Klin Padiatr 2022; 234(05): 345-346
DOI: 10.1055/s-0042-1754519
Abstracts
Poster
Poster Walk 5: Grundlagenforschung, Sonstiges (Funktionelle Störungen, Rehabilitation, NIV, Schlaf etc.)

CXCL10 deficiency protects from lung macrophage invasion and enables lung growth during acute injury and recovery in experimental bronchopulmonary dysplasia

D Hirani
1   Institute for Lung Health (ILH), Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Germany, Giessen, Germany
2   Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany
3   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany, Cologne, Germany
,
F Thielen
3   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany, Cologne, Germany
,
C Vohlen
3   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany, Cologne, Germany
,
S Danopoulos
4   The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA, Torrance, United States
,
S Mansouri
5   Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, Bad Nauheim, Germany
,
P Haznedar-Karakaya
3   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany, Cologne, Germany
,
J Mohr
3   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany, Cologne, Germany
,
R Wilke
3   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany, Cologne, Germany
,
S Koningsbruggen-Rietschel
6   Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany
,
D Al-Alam
4   The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA, Torrance, United States
,
R Savai
5   Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, Bad Nauheim, Germany
,
J Dötsch
6   Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany
,
MA Alejandre Alcazar
3   Translational Experimental Pediatrics, Experimental Pneumology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany, Cologne, Germany
1   Institute for Lung Health (ILH), Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Germany, Giessen, Germany
2   Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany, Cologne, Germany
7   Cologne Excellence Cluster on Stress Responses in Aging-associated Diseases (CECAD), University Hospital of Cologne, University of Cologne, Cologne, Germany, Cologne, Germany
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Rationale Preterm infants with oxygen supplementation frequently develop a chronic lung disease known as bronchopulmonary dysplasia (BPD). Pathomechanistically, an inflammatory response with increased migration and activation of macrophages plays a major role. Elevated levels of CXCL10 (C-X-C motif chemokine ligand 10), which has chemotactic and activating effects on proinflammatory inflammatory cells, were detected in lungs of infants evolving BPD. Therefore, we investigated whether CXCL10 deficiency protects newborn mice from hyperoxia-induced lung injury (as a model of BPD).

Methods (1) Homozygous CXCL10 knockout (CXCL10-/-) mice as well as wild-type mice (WT) were either exposed to hyperoxia (85% O2, HYX) or normoxia (21% O2, NOX) from postnatal day 1 (P1) to P14 and studied at P14. (2) For recovery, some mice were transferred from HYX to NOX for two additional weeks and were then sacrificed at P28. Excised lungs were snap-frozen for molecular biology studies or pressure-fixed with paraformaldehyde and embedded in paraffin for histomorphometric analyses. (3) J744A.1 macrophages were treated with CXCL10 or CXCR3 antagonist, and cell migration was studied.

Results (1). Lungs of HYX-exposed WT showed significantly increased macrophage invasion at P14 compared with the control group. This inflammatory response after HYX resulted in impaired alveolarization, increased apoptosis and extracellular matrix (ECM) remodeling. CXCL10-/- protected the newborn mice from the inflammation and partially from the HYX-induced structural changes. (2) After recovery at P28, CXCL10-/- mice exhibited improved lung structure and attenuated matrix remodeling in comparison to WT. (3) Loss of CXCL10 prevented the macrophage influx to the lungs at both P14 and P28 after HYX. (3) Treatment with recombinant CXCL10 or CXCR3 antagonist significantly promoted and reduced the migration of macrophages, respectively.

Conclusion Our data demonstrate that deficiency of CXCR3-CXCL10 axis blocks macrophage chemotaxis to the lung, partially enables lung growth, and protects from ECM in experimental BPD.



Publication History

Article published online:
21 September 2022

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