Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.
<h4>Background</h4>In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined developm...
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Public Library of Science (PLoS)
2014
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oai:doaj.org-article:54e4a897fc8f4940a384b4aa95d8a42b2021-11-25T05:59:13ZExtracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.1932-620310.1371/journal.pone.0106054https://doaj.org/article/54e4a897fc8f4940a384b4aa95d8a42b2014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0106054https://doaj.org/toc/1932-6203<h4>Background</h4>In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease.<h4>Methods</h4>We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4(R)) mice.<h4>Results</h4>Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4(R/R) mice display severe developmental lung emphysema, whereas Fibulin-4(+/R) mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema.<h4>Conclusions</h4>Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation.Natasja W M RamnathKoen M van de LuijtgaardenIngrid van der PluijmMenno van NimwegenPaula M van HeijningenSigrid M A SwagemakersBibi S van ThielRuziedi Y RidwanNicole van VlietMarcel VermeijLuuk J A C HawinkelsAnne de MunckOleh DzyubachykErik MeijeringPeter van der SpekRobbert RottierHiromi YanagisawaRudi W HendriksRoland KanaarEllen V RouwetAlex KleinjanJeroen EssersPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 9, p e106054 (2014) |
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Medicine R Science Q 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 Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. |
| description |
<h4>Background</h4>In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease.<h4>Methods</h4>We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4(R)) mice.<h4>Results</h4>Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4(R/R) mice display severe developmental lung emphysema, whereas Fibulin-4(+/R) mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema.<h4>Conclusions</h4>Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Natasja W M Ramnath |
| title |
Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. |
| title_short |
Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. |
| title_full |
Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. |
| title_fullStr |
Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. |
| title_full_unstemmed |
Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. |
| title_sort |
extracellular matrix defects in aneurysmal fibulin-4 mice predispose to lung emphysema. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/54e4a897fc8f4940a384b4aa95d8a42b |
| work_keys_str_mv |
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