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Printable Handouts
Navigable Slide Index
- Introduction
- Overview
- Asthma in the Western world
- Asthma Pathophysiology: a T2-driven eosinophilia
- Effect of topical corticosteroids in asthma
- Th2-driven inflammation defines major subphenotypes of asthma
- Why not just increase ICS/OCS doses?
- Severe asthma: the problem
- Marije Kootstra, aged 17 years, The Netherlands
- Asthma Can Remain Uncontrolled Despite ‘Optimal’ Therapies
- T2-directed biologicals
- Possible reasons for relative steroid insensitivity
- A large percentafe of asthmatics are not adherent to ICS
- The Glucocorticoid Receptor
- Steroid insensitivity seen in different cells/tissues in severe asthma
- GR-response signature in U-BIOPRED
- GR nuclear expression and import in cells from severe asthmatics
- Endobronchial Biopsy GR expression levels
- Functional consequences of patient characteristics
- Sputum Importin 7 expression levels (U-BIOPRED)
- Reduced HDAC and increased HAT activity in asthmatic children
- Absence of PI3Kd but not g activity restores steroid sensitivity
- Targeting PI3K
- I-BET suppresses TGFβ+FCS-induced ASM cell proliferation
- Oxidative stress in airways disease and steroid function
- Oxidative stress reduces steroid responsiveness
- Smoking and steroid responses in asthma
- Reduced GR nuclear translocation
- p38 MAPK activity and steroid sensitivity in BAL macrophages
- Targeting p38 MAPK restores steroid sensitivity in COPD macrophages
- Infection is associated with steroid insensitivity
- RV16 infection attenuates steroid function
- RV16 infection reduces GR nuclear import
- Inflammatory phenotypes in patients with severe asthma
- Superantigens
- The effect of azithromycin on asthma exacerbations
- The JAK-STAT signalling pathway: steroid-insensitive inflammation
- Janus kinase (JAK) activation
- IFN-stimulated gene expression
- Up-regulation of Th1 IFN signature in severe asthma sputum
- IL-6 trans-signaling
- Bioinformatic analysis
- Summary
- Summary and conclusions
- Treatment options in type 2 low asthma
- Acknowledgements
Topics Covered
- Asthma pathophysiology
- The use of corticosteroids
- Reasons for steroid resistance or insensitivity
- Methods to improve steroid efficacy in severe asthma
- Mechanisms that induce steroid insensitivity
- Problems occurring due to oxidative stresses
- Novel anti-inflammatory approaches
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Adcock, I. (2022, January 31). Steroid resistance in asthma: mechanisms and potential therapies [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 6, 2024, from https://doi.org/10.69645/UVIR4393.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Ian Adcock has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Pharmaceutical Sciences
Transcript
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0:00
Hello. In this talk,
we will discuss the mechanisms that drive relative steroid resistance in asthma,
and how understanding these mechanisms may lead to potential therapies.
0:12
As an overview, we will discuss
the distinct types of inflammation that we see in asthma,
and how these may determine a steroid response. So, we know that,
for example, T2 asthma is associated with steroid-responsive asthma.
We'll talk about the factors that influence steroid function in severe asthma;
how to use the inhaler correctly;
what are the effects of oxidative stress or infections on relative steroids responses,
and also look at approaches to severe asthma therapy or improving steroid function,
and how new drug combinations may improve
relative steroid resistance, or give insight into potential novel anti-inflammatory drugs.
0:54
Asthma is characterized by chronic airway inflammation.
Patients with asthma have a history of respiratory symptoms,
such as disease,
breathlessness, chest tightness, and coughing.
They also have physiologically variable airflow limitations.
In the UK, for example,
there are over 5 million people who suffer from asthma,
a quarter a million of whom have severe disease.
The National Health Service spends over 1 billion pounds
a year treating and caring for patients with asthma.
This failure to treat patients effectively means we are still
getting 1,100 patients dying from asthma.
These deaths, and also hospitalizations for exacerbations are preventable.
1:38
If we look at the airways of an asthmatic patient here in the lower panel,
we can see the various features that characterize asthmatic airways,
such as mucus plugging,
airway remodeling associated with increased airway smooth muscle, and
mucous glands, which account for the increase mucous plugging.
There's a denuded or altered epithelium and a thickened basement membrane.
In allergic asthma, we know that exposure to an allergen causes epithelium,
for example, to be activated,
which can result in the production of mucus.
We see changes even in very young children that reflect this impact of allergen.
The activated epithelial cell can also impact
mast cells causing degranulation and the release of bronchoconstrictor agents.
We also see the activated epithelium releasing
factors that can impact mast cell activation,
and also affect the activation and state of macrophages and airways dendritic cells.
The combination of activation of these cell types
leads to the production of a classic Th2 induced
inflammatory response characterized by the presence of Th2 cytokines,
such as IL-4, 5, and 13,
and the release of eosinophil chemoattractants and into the systemic blood.
This allows eosinophils to be recruited from
the bone marrow into the airways where they release factors that are
important for controlling airway hyper-responsiveness
and other remodeling factors associated with asthma.