Collagen vascular diseases associated with interstitial lung diseases : analysis of alveolar epithelial cellular stress mechanisms
Lade...
Datum
Autor:innen
Betreuer/Gutachter
Weitere Beteiligte
Beteiligte Institutionen
Herausgeber
Zeitschriftentitel
ISSN der Zeitschrift
Bandtitel
Verlag
Lizenz
Zitierlink
Zusammenfassung
Interstitial lung diseases (ILD) or diffuse parenchymal lung diseases (DPLD) are a heterogenous group of chronic disorders that affect the distal lung. They are largely unresponsive to any currently available therapy and lead to architectural distortion of the lung parenchyma and rapid respiratory failure. The pathogenesis of the disease is not completely understood. In some ILDs like the idiopathic pulmonary fibrosis (IPF) the initial alveolar epithelial cell injury followed by ER-stress and apoptosis of alveolar epithelial cells type II (AECII) seems to be the triggering factor. Collagen vascular diseases (CVD) are a group of immunologically mediated inflammatory disorders affecting predominantly the connective tissue and the vessels, however, quite frequently, also the lung. Especially in Polymyositis (PM), Dermatomyositis (DM) and Systemic Sclerosis (SSc), ILD determines morbidity and mortality of the disease. Autoantibody expression seems to be highly predictive for pulmonary involvement. An autoantibody frequently found in PM/DM is anti histidyl-tRNA-Synthethase (anti-HisRS), most specific autoantibodies in SSc are anti-Topoisomerase1 (anti-Topo1), anti-Topoisomerase2alpha (anti-Topo2alpha) and anti-Topoisomerase2beta (anti-Topo2beta). In the present project it was hypothesized that autoantibodies cause development of ILD in CVD via alveolar epithelial cell injury leading to an ER-stress and apoptotic response in AECIIs. We supposed that the binding of pathogenetic antibody directed against HisRS and topoisomerases results in a loss of function of the respective proteins, which again causes aleveolar epithelial cell injury. In order to evaluate such proposed mechanism, HisRS, Topo1, Topo2alpha and Topo2beta were silenced via siRNA transfection in vitro in A549 cells. Furthermore, inhibition of topoisomerases was performed in vitro by treating A549 cells with topotecan and etoposide. ER-stress and apoptosis were analyzed employing Western Blot, semiquantitative RT-PCR and quantitative RT-PCR.In vitro knockdown experiments (siRNA mediated) for HisRS, Topo1, Topo2alpha and Topo2beta did not result in ER-stress or increased apoptosis markers. On the other hand it was shown that ER-stress and apoptosis occur in A549 cells after inhibition of topoisomerases with topotecan or etoposide. Performing immunohistochemistry of lung sections of a patient with SSc associated ILD revealed ER-stress and apoptosis in AECIIs. These results suggest that autoantibodies found in CVD may contribute to the development of ILD by causing ER-stress and apoptosis in AECIIs.Verknüpfung zu Publikationen oder weiteren Datensätzen
Beschreibung
Anmerkungen
Erstpublikation in
Gießen : VVB Laufersweiler Verlag