DMBT1 is upregulated in cystic fibrosis, affects ciliary motility, and is reduced by acetylcysteine

Alexander Kiefer; Erika Plattner; Renate Ruppel; Christel Weiss; Zhe Zhou-Suckow; Marcus Mall; Marcus Renner; Hanna Müller

doi:10.1186/s40348-022-00136-0

DMBT1 is upregulated in cystic fibrosis, affects ciliary motility, and is reduced by acetylcysteine

Mol Cell Pediatr. 2022 Mar 5;9(1):4. doi: 10.1186/s40348-022-00136-0.

Authors

Alexander Kiefer^{1

2}, Erika Plattner¹, Renate Ruppel¹, Christel Weiss³, Zhe Zhou-Suckow⁴, Marcus Mall⁵, Marcus Renner⁶, Hanna Müller^{7

8}

Affiliations

¹ Department of Pediatrics, University Hospital Erlangen, University of Erlangen-Nürnberg, Loschgestr. 15, 91054, Erlangen, Germany.
² Department of Pediatric Pneumology and Allergology, St. Hedwig's Hospital of the Order of St. John, University Children's Hospital Regensburg (KUNO), Steinmetzstr. 1-3, 93049, Regensburg, Germany.
³ Department of Medical Statistics and Biomathematics, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
⁴ Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld, 69120, Heidelberg, Germany.
⁵ Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
⁶ Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
⁷ Department of Pediatrics, Neonatology and Pediatric Intensive Care, University of Marburg, Baldingerstraße, 35043, Marburg, Germany. Hanna.Mueller@med.uni-marburg.de.
⁸ Department of Pediatrics, Division of Neonatology and Pediatric Intensive Care, University Hospital Erlangen, University of Erlangen-Nürnberg, Loschgestr. 15, 91054, Erlangen, Germany. Hanna.Mueller@med.uni-marburg.de.

Abstract

Background: Cystic fibrosis (CF) is the most common genetic disorder in the Caucasian population. Despite remarkable improvements in morbidity and mortality during the last decades, the disease still limits survival and reduces quality of life of affected patients. Moreover, CF still represents substantial economic burden for healthcare systems. Inflammation and infection already start in early life and play important roles in pulmonary impairment. The aim of this study is to analyze the potential role of DMBT1, a protein with functions in inflammation, angiogenesis, and epithelial differentiation, in CF.

Results: Immunohistochemically DMBT1 protein expression was upregulated in lung tissues of CF patients compared to healthy controls. Additionally, pulmonary expression of Dmbt1 was approximately 6-fold increased in an established transgenic mouse model of CF-like lung disease (ENaC tg) compared to wild-type mice as detected by qRT-PCR. Since acetylcysteine (ACC) has been shown to reduce inflammatory markers in the airways, its potential influence on DMBT1 expression was analyzed. A549 cells stably transfected with an expression plasmid encoding the largest (8kb) DMBT1 variant (DMBT1+ cells) or an empty vector control (DMBT1- cells) and incubated with ACC both showed significantly reduced DMBT1 concentrations in the culture medium (p = 0.0001). To further elucidate the function of DMBT1 in pulmonary airways, respiratory epithelial cells were examined by phase contrast microscopy. Addition of human recombinant DMBT1 resulted in altered cilia motility and irregular beat waves (p < 0.0001) suggesting a potential effect of DMBT1 on airway clearance.

Conclusions: DMBT1 is part of inflammatory processes in CF and may be used as a potential biomarker for CF lung disease and a potential tool to monitor CF progression. Furthermore, DMBT1 has a negative effect on ciliary motility thereby possibly compromising airway clearance. Application of ACC, leading to reduced DMBT1 concentrations, could be a potential therapeutic option for CF patients.

Keywords: Acetylcysteine; Ciliary motility; Cystic fibrosis; DMBT1; Inflammation.