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Die Blockade der Atemwegsrestrukturierung bei Asthma; durch unterdrückung der Neubildung von Blutgefässe in der lamina propria

English title Counteracting airway wall remodelling in asthma: blocking the neo-vascularization of the lamina propria
Applicant Borger Pieter
Number 124905
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Structural Research
Start/End 01.04.2009 - 31.03.2012
Approved amount 280'000.00
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All Disciplines (2)

Discipline
Structural Research
Respiratory Diseases

Keywords (5)

asthma; airway wall remodelling; bronchial smooth muscle; neovascularization; airway smooth muscle, neo-vascularization

Lay Summary (English)

Lead
Lay summary
Asthma is a clinically and socio-economically important chronic disease affecting 8-12% of the population of Western countries. Although asthma prevalence has been steadily increasing worldwide during the past two decades, we still don't know why so many people developed asthma. Neither do we understand the origin of the disease. In 1995 the Global Strategy for Asthma Management and Prevention Report defined asthma as "a chronic inflammatory disease of the airways in which many cell types play a role, in particular mast cells, eosinophils and Th2 lymphocytes. In susceptible individuals, the inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or early morning. These symptoms are usually associated with widespread and variable airflow obstruction that is at least partly reversible, either spontaneously or after treatment with steroids and/or beta-mimetic drugs. The inflammation also causes an associated increase in airway responsiveness to a variety of stimuli". Currently, an increasing volume of data is emerging that the inflammatory response in asthma is of more general character with enhanced levels of all sorts of inflammatory mediators (both Th1 and Th2). The proposition is therefore that a more fundamental defect of the airway smooth muscle (ASM) cells may be underlying the disease. The role of inflammation in the pathology of asthma is recently reconsidered due to the fact that remodeling cannot be sufficiently explained by inflammation alone. The resident cells of the airways, in particular overactive smooth muscle cells, may be of importance. Recent studies showed that bronchial thermoplasty (a novel bronchoscopic strategy to reduce the mass of ASM) markedly improved asthma symptoms in subjects with mild or severe asthma. This suggests that asthma may result from aberrant behavior of the ASM cells. We hypothesize that the limitation of the oxygen supply to ASM tissue provides a powerful novel strategy to counteract airway wall remodelling. In this proposal we will address the question whether and how ASM cells and airway wall fibroblasts orchestrate the building of new blood vessels of the lamina propria (this is the area of the lung where the remodeling takes place) 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 that counteracts the formation of new vessels (e.g. thalidomide and vasostatin; VEGF antibodies, including bevacizuma
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Asthma and COPD – The C/EBP connection. The Open Respiratory Medicine Journal.
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.
Calreticulin is a negative regulator of bronchial smooth muscle cell proliferation.
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.
Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms.
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.
House dust mite extract downregulates C/EBPα in asthmatic bronchial smooth muscle cells.
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.

Associated projects

Number Title Start Funding scheme
116022 Pathogenesis of asthma and COPD: a defect of translation control of CCAAT/enhancer binding proteins? 01.04.2007 Project funding (Div. I-III)

Abstract

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.
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