Acute References Flashcards
(52 cards)
- The bar graphs show levels of ICAM-1 and VCAM-1.
- WT (wild type) mice: Show high levels of ICAM-1 and VCAM-1 after injury (MCAo — a model of stroke).
- IL-1α/β⁻/⁻ mice (which lack the inflammatory cytokines IL-1α and IL-1β): Have much lower expression of ICAM-1 and VCAM-1 even after injury.
- This means IL-1 signaling is crucial for the vascular inflammatory response after injury.
- The role of IL-1:
- IL-1 (Interleukin-1) is described as a “key driver” of vascular inflammation.
Without IL-1α and IL-1β, the vascular system does not properly activate after injury — less expression of adhesion molecules, less inflammation.
- IL-1 (Interleukin-1) is described as a “key driver” of vascular inflammation.
Thornton et al 2010
Pentraxin-3, important in vascular remodelling is expressed in the brain after an acute injury and is driven by IL-1
If KO IL-1 then upregulation post stroke does not occur
If look at neurogenesis, it is impaired in KO PTX3 animals and compromises the formation of a glial scar, and reduces vessel lancities which are a measure of angiogenesis
Rodriguez-Grande et al 2014 and 2015
IL-1a promotes brain repair
Drives long-term neurogenesis and angiogenesis, if apply 3 days post stroke at a low dose, it promotes these
If delete IL-1a in microglial cells, the brain will impair the glial scar formation
Salmeron et al 2019 and Grayston et al 2025
Pathophysiology of ischaemic stroke
Moskowitz 2010
Sums up the evidence for inflammation across the life-course of stroke
Additionally showed that after COVID there is a increased risk of stroke, perhaps because the SARS binds to the vasculature causing damage/clots
Furthermore, natalizumab blocks leucocyte entry but is a neutral trial
Endres et al 2022
Looked at GP records in the UK, when someone has a RI or UTI, it increases the likelihood of stroke by 3x
Smeeth et al 2004
Injected mice with LPS and IL-1 found that it increased the ischaemic fallout by double
If give a IL-1 antagonist, this was abolished therefore is through an IL-1 dependent mechanism
Then depleted neutrophils using anti-PMN antibody and found that when neutrophils were depleted there was less brain damage compared to IL-1B without this depletion, therefore removing neutrophils protects the brain even when IL-1B is present
McColl et al 2007
Caused inflammation and then looked at the BBB tight junction marker Claudin 5 levels.
When there was no inflammation, recovery happened by 8 hours, increased levels of Claudin 5 back to normal
When there was inflammation, Claudin 5 levels remain disrupted for at least a day, worsening and prolonging BBB damage
McColl et al 2008
Gave pneumonia to mice who are co-morbid for vascular risk factors (obese insulin resistant metabolic syndrome rats)
Worsens the damage when give a stroke, damage is worse and BBB disruption is worse.
Platelets may drive this BBB damage as they adhere to the vasculature of the brain leading to increased damage but if block GP1B, it reduces damage- threfore unerlying inflammatory status worsens outcome
Denes et al 2014
Different molecules driving immune response post stroke, such as micrlglia and macrophage phenotyping and late adaptive immune response
Rayasam et al 2017
Anti-ICAM1 results
Fu et al 2015
Used Natalizumab onn 2 different models, filament occlusion and cortical, and showed that there were no overall effects.
It is an antibody for VLA-4 integrin preventing the binding of the neutrophil to VCAM
Llovera et al 2015
IL-1 is expressed early in the tissue after stroke, in 60 mins and then there is reperfusion in 4h
Luheshi et al 2011
If block IL-1 with IL-1Ra it retrieves both therapeutic concentrations in CCSF and blood and reduces damage by 50%
Geenhalgh et al 2010
IL-1Ra is still effective in the presence of co-morbidity
Used old-unhealthy mice and blocked the artery, gave antagonist and is still protective, suggesting IL-1 involvement
ALso measured the effects after 7 days rather than just 24 hours and was still protective when dosed 3 hours after stroke
Pradillo et al 2012
Cross lab study improving the power found that the drug was protective (IL-1Ra) in all treatment sites
Maysami et al 2016
Genetically manipulate receptors on the cells, deleted the signalling receptor for IL-1 and created mice where the receptor was removed from only brain endothelial cells subject to tamoxifen
The damage is less and BBB is less with improved behaviour
Wong et al 2018
TLR4 is important in man aspects of stroke so would be a good therapeutic target
Duran Laforet et al 2021
Aptamer DNA molecule to bind to TLR4 as a clinical trial is neuroprotective
In phase 2 study alonside endovascular thrombectomy had a positive effect
Fernandez et al 2018 and Meglio et al 2023
- Post-stroke cognitive decline
- Lots of B cells in the brain after stroke and then measure LTP, causes an effect
- If lack B cells there is improved memory and cognition- there are immune changes post stroke that change the outcome
Doyle et al 2015
Outline of thromboinflammation
De Meyer et al 2016
Thromboinflammation and Immunothrombis are bi-directional
and the neutrophil net example of them coming together
And the role of platelets becomming reprogrammed
Schrottmaier and Assinger 2024
VWF and ADAMS13 axis
Their role as primary haemostasis
Chen et al 2022
The role of VWF in platelet priming, affecting neutrophils and macrophages
Constantinescu-Bercu et al 2020 and Hottz et al 2022
