Airway wall remodeling in asthma : novel mechanisms of human bronchial smooth muscle cells in the induction of angiogenesis

Asthma is a global major health concern and it affects estimated 300 million people. The prevalence of asthma is rising and there is no cure for asthma, only the symptoms can be controlled. Acute asthma attacks are characterized by severe symptoms such as breathlessness, wheezing, tightness of the chest, and coughing, which may lead to hospitalization or death. Besides the acute symptoms, asthma is characterized by persistent airway inflammation and airway wall remodeling. The term airway wall remodeling summarizes the structural changes in the airway wall: epithelial cell shedding, goblet cell hyperplasia, hyperplasia and hypertrophy of the bronchial smooth muscle (BSM) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma and today it is suggested that remodeling is a prerequisite for other asthma pathologies. Furthermore, novel invasive therapies used to treat severe asthma provide evidence that the BSMC is a major effector cell in the pathology of asthma. In the present thesis novel mechanisms of BSMC regulation and their role in the induction of asthma-associated angiogenesis have been elucidated. Therefore, the differences in the angiogenic capacities of BSMC from asthma and non-asthma patients and their modification by different conditions, such as an (i) inflammatory microenvironment, (ii) the influence of low oxygen concentration, and (iii) the stimulation with the most potent asthma relevant allergen (house dust mite (HDM) allergen) on the angiogenic properties of BSMC have been studied. A major finding of this thesis is the increased angiogenic potential of BSMC from asthma patients and the altered release of CXCR2 ligands in an in vitro inflammatory environment. It has been demonstrated that BSMC from asthma patients release significantly more of the CXCR2 ligands ENA-78, GRO-a and IL-8, which may explain the increased vascular density in the sub-epithelial cell layers observed in the airways of asthma patients. These finding adds to previous studies showing that BSMC are a source of angiogenic factors (e.g. VEGF) and that CXCR2 ligands are elevated in the airway lining fluids of asthma patients. In this thesis BSMC have been shown to be a potential source of CXCR2 ligands, which induced spout outgrowth from endothelial cell spheroids in an in vitro model of angiogenesis. Furthermore, this thesis investigated the effect of hypoxia on BSMC. Local restricted hypoxia in the airways of asthma patients had only recently been suggested. The animal model based hypothesis that hypoxia directly causes BSMC hyperplasia was tested. This hypothesis was not confirmed in human BSMC but nonetheless it was demonstrated that hypoxia leads to increased release of inflammatory and angiogenic mediators; as conditioned medium from BSMC grown under hypoxia induced angiogenesis in an in vitro model via VEGF. These findings suggest that different conditions or stimuli induce angiogenesis in asthma through different pathways and therefore, different therapeutic strategies might be needed. In the third part of this thesis the effect of HDM allergen on the release of inflammatory and angiogenic mediators from BSMC was assessed. Animal models demonstrated that exposure to HDM allergens increased airway wall vascularization. No direct contribution of BSMC to HDM extract induced angiogenesis was observed. However, HDM extract proteases degraded ENA-78, which is an import chemokine for neutrophil recruitment into the inflamed lung. Thus HDM allergens may alter the bio-availability of ENA-78 in the airways of asthma patients and modulate the immune response. The findings of this thesis add a small piece to the knowledge of asthma pathology, the mechanisms underlying airway wall remodeling and in particular BSMC hyperplasia and neovascularization. This might represent novel targets for treatment, especially for the prevention or reversal of airway wall remodeling