Asthma

Our translational, clinical and epidemiologic research encompasses both asthma and COPD.

Asthma

Asthma is a common chronic inflammatory airway disease characterized by variable respiratory symptoms and airflow limitation, which affects 334 million people worldwide. Asthma development is determined by environmental exposures (e.g. allergens and air pollution) and individual genetic susceptibility. When looking at the overall asthma prevalence, there is a clear sex disparity. Epidemiological data show a significant difference in prevalence of asthma by sex according to age. In childhood, two-thirds of all asthma patients are boys. In contrast, in adulthood, two-thirds of patients with (severe) asthma are women.

Asthma is a heterogeneous disease, encompassing several asthma phenotypes which can be distinguished based on severity, presence or absence of allergy, inflammatory profile (e.g. eosinophilic, neutrophilic, or mixed granulocytic airway inflammation), and type of immune responses (e.g. type 2-high vs type 2-low asthma). Patients with severe asthma have persistent respiratory symptoms, a reduced quality of life and frequent exacerbations, which require treatment with oral corticosteroids, hospitalization and may even be fatal.

We contributed to landmark clinical trials demonstrating that treatment with biologicals (e.g. monoclonal antibodies against the type 2 cytokine IL-5, mepolizumab and the IL-4 receptor α, dupilumab) significantly reduces asthma exacerbations in severe eosinophilic and type 2-high asthma, respectively. Asthma exacerbations (i.e. attacks) are induced by viral infections, allergens and air pollutants, triggering airway epithelial damage and proinflammatory immune responses. Despite important breakthroughs in the treatment of severe asthma, it remains difficult to predict which patient is at risk of future exacerbations and who will respond optimally to a specific biological therapy. Identification of early, accurate biomarkers of (1) future risk and (2) treatment response is much needed.

Research aims and objectives:

1. Explore the accuracy of prognostic and theragnostic biomarkers in asthma.
2. Investigate changes in respiratory symptoms and lung function following exposure to gender-affirming hormonal therapy (GAHT; i.e. testosterone therapy, testosterone suppression and/or oestrogen therapy).
3. Elucidate the impact of sex hormones on the number and function of circulating immune cells (focusing on CD4+ T helper-cells [Th-cells]) and asthma type 2 biomarkers (e.g. blood eosinophil count and Fractional excretion of Nitric Oxide [FeNO]).
4. Investigate the molecular mechanisms by which sex hormones modulate the systemic and mucosal immune system (in the blood circulation and in the airways, respectively).

Research hypotheses:

1)There is an immunomodulatory effect of testosterone, which improves lower respiratory tract (LRT) symptoms and increases lung volumes independent of the expected increase in lean mass and functional capacity, even in healthy individuals. On the other hand, the immune enhancing effects of oestrogen or testosterone suppression can give rise to LRT symptoms in healthy individuals and may reduce lung function.

2)Sex hormones produce a shift in circulatory immune cells (especially CD4+ Th-cells), responsible for the production of type 2 cytokines involved in asthmatic airway inflammation.

3)The transcription and expression of steroid receptors and enzymes is altered by gender-affirming hormonal therapy (GAHT).

Research methods:

Translational studies using preclinical animal models of asthma;

clinical research in a prospective cohort of transgender persons (ENIGI-Lung cohort); and

epidemiological research in a large population-based prospective cohort study (the Rotterdam Study).

COPD

Patients with chronic obstructive pulmonary disease (COPD) suffer from a persistent and usually progressive airflow limitation and severe breathing difficulties. Cigarette smoke (CS) is the most important risk factor and causes an abnormal inflammatory response in the airways and lungs, resulting in airway remodeling and the destruction of lung parenchyma (=emphysema)¹. In Belgium approximately 600.000 people suffer from COPD; worldwide there are more than 300 million COPD patients. More than 3 million people die from COPD each year, making it the third leading cause of death. Current medications for COPD merely suppress symptoms. There are no treatments that stop disease progression, and no cure. The lack of drugs that slow down disease progression is largely due to a poor understanding of the underlying mechanisms.

Remarkably, the inflammation in patients with COPD persists even after cessation of smoking, indicating that it is maintained through autonomous mechanisms. One of the factors that contributes to the ongoing inflammation is an imbalance between cell survival and cell death. Exaggerated death of lung structural cells leads to tissue destruction but can, depending on the type of cell death, also trigger inflammatory responses through the release of danger signals and inflammatory mediators. Importantly, impaired phagocytosis of dead or dying cells (i.e. efferocytosis) may be an additional driver of ongoing inflammation and even autoimmunity. Reduced efferocytosis capacity has been demonstrated in macrophages from COPD patients.

Research aims and objectives:

Elucidating the contribution of cell death processes and impaired clearance mechanisms to the ongoing inflammation and tissue destruction in COPD will lead to an improved understanding of disease pathogenesis and will open new avenues for therapeutic intervention. The specific research objectives are:

1. Characterize the pathogenic contribution of different modes of regulated cell death in experimental COPD;
2. therapeutically target these cell death modalities.
3. Elucidate the defects in the different phases of efferocytosis in both experimental and human COPD; 4. boost efferocytosis in experimental models of both stable and exacerbated COPD.

Overarching research hypothesis:

Disturbances in pulmonary cell death pathways (including apoptosis, necroptosis and ferroptosis) as well as impaired clearance of dead and dying cells (efferocytosis) contribute to the chronic inflammation and tissue destruction in patients with COPD. Pharmacological interventions in these processes may be novel treatments for COPD.

Research methods:

Translational studies using preclinical animal models of COPD (in vivo); and investigations on our large human lung tissue biobank of well-characterized patients with COPD and control subjects (ex vivo).