專科醫師陳光裕的部落格

夜眠時往頭頸部水分子集聚與阻塞型睡眠呼吸中止症關係的實證醫學查證
Kuang -Yu Chen, Ming-Hui Hung, Kuo-Chin Chiu, Wei-Chun Lin, Fung-J Lin
Pulmonary and Critical Care Medicine, Poh-Ai Hosp, Yi-Lung County, Taiwan

Introduction: Patients of obstructive sleep apnea (OSA) might be in high risk on the development of cardiovascular, new-growth lesions and airway diseases. Intermittent hypoxia and high loop gain both might predispose angiogenesis under system effect of molecule named vascular endothelial growth factor (VEGF). VEGF and its receptor VEGFR were known to act intracellularly via integrins-VEGF association at the cell surface. To update current research finding on these factors those might interfere the nocturnal rostral fluid accumulation, an evidence-based research was performed.

Materials and methods: An evidence-based medicine, EBM, searching for articles in PubMed, 2012/Jan/1 to 2017/Jun/1, with keywords as "sleep apnea syndrome", "nocturnal rostral fluid ", "angiogenesis", "VEGF", “integrins” and "loop gain". Then further stratifying the results by "airway diseases", "bronchospasm" and "intermittent hypoxia". 2000 Oxford’s CEBM levels of evidence (LoE) were followed.

Results: 

• (a). Nejat Altintas et al [Angiology 2016;67(4):364–374][LoE:2c] In Pearson correlation, there was a significant positive correlation between serum endocan levels and apnea-hypopnea index (AHI) (rho = 0.714, p<0.001). After 3 months of CPAP treatment, endocan levels were significantly decreased compared to baseline values (3.25 ± 2.24 vs 5.01 ± 3.17 ng/dL) (p< 0.001). 
• (b). Filip Roudnicky et al [Cancer Research 2012;73(3);1097–1106.][LoE:4] TaqMan-based qRT-PCR showed that endocan mRNA expression was 1,000- to 100,000-fold higher in tumor-associated microvasculature-derived endothelial cells (BECs) than in normal. Knockdown of endocan, followed by incubation of HUVECs with VEGF-A for 10 minutes, resulted in a strong reduction of VEGFR-2 phosphorylation, whereas the total amount of VEGFR-2 was unchanged. These findings indicate that endocan is necessary for VEGF-A–induced signaling and VEGFR-2 phosphorylation. 
• (c). Kanbay A. et al [Clin Respir J. 2016;Apr:26 doi: 10.1111/crj.12487] [LoE:3b] In this 128 patients’ cohort study, there was a positive correlation between AHI and serum endocan levels (rho= 0.826, p<0.0001) and further observation revealed a strong negative correlation between serum endocan level and flow-mediated dilatation which represented endothelial function  (rho = -0.613, p<0.0001). 
• (d). Turnbull CD et al [Respirology 2017;22(4):793-799][LoE:3b] In this 109 patients’ cohort sham CPAP study, those with sham CPAP was associated with a return of OSA (between-group difference in oxygen desaturation index (ODI) 36.0/h (95% CI 29.9-42.2)(p < 0.001). But return of OSA seemed not with association to changes in endocan, or VEGF. 
• (e). Anne Briançon-Marjollet et al [Sleep Medicine 2014;15:1424–1429][LoE: 4] For the first time, the intermittent hypoxia exposure for 14 nights is a sufficient stimulus to induce a significant increase in serum VEGF level in healthy subjects, supporting the hypothesis that OSA through intermittent hypoxia could be an independent risk factor inducing the secretion of VEGF. 
• (f). Janette K Burgess et al [Journal of Pathology 2016;240: 397–409][LoE:3a] Extracellular matrix (ECM) is a highly dynamic environment, with some molecules changing rapidly and other components maintaining a steady state. Parts of the ECM are being constantly remodelled and subjected to post-transcriptional changes. Collagen turnover rates in the lung have been estimated to be up to 10–15% per day. 
• (g). Kelsey D. Sack et al [J. Cell. Physiol. 2016;231:2026–2039][LoE:5] Extracellular matrix binding is necessary for VEGF internalization. Stiffness modifies the coordinated actions of VEGF-matrix binding and b1 integrin binding/activation, which together are critical for VEGF internalization. This study provides insight into how the microenvironment may influence tissue regeneration and response to injury and disease. 

More well-designed randomized clinical trial designed for different loop gain to VEGF-integrins interaction are urgently needed.

References:

1. Kelsey D. Sack et al Extracellular Matrix Stiffness Controls VEGF Signaling and Processing in Endothelial Cells J Cell Physiol 2016;231:2026-2039 
2. Michael Schuliga et al The Coagulant Factor Xa Induces Protease-Activated Receptor-1 and Annexin A2–Dependent Airway Smooth Muscle Cytokine Production and Cell Proliferation Am J Respir Cell Mol Biol 2016 Feb;54(2):200-209
3. Janette K Burgess et al The extracellular matrix – the under-recognized element in lung disease? J Pathol 2016; 240: 397–409 DOI: 10.1002/path.4808
4. Anne Briancon-Marjollet et al Intermittent hypoxia upregulates serum VEGF　Letters to the Editor Sleep Medicine  2014;15 :1424-1429