BioGPS Featured Article – Extracellular Matrix Defects in Aneurysmal Fibulin-4 Mice Predispose to Lung Emphysema

BioGPS has become the valuable resource that it is because of the contributions from our wonderful user community. Thank you for contributing plugins, suggestions, and ideas–all of which have improved BioGPS for everyone. In order to celebrate the contributions of BioGPS users to the scientific research community, this series will feature publications and articles generated by BioGPS users. We sincerely hope you will join us in celebrating the fascinating work that YOU do.

This week, we will feature an article from a highly interdisciplinary team of researchers from nine different departments at Erasmus MC in Rotterdam, two departments from Leiden University Medical Centre, and one at the University of Texas Southwestern Medical Center: Extracellular Matrix Defects in Aneurysmal Fibulin-4 Mice Predispose to Lung Emphysema by Natasja W.M. Ramnath, Koen M. van de Luijtgaarden, Ingrid van der Pluijm, Menno van Nimwegen, Paula M. van Heijningen, Sigrid M.A. Swagemakers, Bibi S. van Thiel, Ruziedi Y. Ridwan, Nicole van Vliet, Marcel Vermeij, Luuk J.A.C. Hawinkels, Anne de Munck, Oleh Dzyubachyk, Erik Meijering, Peter van der Spek, Robbert Rottier, Hiromi Yanagisawa, Rudi W. Hendriks, Roland Kanaar, Ellen V. Rouwet, Alex KleinJan, Jeroen Essers. (DOI 10.1371/journal.pone.0106054)

Dr. Jeroen Essers kindly answered our inquiries for this series.

1. Who is the team behind the work that was published in Extracellular Matrix Defects in Aneurysmal Fibulin-4 Mice Predispose to Lung Emphysema?.
   Authors: Natasja W.M. Ramnath^1,7, Koen M. van de Luijtgaarden⁷, Ingrid van der Pluijm^1,7, Menno van Nimwegen², Paula M. van Heijningen¹, Sigrid M.A. Swagemakers^1,3, Bibi S. van Thiel^1,7,8, Ruziedi Y. Ridwan^1,7,8, Nicole van Vliet¹, Marcel Vermeij⁴, Luuk J.A.C. Hawinkels⁹, Anne de Munck¹⁰, Oleh Dzyubachyk^5,11, Erik Meijering⁵, Peter van der Spek³, Robbert Rottier¹⁰, Hiromi Yanagisawa¹², Rudi W. Hendriks², Roland Kanaar^1,6, Ellen V. Rouwet⁷, Alex KleinJan², Jeroen Essers^1,6,7

   Affiliations:
   ¹Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands.
   ²Department of Pulmonary Diseases, Erasmus MC, Rotterdam, The Netherlands.
   ³Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
   ⁴Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
   ⁵Department of Medical Informatics and Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
   ⁶Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
   ⁷Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
   ⁸Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
   ¹⁰Department of Pediatric Surgery, Erasmus MC, Rotterdam, The Netherlands. ⁹Department of Molecular Cell Biology and Centre for Biomedical Genetics. ¹¹Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands. ¹²Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

   Corresponding author:
   J. Essers
   Erasmus MC Room Ee669
   Wytemaweg 80
   3015 CN Rotterdam
   POB 2040
   3000 CA Rotterdam
   The Netherlands
   tel: +31 10 7043604
   fax: +31 10 7044743
   Email: jesserserasmusmcnl

 

2. Please provide a brief summary of the findings reported in your article, Extracellular Matrix Defects in Aneurysmal Fibulin-4 Mice Predispose to Lung Emphysema.
   In this study we set out to investigate the clinically observed relationship between susceptibility for chronic obstructive pulmonary disease (COPD) and aortic aneurysms (AA). First we analyzed this relationship in a clinical cohort of patients with AA or arterial occlusive disease (AOD) and found that COPD was significantly more prevalent in AA patients as compared to AOD patients. Importantly, this was independent of smoking and other cardiovascular risk factors. We then tested the hypothesis that an inborn deficiency of the connective tissue might play a role in this relationship using an aneurysmal Fibulin-4 mouse model.

   Fibulin-4 is essential for proper elastogenesis and extracellular matrix organization. We previously showed in this hypomorphic Fibulin-4 mouse model that decreased Fibulin-4 expression leads to a gradual decay of the extracellular matrix in the aorta, ultimately resulting in aneurysm formation. Here, we analyzed the lungs of these Fibulin-4 animals for signs of chronic lung disease. We observed severe developmental lung emphysema in the homozygous Fibulin-4R/R mice (with a 4-fold reduction in the amount of Fibulin-4). In contrast, heterozygous Fibulin-4+/R mice, which have only a 2-fold reduction in the amount of Fibulin-4, are born with normal elastin structures and without alveolar airspace enlargement, but acquire alveolar breakdown with ageing. Thus, this mild Fibulin-4 deficiency induces disruption of the ECM, which subsequently predisposes to an enhanced inflammatory response with further breakdown of alveolar walls. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema. Our experimental data suggest that a generalized genetic susceptibility to extracellular matrix degradation and secondary inflammation might be the common pathophysiologic mechanism underlying the tissue destruction in both COPD and aneurysm formation.

 

3. How did the team learn about BioGPS?
   The ErasmusMC department of bioinformatics is a strategic development partner from Affymetrix in the translational research space. Moreover the group has extensive links with pharmaceutical industry. Therefore we knew from the very early start about the existence of this very valuable data resource. We use this to validate any expression related observation in our R&D projects that we support in our non-for profit Dutch Academic University Medical Center..

 

4. How did your team utilize BioGPS in this research?
   Using independent gene expression comparison methods between datasets from lungs of Fibulin-4R/R mice and patients with COPD and lung emphysema we found an overlapping downregulated gene: SERPINA1, which encodes for α-1 antitrypsin. In order to determine local expression of α-1 antitrypsin in the lung we used the gene portal BioGPS, which identified expression of α-1 antitrypsin in the lung in the human Geneatlas U133A and mouse GeneAtlas MOE430 datasets.

 

5. What are some future directions for the team behind this research?
   We are interested in identifying molecular mechanisms of COPD and aneurysm formation and their link with aging. Using whole genome analyses of mouse models and comparison of these with the human disease we aim to identify predictive biomarkers.

Thanks again to Dr. Jeroen Essers for taking the time to answer our questions. Click here to read their fascinating article. Have a look because these awesome researchers have made their compelling research open access–so you can read the whole exciting article for free!

Used BioGPS and cited it in your publication? Let us know! We would love to feature YOUR work, no matter how long ago it was published. BioGPS Featured Article Series only started recently, but we know your contributions to science is ongoing.