The challenges to finding a cure to asthma
According to the World Health Organization, asthma currently affects 300 million people worldwide and will reach 400 million by 2025. In Europe, asthma is one of the most common non-transmittable chronic diseases. Its prevalence varies between different geographic regions (3-18%) and in ethnic groups. With 9% of its population suffering from he affliction, the UK ranks first in Europe, whilst Australia, with 11%, ranks highest in the world. Among the ethnic groups, the Maori (New Zealand) have the highest incidence with in excess of 20% being sufferers.
The economic and social impact is underestimated by both the public and in politics. In 2016, the EU Symposium on the Awareness of Allergy summarised that approximately 45% of patients are misdiagnosed and therefore received the wrong therapy within the EU. In 2015, the Asthma and Allergy Foundation estimated the healthcare costs in the US as $51bn (~€42bn).
In Europe, the costs were reported as being €19.6bn in 2016. The UK Asthma Foundation presented that three people per day die from asthma on average, and the World Health Organization stated that the difficulty to define it as a cause of death makes it likely that this number is underestimated. This is the problem: there isn’t any single objective test or method of classification that allows diagnosis without any doubt.
Inhaled anti-inflammatory glucocorticoids and muscle relaxing long acting ß2-agonists are the most frequently prescribed drugs for asthma patients to control symptoms. For allergic asthma, there are recently developed anti-IgE and anti-IL-5 antibodies available which lastingly limit inflammation. Other neutralising antibodies specific to other asthma-relevant cytokines are in the test phase. Most of these drugs reduce inflammation and thereby improve symptoms. However, none of these drugs have any proven effect on airway wall remodelling.
What is asthma?
The clinical symptoms are:
- shortness of breath;
- airway hyper-reactivity;
- chest tightness; and
Furthermore, asthma attacks can be triggered by a wide range of factors, of which are present in the environment, such as:
- plant pollen;
- animal hair;
- dust or ashes; and
- physical or psychological stress.
Asthma: an ever-changing environment
Today we have some understanding of the mechanisms of how allergens or dust cause asthma, but we have little knowledge of how changes in air humidity or any kind of stress result in the condition. In order to find better indicators, two approaches have been taken:
- Classifying asthma into sub-types based on clinical characteristics of the patients; and
- Classifying asthma by the pathologies presented in the lung, such as remodelling and/or inflammation.
Following the first strategy, several studies sub-divided asthma into different phenotypes by combining clinical data, such as age, gender, lung function, presence of certain immune cell types, obesity, or response to drugs, etc. It is questionable if the results can be generalised as some data indicated that these markers vary in different ethnic groups or geographic locations. The second approach needs invasive sampling which is hindered by ethical approval. Thus, there is a lack of patient data to support classification according to tissue pathologies.
However, the available data indicated that some patients may have extensive airway wall remodelling while others have none of a very mild form. These variations may be due to a patient’s pre-condition, therapies, or severity.
Chronic airway inflammation
For a long time, it was assumed that chronic airway inflammation causes all other asthma pathologies. Chronic airway inflammation in asthma is described as the shift from ‘Th-1’ to ‘Th-2’ cytokines (IL-4, IL-5, IL-13) which induce:
- immune-cell infiltration;
- airway hyper-responsiveness; and
However, neither existing anti-inflammatory drugs nor those developed to limit Th-2 cytokine effects achieved the expected results, and may only be helpful for a small subset of patients.
Other clinical studies suggested that Th-9 cells, TReg-cells, NKT cells, γδ-cells, CD8 T-cells, or Th-17 immune cells lead to asthma, and the corresponding animal models confirmed their link to other relevant cytokines including TGF-β, IL-6, IL-21 and IL-23. The future has to show if limiting the action of any of these cell types will cure the affliction.
The hypothesis that chronic airway inflammation causes asthma is now being challenged by an increasing number of studies reporting that remodelling occurred without or before inflammation. Investigations into this area are most often rejected with the argument that there were insufficient data to support such claims. In 2016, the American Thoracic Society recognised this lack of information on airway wall remodelling in asthma, and emphasised the need to support respective studies in order to find new therapies.
In childhood asthma, wheezing correlated with airway wall remodelling without any sign of inflammation. In adults, the inhalation of an allergen or a cholinergic substance triggered airway wall remodelling within eight days. New animal models which respond to allergens with airway wall remodelling support the hypothesis that inflammation and remodelling are two independent parallel events in asthma.
These studies provided evidence that remodelling and inflammation can be initiated by well-known asthma triggers, which are present in the environment, through mechanisms assigned as epigenetic events. Literally, epigenetic means ‘above or on top’ of genes; it therefore describes the modification of gene products by the environment without changing the genes.
How can an asthma cure be discovered?
In order to find a cure, it is essential to understand how the pathologies described above – inflammation and remodelling – interact and lead to asthma. Together with our colleagues from Australia, China, Canada, Greece, and the Netherlands, we have been studying primary human tissue formations of airway wall cells obtained from asthma patients. The investigated cell types included epithelial cells, fibroblasts and smooth muscle cells. In these cells we described new disease specific alterations of cellular signalling, extracellular matrix processing, and proliferation controlling mechanisms.
In regards to allergic asthma, increased serum IgE is a typical pathology which causes an over activation of the immune system in response to allergens. Neutralising anti-IgE antibodies have been developed as a new type of therapy for allergic asthma and clinical studies documented a lasting beneficial effect in inflammation reduction, however, it is unclear if these drugs reduce airway wall remodelling.
Our studies have shown that the presence of IgE, in the absence of an allergen, is sufficient to specifically activate airway smooth muscle cells to produce more extracellular matrix, increase proliferation and secrete more pro-inflammatory cytokines. The data revealed that IgE primed airway smooth muscle cells towards inflammation, independent of the tissue donor’s disease. Thus, anti-IgE therapy may have a beneficial effect even in the absence of allergens.
Translational studies revealed that a modified turnover of specific collagens contributed towards inflammation in asthma patients, which was absent in healthy controls or Chronic Obstructive Pulmonary Disease (COPD) patients. Beside the increased degradation of collagens, the modification of the hyaluronic acid metabolism was described and may present a novel target for asthma therapies.
A synergised approach to research
Based on an animal model developed by our Chinese colleagues, we described a novel epigenetic mechanism which affects gene transcription by modification of histone methylation. Using primary human tissue forming airway cells and tissue biopsies from asthma patients, we could confirm this model in humans and provide several new targets for developing diagnostic tools and therapeutic strategies.
The recently published data showed that microRNA-19a controls the expression of the methyltransferase PRMT1 and thereby contributes to cell proliferation, extracellular matrix deposition and mitochondrial activity, all of which have been described by others as typical for asthmatic cells. In other diseases, especially cancers, PRMT1 is in the focus of drug development that aims to limit cell proliferation. Thus, our findings may widen the therapeutic application of this new class of drugs to chronic inflammatory lung diseases, including asthma.
In conclusion, asthma is a disease which presents with many different shades and grades. We need to understand if these present different phenotypes of the same disease, or whether they are different diseases. Therefore, the pathogenesis has to be reinvestigated and the focus should be shifted from a single cytokine or cell type to the organ as a unit, where every cell type interacts with every other cell type.