eprintid: 23699
rev_number: 17
eprint_status: archive
userid: 3411
dir: disk0/00/02/36/99
datestamp: 2017-11-17 07:45:55
lastmod: 2017-12-22 10:00:48
status_changed: 2017-11-17 07:45:55
type: doctoralThesis
metadata_visibility: show
creators_name: Hagner, Matthias
title: Relationship between impaired mucociliary clearance and airway inflammation in chronic airway diseases
subjects: ddc-570
subjects: ddc-610
divisions: i-910500
adv_faculty: af-14
keywords: Asthma
Cystic Fibrosis
cterms_swd: Mucociliary clearance
cterms_swd: airway inflammation
cterms_swd: chronic airway disease
abstract: Chronic airway diseases including cystic fibrosis (CF), asthma and chronic obstructive pulmonary disease (COPD) are characterized by reduced mucociliary clearance (MCC) that leads to mucus-obstructed and chronically inflamed airways and structural changes of the lung. Mice with airway-specific overexpression of the β-subunit of the epithelial sodium channel (Scnn1b) exhibit airway surface dehydration, mucus hyperconcentration and impaired MCC and share pathogenic key features of CF and other muco-obstructive lung diseases. Therefore, the Scnn1b-transgenic (Tg) mouse is a useful model to study pathophysiological mechanisms of chronic airway diseases in vivo. In this study, we investigated the role of MCC as an important innate defense mechanism in the pathogenesis of allergic airway disease and also aimed to understand the role of T and B cells as key cells of the adaptive immunity in chronic airway diseases.
We analyzed allergen clearance mechanisms in juvenile wild-type (WT) and Scnn1b-Tg mice and validated the role of impaired MCC on allergen-induced type 2 airway inflammation in a house dust mite allergen (HDM) exposure model. Further, we determined effects of impaired MCC and allergen-induced type 2 airway inflammation in adult mice. Finally, we investigated if pharmacological improvement of MCC could prevent allergen-induced type 2 airway inflammation. To investigate the role of T and B cells in the pathogenesis of chronic airway diseases in vivo, we crossed Scnn1b-Tg mice with recombination activating gene 1 (RAG1) deficient mice (Rag1-/-) that lack mature T and B cells and compared inflammatory cell counts in bronchoalveolar lavage (BAL), transcript levels of T helper (Th)1, Th2 and Th17 cytokines, airway mucus obstruction and structural lung damage in juvenile Scnn1b-Tg mice with Scnn1b-Tg/Rag1-/- mice, and their WT and Rag1-/- littermates.
We found that reduced allergen clearance from the airways aggravated eosinophilic airway inflammation, secretion of type 2 signature cytokines, and airway hyperresponsiveness (AHR) in juvenile Scnn1b-Tg mice. Interestingly, the induction of allergen-induced type 2 airway inflammation in adult WT and Scnn1b-Tg mice was abrogated demonstrating an age-dependent susceptibility caused by a type 2 biased immunity during the neonatal/juvenile age. Pharmacological improvement of airway surface hydration reduced allergen-induced airway inflammation and AHR in Scnn1b-Tg mice. Lack of Rag1 had no effect on elevated levels of neutrophils and eosinophils in BAL from juvenile Scnn1b-Tg mice. We identified elevated transcript levels of the cytokine Interleukin (IL)-17A in juvenile Scnn1b-Tg mice that was reduced in Scnn1b-Tg/Rag1-/- mice. Flow cytometry revealed γδ T, CD4+ T cells and type 3 innate lymphoid
Abstract
XIV
cells (ILC3s) as major sources of IL-17A in lungs of Scnn1b-Tg mice. Increased IL-17A-production did not affect mucus plugging but might be associated with structural lung damage in juvenile Scnn1b-Tg mice.
In summary, our data support that impaired clearance of inhaled allergens plays an important role in the pathogenesis of type 2 airway inflammation and suggest that therapeutic improvement of MCC may be an effective strategy to prevent disease-aggravating inflammatory responses in patients with allergic asthma and other chronic airway diseases associated with mucociliary dysfunction including CF and COPD. Further, results from our study provide first insights into T and B cell-dependent mechanisms that might contribute to pathophysiological features of CF lung disease.
date: 2017
id_scheme: DOI
id_number: 10.11588/heidok.00023699
ppn_swb: 1658527771
own_urn: urn:nbn:de:bsz:16-heidok-236993
date_accepted: 2017-11-07
advisor: HASH(0x558ea3b81a28)
language: eng
bibsort: HAGNERMATTRELATIONSH2017
full_text_status: public
citation:   Hagner, Matthias  (2017) Relationship between impaired mucociliary clearance and airway inflammation in chronic airway diseases.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/23699/1/PhD%20Thesis_Matthias%20Hagner.pdf