MOD 2 Inflammation

Question 1

Explain signal transduction pathway through TLR-4 in response to LPS

Answer 1

Binding to TLR-4 leads to TIR (Toll-interleukin 1 receptor) activation –> adaptor protein recruitment. 2 pathways:
1. Myd88 adaptor protein –> Myd88 dependent pathway - activation of NF-kB leading to pro-inflammatory gene expression

2. Myd88 independent pathway: TRIF adaptor protein leads to Type 1 IFN gene expression again through NF-kB activated gene expression

Question 2

Sterile inflammation: Clinical significance

Answer 2

Graft rejection
Ischaemia-Reperfusion injury
Systemic response to burns/trauma - ARDS

Question 3

Sensors within innate inflammatory response

Answer 3

Within ECM: Complement, Mannose binding lectins, natural antibodies
Cell membranes: TLR, scavenger receptors
Cytoplasm: 
Nod-like receptors
RIG-like receptors

Question 4

What is danger theory

Answer 4

Generic host response to normally hidden molecules - DAMPS (e.g. ATP/DNA - usually intracellular)
Overlap with PAMP recognition molecules - e.g. HMGB1 is a DAMP that can activate the LPS receptor

Question 5

Pleitropy

Redundancy

Answer 5

Pleitropy: Producing more than 1 effect in a given tissue
E.g. TNF-a:
induces pro-inflammatory cytokine release
Induces release of NO and ROS

Redundancy: Multiple cytokines may produce the same effect in a given tissue
E.g. IL1, IL6 & TNF-a all involved in NO and free radical release

Question 6

How does a chemokine induce neutrophil recreuitment

Answer 6

Chemokine gradient - neutrophil travels towards increasing concentration
Normally neutrophils internalise the chemokine to limit recruitment.
However, neutrophils treated with inflammatory soup lose this ability –> idea of loss of regulation in inflammatory states

Question 7

Explain TNF-a biology

Cleavage, receptors, ligand passing

Answer 7

TNF-a is membrane bound
Cleaved to soluble form by TACE (TNF-a converting enzyme)
Receptors: p55 (deleterious) and p75 (protective)
‘Ligand passing’ - p75 higher affinity. TNF binds p75 and it then passes it to p55.
TNF - example of pleitropy! 2 receptors effect different actions in a given cell

Question 8

How can coagulation initiate inflammatory response?

Answer 8

Serine proteases involved in coagulation (e.g. thrombin) cleave part of the PAR (protease activated receptor)
Active PAR then induces pro-inflammatory gene expression

Question 9

Factors involved in regulating coagulation

Answer 9

Tissue Factor pathway inhibitor
Anti-thrombin III
Thrombomodulin
Protein C complex receptor (receptor for APC which inactivates Va and VIIIa
Glycocalyx (it binds antithrombin)

Also:
Endothelium expresses tissue-type plasminogen activator which increases plasmin levels (anti-fibrinolytic)

ATPases that breakdown ATP to prevent platelet aggregation

Question 10

Type 1 vs Type 2 endothelial activation

Answer 10

Type 1 endothelial activation
Quick, reversible, INDEPENDENT on gene expression
Histamine/PAF/thrombin bind G-protein coupled receptor. Ca2+ release from ER.
This activates myosin which pulls adherins junctions apart
Also release of PGI2, PAF and NO

Type 2 endothelial activation
Sustained, potent, DEPENDENT on gene expression
IL-1/LPS/TNF signalling induces up-regulation of inflammatory gene expression via NF-kB
Also COX-2 expression –> greater prostaglandin expression
More substantial leukocyte extravasation

Question 11

Epigenetics definition

Answer 11

Heritable changes in gene expression that occur without a change in DNA sequence