Klin Padiatr 2022; 234(05): 320-321
DOI: 10.1055/s-0042-1754452
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Targeting IL-6 to prevent vascular and bronchial remodeling in an experimental model of bronchopulmonary dysplasia

C Bartz
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
D Hirani
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
2   Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
J Selle
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
C Vohlen
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
R Wilke
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
C Kuiper-Makris
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
3   Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
C Nies
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
V Wagde
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
J Dötsch
3   Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
,
MA Alejandre Alcazar
1   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
2   Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany
4   Cologne Excellence Cluster on Stress Responses in Aging-associated Diseases (CECAD), University Hospital of Cologne, University of Cologne, Cologne, Germany
5   Institute for Lung Health (ILH), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
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Rationale Bronchopulmonary dysplasia (BPD) is a chronic lung disease of the premature infant following respiratory support, e.g., oxygen supplementation, and characterized by impaired alveolar and microvascular formation and a higher risk for pulmonary arterial hypertension (PAH). Prior studies identified IL-6 signaling being central in clinical and experimental BPD. Since inflammation is important in the pathogenesis of pulmonary vascular and bronchial disease, we now investigate the functional role of IL-6 in vascular and bronchial remodeling in experimental BPD.

Methods (1) Neonatal WT, IL-6 knockout mice (IL-6-/-) as well as WT mice with pharmacological inhibition of IL-6 cis (IL-6 mAb) – and trans (sgp130-Fc) signaling were exposed to hyperoxia (85% O2, HYX) or normoxia (21% O2, NOX). Lungs were excised and used either for molecular biology studies or for histomorphometric analysis. (2) Primary murine bronchial smooth muscle cells (pmBSMCs) were exposed to hyperoxia and IL-6/sIL-6 receptor (IL-6+R), followed by assessment of viability and proliferation.

Results (1) Histomorphometric analysis revealed a thickening of the vascular and bronchial wall of WTHYX compared to WTNOX. WTHYX mice showed reduced microvascular formation and a higher number of partly and completely muscularized small vessels (20-100 micrometer) compared to WTNOX. Moreover, the number of vascular KI-67+/aSMA+ cells and the amount of aSMA+ cells per vessel, both indicators of proliferation, were higher in WTHYX than in WTNOX. In contrast, IL-6 deficiency (IL-6-/-) and pharmacological inhibition of IL-6 cis- and trans-signaling protected from hyperoxia-induced vascular and bronchial remodeling, but not from reduced microvascularization. (2) Exposure of pmBSMCs to HYX decreased viability compared to NOX. While IL-6+R decreased viability of pmBSMCs under NOX, we detected an increase under HYX. Finally, IL-6+R increased proliferation of pmBSMCs under both NOX and HYX.

Conclusion Our data demonstrate a critical role of IL-6 signaling in vascular and bronchial remodeling via hyperproliferation of SMCs.



Publication History

Article published online:
21 September 2022

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