Keglowich, Laura Franziska. Airway wall remodeling in asthma : novel mechanisms of human bronchial smooth muscle cells in the induction of angiogenesis. 2014, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_11081
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.
|Advisors:||Hall, Michael N.|
|Committee Members:||Roth, Michael and Chiquet-Ehrismann, Ruth|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||134 S.|
|Last Modified:||30 Jun 2016 10:56|
|Deposited On:||13 Jan 2015 14:49|
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