asthma; airway wall remodelling; bronchial smooth muscle; neovascularization; airway smooth muscle, neo-vascularization
Miglino N M. Roth D. M. Tamm M P. Borger. (2012), Asthma and COPD – The C/EBP connection. The Open Respiratory Medicine Journal., in The Open Respiratory Medicine Journal
, Open Resp Med J. 2012; 6, 1-13.(6), 1-13.
Miglino N Roth M Lardinois D Tamm M Borger P. (2012), Calreticulin is a negative regulator of bronchial smooth muscle cell proliferation., in Journal of Allergy
, J Allergy 2012; 2012:783290. (2011-2012), 1-8.
Miglino N M. Roth D. Lardinois C. Sadowski M. Tamm M P. Borger. (2012), Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms., in European Respiratory Journal
, Eur Respir J. 2012, 39(3):705-11.(39(3)), 705-711.
Miglino N M. Roth M. Tamm P. Borger. (2011), House dust mite extract downregulates C/EBPα in asthmatic bronchial smooth muscle cells., in European Respiratory Journal
, Eur Respir J. 2011, 38(1):50-8.(38(1)), 50-58.
Persistent airway wall remodeling is an important pathology of asthma characterized by basement-membrane thickening, a marked increase of the bulk of bronchial smooth muscle (BSM) cells and neo-vascularisation. The airway wall remodeling is of unknown etiology, but has a major effector function in airway constriction. Recent studies showed that bronchial thermoplasty (a novel bronchoscopic strategy to reduce the mass of BSM) markedly improved asthma symptoms in subjects with mild or severe asthma showing that asthma may result from aberrant behavior of the BSM cells. We hypothesize that the limitation of the oxygen supply to BSM tissue provides a powerful novel strategy to counteract airway wall remodeling. In this proposal we will address the question whether and how BSM cells and airway wall fibroblasts orchestrate the neo-vascularisation of the lamina propria and whether we can find differences comparing cells isolated from the lungs of asthma patients relative to those of healthy controls. The findings may prove valuable for developing novel therapeutic strategies for asthma, or lead to the development or alternative use of already existing medication (e.g. thalidomide and vasostatin; VEGF antibodies, including bevacizumab, ranibizumab).Scope of the study:1)How do human primary BSM cells and airway wall fibroblasts affect neo-angiogenesis? Development of in vitro interactive models with primary human cells to address the following questions: 1.a. What vascular remodeling relevant factors do human primary BSM cells produce? 1.b. How do BSM cells affect endothelial cell behavior, such as activation, proliferation and migration? 1.c. Does hypoxia affect the remodeling parameters of bronchial cells described above? 2)Is there a difference between cells obtained from asthma patients compared to those obtained from healthy controls with respect to the parameters described in 1.a.-1.c? 3)What are the direct, IgE-independent, effects of exposure to asthma relevant antigens such as house dust mite (HDM) on these parameters?4)Can we block neo-vascularisation by inhibition of the above determined pro-angiogenic factors with either the existing drugs (e.g. thalidomide and vasostatin; VEGF antibodies, including bevacizumab, ranibizumab) or by small inhibitory RNAs? The perspectives of the study are: (i) to clarify the contribution of airway wall resident cells to the process of neo-vascularisation in the lamina propria,(ii) the role of disease triggering allergens to this process, and (iii) to characterize the molecular biological basis for new therapeutic options such as inhalation of drugs that counteract neo-vascularisation.