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Association between pulmonary function and peak oxygen uptake in elderly: the Generation 100 study
Authors:Hassel  Erlend  Stensvold  Dorthe  Halvorsen  Thomas  Wisløff  Ulrik  Langhammer  Arnulf  Steinshamn  Sigurd
Institution:1.Department of Pneumology, Unit of Interstitial Lung Diseases, University Hospital of Bellvitge, Barcelona, Spain
;2.Pneumology Research Group, IDIBELL, University of Barcelona, Barcelona, Spain
;3.Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain
;4.Department of Preventive Medicine, University Hospital of Bellvitge, Barcelona, Spain
;5.Department of Pathology, University Hospital of Bellvitge, Barcelona, Spain
;6.Department of Thoracic Surgery, University Hospital of Bellvitge, Barcelona, Spain
;7.Research Network in Respiratory Diseases (Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias), ISCIII, Barcelona, Spain
;8.Department of Biochemistry, University of Geneva, Science II, Geneva, Switzerland
;
Abstract:Chronic obstructive lung disease (COPD) is a common cause of death in industrialized countries often induced by exposure to tobacco smoke. A substantial number of patients with COPD also suffer from pulmonary hypertension that may be caused by hypoxia or other hypoxia-independent stimuli - inducing pulmonary vascular remodeling. The Ca2+ binding protein, S100A4 is known to play a role in non-COPD-driven vascular remodeling of intrapulmonary arteries. Therefore, we have investigated the potential involvement of S100A4 in COPD induced vascular remodeling. Lung tissue was obtained from explanted lungs of five COPD patients and five non-transplanted donor lungs. Additionally, mice lungs of a tobacco-smoke-induced lung emphysema model (exposure for 3 and 8 month) and controls were investigated. Real-time RT-PCR analysis of S100A4 and RAGE mRNA was performed from laser-microdissected intrapulmonary arteries. S100A4 immunohistochemistry was semi-quantitatively evaluated. Mobility shift assay and siRNA knock-down were used to prove hypoxia responsive elements (HRE) and HIF binding within the S100A4 promoter. Laser-microdissection in combination with real-time PCR analysis revealed higher expression of S100A4 mRNA in intrapulmonary arteries of COPD patients compared to donors. These findings were mirrored by semi-quantitative analysis of S100A4 immunostaining. Analogous to human lungs, in mice with tobacco-smoke-induced emphysema an up-regulation of S100A4 mRNA and protein was observed in intrapulmonary arteries. Putative HREs could be identified in the promoter region of the human S100A4 gene and their functionality was confirmed by mobility shift assay. Knock-down of HIF1/2 by siRNA attenuated hypoxia-dependent increase in S100A4 mRNA levels in human primary pulmonary artery smooth muscle cells. Interestingly, RAGE mRNA expression was enhanced in pulmonary arteries of tobacco-smoke exposed mice but not in pulmonary arteries of COPD patients. As enhanced S100A4 expression was observed in remodeled intrapulmonary arteries of COPD patients, targeting S100A4 could serve as potential therapeutic option for prevention of vascular remodeling in COPD patients.
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