Research project P6/35 (Research action P6)
DOMAIN
Asthma and Chronic Obstructive Pulmonary Disease (COPD) are prevalent diseases of the lower airways, wich cause worldwide significant morbidity and mortality and represent a significant socio-economic burden 1,2. In recent years, progress has been made to elucidate the underlying pathogenetic mechanisms of these diseases. Moreover it has become increasingly apparent that these lower airway diseases are linked with upper airway diseases such as rhinitis, sinusitis and nasal polyposis. One of the mainstream findings is that the symptoms caused by upper and lower airway diseases are causally linked with underlying inflammatory and remodelling processes3. This insight led to the concept of “united airways” possibly explaining why as many as 80% of allergic asthma patients for example also suffer from rhinitis. Treating inflammation with anti-inflammatory agents such as steroids is only temporally successful, but does not cure the disease. Further characterisation of the cellular and molecular immune mechanisms involved in these diseases is a priority in order to develop more effective and long lasting therapies. Furthermore, since genetic drifts cannot explain the ever increasing trend in airway diseases, we propose that environmental factors such as allergen exposure, pollution and infection and their interactions are causally involved in the pathogenesis.
OBJECTIVES
The acronym AIREWAY (Effects and interactions of Allergy, Infections and Respiratory Environmental exposures on the development and chronicity of upper and lower airWAY diseases) describes the global objective of this project. With this interuniversity approach, we want to unravel cellular and molecular mechanisms underlying the upper (rhinitis, sinusitis, nasal polyposis) and lower airway diseases (asthma and COPD). The individual and combined effects of allergens, infections and air pollution on the main cellular and molecular mediators, will be characterized at different phases typing the natural history of each disease entity, using experimental animal models. In addition, validation will be realized by analyses on material from healthy controls and defined study populations.
METHODOLOGY
The cellular and molecular mechanisms underlying the chronic inflammation in these airway diseases is approached in a multimodality fashion. The research groups are equipped and experienced to perform cellular and molecular in vitro studies eg on human primary (nasal, bronchial and alveolar) epithelial cell cultures. They have a large expertise with in vivo animal models of airway diseases 4-10. In addition and to assure clinical relevance, the research groups have access to serum, sputum, nasal and bronchial lavage and tissue samples from several patient groups (COPD, asthma, nasal polyposis, sinusitis and rhinitis) for validation of the findings from the basic research 11-13.
SPECIFIC AIMS
1. Further characterization of sensitisation, inflammation and remodelling in chronic upper and lower obstructive airway diseases
The animal models available in the consortium to study the respective diseases (asthma, COPD, rhinitis, polyposis nasi, sinusitis) mimic closely the global pathology seen in the patient. The basic idea of those animal models is to enable fundamental research with relevance to the clinic. Therefore, these models need to be characterized thoroughly before the effects of exogenous factors can be evaluated.
Read-out of physiological parameters (pulmonary function and endurance testing), inflammation and remodelling (cellular level – cytology – (immuno)histology – FACS analysis) and molecular pathways (cytokines, chemokines, growth factors, ECM-related enzymes) will be performed. At the cellular level, main interest will go to the interaction between different T-cells (Th-1, Th-2, NKT, T-reg, …) orchestrating the inflammatory processes, antigen presenting cells (dendritic cells and macrophages) and the epithelium. Respective important molecular pathways can be documented by both in vitro and in vivo experiments for the different disease entities of interest. The latter will be based on the use of monoclonal antibodies targeting certain molecules of interest (proinflammatory cytokines such as IL-4, IL-13, IFN- versus immunomodulatory cytokines such as TGF- or IL-10; toll like receptors; and subtypes of immunolological cells such as T-reg cells and NKT cells) as well as on the use of genetically modified mice enabling the selective over-expression or suppression of certain genes.
2. The role of infectious agents, allergens and environmental pollutants in the development and maintenance of chronic airway diseases
2.1) Allergic rhinitis (AR) and asthma: Epidemiological data suggest that the exposure to microbial environmental agents has a crucial but at the same time dual role in the natural history of chronic inflammatory airways diseases. Although endotoxins can irritate the airways (pro-inflammatory), it is well documented that prolonged exposures protect the airways from developing allergic upper and lower airway diseases (tolerance). The role of allergy in the development of asthma and allergic rhinitis is well documented, but the fundamental question of why some atopic individuals develop AR or asthma symptoms, whereas others remain asymptomatic, has still to be fully addressed.
2.2) Chronic rhinosinusitis/nasal polyposis and COPD: Recent data suggest a prominent role of microbial factors such as Staphylococcal enterotoxins in the pathogenesis of nasal polyposis. It is obvious that COPD is causally linked with exposure to cigarette smoke, however, the role of infections, bacterial colonization and concurrent allergen exposure in the natural history of the disease in not known.
With the different animal models elaborated in the first work package but also with in vitro experiments (e.g. human primary epithelial cell cultures), the effects of endotoxins, CpGs, polyIC and enterotoxins as most important representatives for respectively bacerial and viral environmental factors will be evaluated. Similarly, the effects of allergens (e.g. house dust mite, pollen and professional allergens) and environmental pollutants (such as cigarette smoke, diesel and ozon) will be tested either separately, or in combination. More specifically, the impact of these factors on the above defined physiological, inflammatory and molecular readouts will be measured for the respective disease entities. The effects of these interventions will then be compared between the different disease entities for identification of possible interactions.
3. Translational research: analysis in clinical samples
Since all study partners have access to clinical samples from the different patient populations, the importance of interesting key molecules or pathways will be confirmed in study patients. As in the animal models, the prominent role of the dendritic cell and T-cell will be further elaborated with the delineation of the key molecules involved in the promotion of certain pro-inflammatory or in the suppression of anti-inflammatory T-cell populations. This approach could lead to interesting new targets for future drug development.
REFERENCES
1. Bousquet et al., J Allergy Clin Immunol, 2001, 108, S147-334 / 2. Pauwels et al., Am J Respir Crit Care Med, 2001, 163, 1256-76 / 3. Fokkens et al., Allergy, 2005, 60, 583-601 / 4. Moerloose et al., Am J Respir Crit Care Med, 2005, 172, 168-72 / 5. D’hulst et al., Eur Respir J, 2005, 26, 204-13 / 6. Hellings et al., Eur J Immunol, 2002, 32, 585-94 / 7. Hellings et al., Am J respir cell Mol biol, 2002, 28, 42-50 / 8. Vanoirbeek et al., Toxicol sci, 2003, 76, 338-46 / 9.Vanoirbeeck et al., J Allergy Clin Immunol, 2006, in press / 10. Gueders et al., J Immunol, 2005, 175, 2589-97 / 11. Bachert et al., J Allergy Clin Immunol, 2001, 107, 607-14 / 12. Cataldo et al., Lab Invest, 2004, 84, 418-24 / 13. Demedts et al., Thorax, 2006, 61, 196-201
