Ramnath Natasja W M, van de Luijtgaarden Koen M, van der Pluijm Ingrid, van Nimwegen Menno, van Heijningen Paula M, Swagemakers Sigrid M A, van Thiel Bibi S, Ridwan Ruziedi Y, van Vliet Nicole, Vermeij Marcel, Hawinkels Luuk J A C, de Munck Anne, Dzyubachyk Oleh, Meijering Erik, van der Spek Peter, Rottier Robbert, Yanagisawa Hiromi, Hendriks Rudi W, Kanaar Roland, Rouwet Ellen V, Kleinjan Alex, Essers Jeroen
Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
PLoS One. 2014 Sep 25;9(9):e106054. doi: 10.1371/journal.pone.0106054. eCollection 2014.
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.
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.
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.
Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation.
在本研究中，我们着手调查临床上观察到的慢性阻塞性肺疾病（COPD）与主动脉瘤之间的关系。我们检验了一种假设，即遗传性结缔组织缺陷可能在肺气肿和血管疾病的共同发展中起作用。
我们首先确定了主动脉瘤患者和动脉闭塞性疾病患者临床队列中慢性阻塞性肺疾病的患病率。随后，我们采用了一种综合方法，包括病理学、功能学、分子影像学、免疫学和基因表达分析，以揭示在动脉瘤性纤连蛋白-4缺陷（Fibulin-4(R)）小鼠中导致肺气肿的一系列事件。
我们在此表明，与动脉闭塞性疾病患者相比，COPD在动脉瘤患者中更为普遍，且与吸烟、其他临床危险因素和炎症无关。此外，我们证明动脉瘤性Fibulin-4(R/R)小鼠表现出严重的发育性肺气肿，而Fibulin-4(+/R)小鼠随着年龄增长和受到感染应激时会出现肺泡破坏。肺部抗蛋白酶能力的降低进一步加剧了这个恶性循环，最终导致肺气肿的发展。
我们的实验数据确定了细胞外基质降解的遗传易感性和继发性炎症是COPD和动脉瘤形成的共同机制。
