Abstract
BackgroundChronic 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.MethodsLung 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.ResultsLaser-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.ConclusionsAs 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0284-5) contains supplementary material, which is available to authorized users.
Highlights
Chronic obstructive lung disease (COPD) is a common cause of death in industrialized countries often induced by exposure to tobacco smoke
S100A4 localization and expression in the tobacco-smoke induced murine model of emphysema Initially we examined the pattern of S100A4 expression in mouse lungs after three and eight months of smoke exposure by immunohistochemical staining
As assessed by real-time Polymerase chain reaction (PCR) analysis, there was no significant change in the mRNA level of S100A4 in lung homogenates after three months (2.58 ± 0.21; p = 0.06) or eight months of smoke exposure (2.22 ± 0.45; p = 0.44) compared to control animals (2.06 ± 0.13 after 3 months; 2.89 ± 0.69 after 8 months) (Fig. 1e)
Summary
Chronic obstructive lung disease (COPD) is a common cause of death in industrialized countries often induced by exposure to tobacco smoke. Chronic obstructive bronchitis is a chronic airway inflammation with loss of the mucociliary clearance, increased infect-exacerbation rate and bronchus wall instability In many cases it is caused by smoking [1]. Data from the Global initiative for chronic Obstructive Lung Disease (GOLD-report) estimated that up to 25 % of the adult population aged 40 years or older have COPD [1]. Based on this high prevalence, COPD is a common cause of death in industrialized countries [2]. Cigarette smoke is one of the highest risk factors known to actively cause the disease [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
