Priority Research Area Chronic Lung Diseases
Mission Projects Funding Techniques Publications Awards Staff
Bronchial asthma is one of the most common chronic diseases in the world and developed to a major health problem of the western world by reason of very high and still increasing incidence and prevalence recorded over the last decades. According to the WHO-funded GINA (Global Initiative for Asthma) Report on the Global Burden of Asthma as many as 300 Million people of all ages and all ethnic backgrounds suffer from asthma with incidences exceeding 10-19% of the population in the US, the UK and Australia.
The disease is clinically characterized by a variable degree of broncho-obstruction together with cough, chest tightness, shortness of breath, and wheezing, which are caused by the development of airway hyperresponsiveness (AHR), structural remodeling of the airway wall and mucus hypersecretion. Depending on the severity of the disease the degree of each of these hallmarks, especially impaired lung function, displays high variability actually leading to the definition of several different asthma endotypes. It is likely that these endotypes arise from a different etiology and pathogensis, which necessitates a customized therapy in thes sense of precision medicine. This can only be established on the basis of an deep understanding of those pathogentic mecahnisms that ultimately lead to the formation of each disease endotype. Nevertheless, the complex phenotype of bronchial asthma arises from chronic inflammation of the airways in response to the inhaled allergen(s).
In mild-to-moderate asthma this inflammation represents a classic allergic immune response whereat T helper 2 (TH2) cells play a critical role in directing the allergic immune response. By producing a characteristic pattern of cytokines, chemokines and growth factors these cells drive allergic inflammation that follows allergen inhalation, while eosinophils act as the main effector cell type of the allergic inflammatory response. Eosinophil products such as cytotoxic proteins and enzymes are involved in the development of AHR and cause marked destruction of the airway tissue, which in turn triggers repair processes. In contrast, the inflammatory response underlying the formation of severe asthma appears to be much more complex and involves prominent infiltration of several leukocyte subsets (e.g. NK cells) producing the highly proinflammatory cytokine Interleukin 17 (IL-17).
The mechanisms underlying the aggravation of mild-to-moderate asthma towards the development of a severe phenotype still remain enigmatic. Acute episodes of asthma aggravation – so-called exacerbations – represent a typical hallmark of asthmatic diseases and are typically triggered by viral or bacterial infection of the airways. Such infections lead to an amplified inflammatory reaction resulting in a further increase in mucus production and a further decline in lung function. Interestingly, also in acute asthma exacerbation neutrophils and IL-17-producing leukocyte subsets infiltrate into the airways, which at least in parts resembles the inflammatory situation in severe asthma. To date it is not clear, which factors orchestrate the differentiation and the recruitment of these cells to the lung and what is actually their role in the pathogenesis of acute asthma exacerbations.
Eventually, another regulatory level could be the key for understanding this process, namely the balance between generally pro- and anti-inflammatory mediators. Clinical studies clearly demonstrate that pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IL-1β and IL-6 as well as growth factors like granulocyte-macrophage colony stimulating factor (GM-CSF), neurotrophins or vascular-endothelial growth factor (VEGF) are produced in large amounts in airways of asthmatic patients, whereas the production of anti-inflammatory mediators such as IL-10 or relatively new members of the IL-1 cytokine family such as IL-37 are markedly decreased. These mediators cannot be attributed to the formation of a special immune response, but generally amplify all kinds of inflammation by activating the transcription factor nuclear factor κB (NFκB). This in turn seems to result in a predominance of pro-inflammatory factors permanently overwhelming counterbalancing feedback loops, and loss of control of inflammatory processes (and the resulting symptoms). This ultimately leads to creating an environment allowing chronic inflammation of the airways. Actually, recorvery of this control represents the aim of every current asthma therapy.
This research group focuses on understanding these regulatory levels in order to find novel targets for therapeutic intervention. Thereby, the development and use of appropriate models reflecting different asthmatic phenotypes is a major part of the research strategy. Actual research projects are:
- Viral induced acute exacerbations of allergic bronchial asthma
- The role of IL-17 producing NK cells in acute aggravation of allergic asthma
- The effects of the α-melanocyte stimulating hormone (α-MSH) and its receptor system in the immune-pathogenesis of allergic asthma
- The function and mode of action of IL-37 during asthma pathogenesis