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Steroid resistance in asthma: mechanisms and potential therapies
Published on January 31, 2022 46 min
A selection of talks on Respiratory Diseases
Molecular epidemiology of lung cancer
- Prof. David Christiani
- Harvard School of Public Health and Harvard Medical School, USA
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- Dr. Carla A. Da Silva
- AstraZeneca, Sweden
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.
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.
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.
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.