibody
responses
3- Adaptive immuno-recognition
* Specific responses (depending on individual immune history)
How is a stimulus recognised innately?
- PRRs (pattern recognition receptors) detect:
1- PAMPs (pathogen-associated molecular patterns)
2- DAMPs (damage-associated molecular patterns)
3- LAMPs/MAMPs,
(lifestyle- and metabolism- associated molecular patterns)
4- SAMPs, (self/suppression-associated molecular patterns)
What do the different PRRs detect?
TLRs - anything
CLRs ( c-type lectin) - fungi
RLRs - viral RNA
NODs - bacteria
What do we mean by homeostasis of inflammation?
We need more SAMPs than DAMPs to return back to normal and inflammation to stop.
What happens once the stimulus has been recognised?
Initial mediator release (at first locally)
What causes vasodilation?
- Mainly due to Histamine and NO, released by Mast cells and macrophages
1- Why does vascular permeability change?
2- Vasodilation and vascular permeability increase causes what to happen?
1- Mainly due to Histamine, released by Mast cell
2- Endothelial cells retraction and rearrangement of tight-junctions, forming gaps between them and allowing fluid exudation - Loss of protein leads to oedema (swelling)
What are the mediators of inflammation?
hints:
- Amines
- Lipids
- Peptides+ Proteins
- Small molecules
Where is histamine released from?
What is its function in inflammation?
What does it bind to?
Histamine has great importance in…
– Released from mast cells
–> dilate blood vessels + increase microvascular permeability
-> G-protein coupled receptors (H1)
-> Asthma and allergies
How are lipids mediators of inflammation?
- Cell undergoes Inflammatory stimuli:
Phospholipid targeted by
phosphorylated Phospholipase A2 = Arachidonic acid (omega 6 fatty acid) + Lyso-glyceryl phosphorylcholine - Arachidonic acid (AA) is a precursor to several pro-inflammatory lipid mediators, including prostaglandins and leukotrienes.
- Lyso-glyceryl phosphorylcholine acts as an intermediate in Platelet activating factor formation
What cells produce PAF? (5)
- How is it made?
Platelets, mast cells, neutrophils, macrophages, endothelial cells
-> Enzymatic conversion of lyso-PAF to PAF through acetylation.
When platelet activation factor binds to PAF-receptors what happens? (7)
(PAF is a potent mediator of inflammation)
1- Strong Vasodilation + vascular permeability more potent than Histamine
2- Bronchoconstriction
3- Platelet aggregation and degranulation
4- Leukocyte chemotaxis, extravasatio
5- Promote Neutrophil oxidative burst
6- Increase production of eicosanoids by inducing
Cox2 transcription
7- Increase transcription of IL6, MMPs, iNOS
What are Eicosanoids? Docosanoids?
What is significant about Eicosapentaenoic acid?
- Eicosanoids = lipid molecules derived from arachidonic acid, a 20-carbon polyunsaturated fatty acid.
- Docosanoids, as the name suggests, are derived from docosahexaenoic acid (DHA) 22 carbons
> Includes molecules such as resolvins, protectins and Maresins - EPA, while also an omega-3 fatty acid, is a 20-carbon molecule, so it does not fit into either the eicosanoid or docosanoid categories.
> Includes Resolvins
What molecules are derived from Aracadonic acid? “Eicosanoids”
1- Epoxy-Eicosa Tetraenoid acids (EETs)
2- Prostaglandins, Prostacyclins and Thromboxanes
3- Leukotrienes
4- Lipoxins (anti inflammatory)
5- “Isoprostanes due to oxidative stress”
How are Ecosanoids produced?
-
Consumption of essential fatty acids:
a-linolenic acid (omega-3 fatty acid) and linoleic acid (omega-6 fatty acid)
Why are EPA and DHA important?
- Omega 3 fatty acids involved in the production of anti-inflammatory molecules.
- Promote healing after danger removed
> DHA: resolvins, maresins, protectins
> EPA: resolvins
What does the effect of Eicosanoids depend on? (2)
1- Half life
2- Type of receptors they interact with … therefore the type of cells and tissues
True/False Eicosanoids are fundamentally important in mediating inflammatory response locally and systemically but also important in physiological daily mechanisms?
TRUEEEEEE
Each cell type has a different set of eicosanoids synthetic enzymes, what does this mean?
- Specific enzymes expressed by the cell determine which type of eicosanoid IS synthesized. (each cell type has a different set of eicosanoids receptors/responses)
- Ensures that eicosanoids are generated in response to specific physiological needs and helps maintain tissue and systemic homeostasis.
We need to maintain equilibria of Eicosanoids. (we have intrinsic regulatory mechanisms and delicate equilibria to contain their effects)
- PGE2 is produced by mast cells and macrophages what contains the effect of PGE2?
Prostacycline PGI2 produced by vascular cells
PGI2: PGI2 has anti-inflammatory properties
PGE2: PGE2 has a more complex role in inflammation.
The thromboxane produced by platelets, TxA2 is unstable and hydrolysed to TxB2 becomes inactive.
What is TxA2 physiological antagonist?
The prostacyclin PGI2
opposite effect to regulate systemic blood pressure and thrombogenesis