Aberrant elastin remodeling in the lungs of O2-exposed newborn mice; primarily results from perturbed interaction between integrins and elastin
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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.
KeywordsBronchopulmonary dysplasia Integrin αv Elastin Alveolarization
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.
Conflicts of Interest
The authors declare that they have no competing interests.
- Alejandre-Alcázar MA, Kwapiszewska G, Reiss I, Amarie OV, Marsh LM, Sevilla-Pérez J, Wygrecka M, Eul B, Köbrich S, Hesse M, Schermuly RT, Seeger W, Eickelberg O, Morty RE (2007) Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 292:L537–L549PubMedCrossRefGoogle Scholar
- Blanchevoye C, Floquet N, Scandolera A, Baud S, Maurice P, Bocquet O, Blaise S, Ghoneim C, Cantarelli B, Delacoux F, Dauchez M, Efremov RG, Martiny L, Duca L, Debelle L (2013) Interaction between the elastin peptide VGVAPG and human elastin binding protein. J Biol Chem 288:1317–1328PubMedCentralPubMedCrossRefGoogle Scholar
- Bland RD, Mokres LM, Ertsey R, Jacobson BE, Jiang S, Rabinovitch M, Xu L, Shinwell ES, Zhang F, Beasley MA (2007a) Mechanical ventilation with 40 % oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 293:L1099–L1110PubMedCrossRefGoogle Scholar
- Bland RD, Xu L, Ertsey R, Rabinovitch M, Albertine KH, Wynn KA, Kumar VH, Ryan RM, Swartz DD, Csiszar K, Fong KS (2007b) Dysregulation of pulmonary elastin synthesis and assembly in preterm lambs with chronic lung disease. Am J Physiol Lung Cell Mol Physiol 292:L1370–L1384PubMedCrossRefGoogle Scholar
- Bland RD, Ertsey R, Mokres LM, Xu L, Jacobson BE, Jiang S, Alvira CM, Rabinovitch M, Shinwell ES, Dixit A (2008) Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice. Prelude to defective alveolar septation during lung development? Am J Physiol Lung Cell Mol Physiol 294:L3–L14PubMedCrossRefGoogle Scholar
- Dabovic B, Robertson IB, Zilberberg L, Vassallo M, Davis EC, Rifkin DB (2014) Function of latent TGF-β binding protein 4 and fibulin 5 in elastogenesis and lung development. J Cell Physiol 229:226–236Google Scholar
- Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG, Griggs DW, Prinsen MJ, Maher JJ, Iredale JP, Lacy-Hulbert A, Adams RH, Sheppard D (2013) Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19:1617–1624PubMedCrossRefGoogle Scholar
- Hilgendorff A, Parai K, Ertsey R, Jain N, Navarro EF, Peterson JL, Tamosiuniene R, Nicolls MR, Starcher BC, Rabinovitch M, Bland RD (2011) Inhibiting lung elastase activity enables lung growth in mechanically ventilated newborn mice. Am J Respir Crit Care Med 184:537–546PubMedCentralPubMedCrossRefGoogle Scholar
- Hilgendorff A, Parai K, Ertsey R, Juliana Rey-Parra G, Thébaud B, Tamosiuniene R, Jain N, Navarro EF, Starcher BC, Nicolls MR, Rabinovitch M, Bland RD (2012) Neonatal mice genetically modified to express the elastase inhibitor elafin are protected against the adverse effects of mechanical ventilation on lung growth. Am J Physiol Lung Cell Mol Physiol 303:L215–L227PubMedCentralPubMedCrossRefGoogle Scholar
- Joss-Moore LA, Wang Y, Yu X, Campbell MS, Callaway CW, McKnight RA, Wint A, Dahl MJ, Dull RO, Albertine KH, Lane RH (2011) IUGR decreases elastin mRNA expression in the developing rat lung and alters elastin content and lung compliance in the mature rat lung. Physiol Genomics 43:499–505PubMedCentralPubMedCrossRefGoogle Scholar
- Kumarasamy A, Schmitt I, Nave AH, Reiss I, van der Horst I, Dony E, Roberts JD Jr, de Krijger RR, Tibboel D, Seeger W, Schermuly RT, Eickelberg O, Morty RE (2009) Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs. Am J Respir Crit Care Med 180:1239–1252PubMedCrossRefGoogle Scholar
- Lohmann P, Luna RA, Hollister EB, Devaraj S, Mistretta TA, Welty SE, Versalovic J (2014) The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia. Pediatr Res 76:294–301Google Scholar
- Madurga A, Mižíková I, Ruiz-Camp J, Vadász I, Herold S, Mayer K, Fehrenbach H, Seeger W, Morty RE (2014) Systemic hydrogen sulfide administration partially restores normal alveolarization in an experimental animal model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 306:L684–L697PubMedCrossRefGoogle Scholar
- Mokres LM, Parai K, Hilgendorff A, Ertsey R, Alvira CM, Rabinovitch M, Bland RD (2010) Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice. Am J Physiol Lung Cell Mol Physiol 298:L23–L35PubMedCentralPubMedCrossRefGoogle Scholar
- Puthawala K, Hadjiangelis N, Jacoby SC, Bayongan E, Zhao Z, Yang Z, Devitt ML, Horan GS, Weinreb PH, Lukashev ME, Violette SM, Grant KS, Colarossi C, Formenti SC, Munger JS (2008) Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am J Respir Crit Care Med 177:82–90PubMedCentralPubMedCrossRefGoogle Scholar
- Wang H, Jafri A, Martin RJ, Nnanabu J, Farver C, Prakash YS, MacFarlane PM (2014) Severity of neonatal hyperoxia determines structural and functional changes in developing mouse airway. Am J Physiol Lung Cell Mol Physiol 307:L295–L301Google Scholar