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Aberrant elastin remodeling in the lungs of O2-exposed newborn mice; primarily results from perturbed interaction between integrins and elastin

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Abstract

Excessive localization of elastin from septal tips to alveolar walls is a key feature of bronchopulmonary dysplasia (BPD). The abnormal accumulation of lung elastin, involving the structural and functional interaction of a series of proteins, remains poorly understood. To further investigate the mechanisms accounting for the abnormal accumulation of elastin in the lungs of newborn mice with BPD, we evaluate elastin distribution and its interaction with proteins involved in its aberrant localization, such as integrin αv, fibulin-5 and transforming growth factor β1 (TGF-β1), in lungs of newborn mice exposed to 60 % O2 for 21 days. Lung histology revealed aberrant elastin production and impaired lung septation in O2-exposed lungs, while tropoelastin, integrin αv, fibulin-1, fibulin-2 and fibulin-4 gene expression were elevated. Dual staining image analysis of lung sections revealed that co-localization of integrin αv and elastin increased following O2 exposure with elastin distributed throughout the walls of air spaces rather than at septal tips. Furthermore, integrin αv appeared to be induced initially. Concurrently, increased fibulin-5 and TGF-β1 (which may regulate elastic fiber assembly) expression was detected, which may explain the altered lung elastin deposition and defective septation that are observed during BPD. These data support the hypothesis that excessive and aberrant αv integrin expression was initially induced by hyperoxia; αv integrin then interacted with and recruited elastin. These alterations were accompanied by fibulin-5 deposition and TGF-β1 activation, which may impede normal matrix remodeling, thereby contributing to the pathological pulmonary features of BPD.

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Acknowledgments

We thank Prof. Xianqing Jin for providing technical assistance and insightful discussions during the preparation of the manuscript. We thank Dr. Xiaoyong Zhang of the Wistar Institute (USA), who provided medical writing services. This research was supported by the National Natural Science Foundation of China (No. 81270058, 30770950) and by the Chongqing Natural Science Foundation (CSTC, 2009BB6072). Wenli Han, Qiutong Liu and Zhaoyun Liu designed and performed the experiments, analyzed the data and prepared the manuscript. Zhaoyun Liu bred the mice. Chunbao Guo, Junqing Yang and Chun Deng designed the experiments, analyzed the data, evaluated the manuscript and wrote the paper.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Neonatology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing, China

    Wenli Han, Qiutong Liu, Benli Yu, Zhaoyun Liu & Chun Deng

  2. Department of Pharmacology, Chongqing Medical University, Chongqing, China

    Wenli Han & Junqing Yang

  3. Department of Hepatology and Liver transplantation Center, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing, China

    Chunbao Guo

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  1. Wenli Han
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  4. Benli Yu
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  5. Zhaoyun Liu
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  7. Chun Deng
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Correspondence to Junqing Yang or Chun Deng.

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Wenli Han and Chunbao Guo contributed equally to the manuscript.

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Han, W., Guo, C., Liu, Q. et al. Aberrant elastin remodeling in the lungs of O2-exposed newborn mice; primarily results from perturbed interaction between integrins and elastin. Cell Tissue Res 359, 589–603 (2015). https://doi.org/10.1007/s00441-014-2035-1

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