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    • Given that A cells we

    2018-11-05

    Given that A549 Autophagy Compound Library we used are not derived from the small airways but are a transformed cell line with a pneumocyte phenotype, and our BMPR2 protein and mRNA expression work was performed in PBMCs but not lung tissue, we performed eQTL look-up in lung cell types (including whole human lung) to see whether or not the studied SNPs rs6435156C>T and rs1048829G>T indeed act as cis acting eQTLs for BMPR2. Based on calculation in the online free resources of SNPexp and GENE Expression VARiation (Genevar), only rs1048829 was found to act as cis acting eQTLs for BMPR2 though with weak statistical difference (P=0.05). The possible reason for the conflicting results between eQTL results and the functional results we obtained in this study might be due to the bank data in SNPexp was not derived from Chinese population and Genevar was not from COPD patients (Cheung et al., 2012; Holm et al., 2010; Yang et al., 2010). It is generally believed that the initial event in the natural history of PH associated with COPD could be due to endothelial dysfunction and inflammation caused by risk factors including cigarette smoke (Barbera and Blanco, 2009). Although the actual role of BMPR2 in PH or COPD development are not fully understood, it was known playing an anti-inflammatory function in endothelial cells in response to proatherogenic stimuli (Kim et al., 2013). In BMPR2 heterozygous mutant mice, BMPR2 deficiency leads to enhanced proinflammatory cytokine production in pulmonary artery smooth muscle cells (Davies et al., 2012). BMP4, a ligand of BMPR2, participates in controlling LPS-induced inflammatory responses in lung epithelial cells (Li et al., 2014). Collectively, these evidence suggest that BMPR2 could be a critical anti-inflammatory factor in the lung, where the mutation of BMPR2 contributes to uncontrolled inflammation and development of COPD. Considering both genetic and environmental factors were involved in COPD pathology, we further tested the interaction between BMPR2 mutation and cigarette smoking on COPD risk. Our results from both population-based in vivo and cell-based in vitro study confirmed that the rs6435156C>T mutation in 3′UTR of BMPR2 contributed to downregulated BMPR2 expression in epithelial and immune cells, at least in part by interacting with cigarette smoke-induced effects. The findings of our study are limited by hospital-based case–control population in southern Chinese. Larger population-based studies in different ethnic groups are warranted for future validation. In addition, this study is also limited by SNP assessment in the 3′UTR of BMPR2, the roles of SNPs or other types of mutations in other regions of BMPR2 gene, i.e. the promoter, the coding exons and introns, etc., worth further investigating to fully understand the relationship of BMPR2 mutation and COPD risk. In summary, this study demonstrated that the functional polymorphism rs6435156C>T in the 3′UTR of BMPR2 contributes to increased risk of COPD likely via binding with has-miR-20a. The rs6435156T genotype of BMPR2 may serve as an important target for novel drug development and as a biomarker for COPD susceptibility assessment. The following are the supplementary data related to this article.
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    Conflicts of Interest
    Introduction The coagulation system and innate immunity are coordinately activated and highly integrated during venous and arterial thrombus formation and progression (von Bruhl et al., 2012; Engelmann and Massberg, 2013; Fuchs et al., 2012). Vascular endothelial activation or damage causes release of ultralarge von Willebrand factor (VWF) and P-selectin from Weibel-Palade bodies, and local activation of complement with liberation of anaphylatoxic and chemotactic factors C3a and C5a. These pathways cooperate to trigger platelet, neutrophil, and monocyte recruitment and activation (von Bruhl et al., 2012). The locally accumulated cells release proteases, reactive oxygen species, and nucleosomes, which provide a scaffold for aggregating platelets and red blood cells and further promote coagulation and fibrin formation (Fuchs et al., 2012). Several complement factors, including C3, C4, C3a, C5a and factor H are incorporated into the thrombus, where they modulate thrombus stability and the inflammatory process (Distelmaier et al., 2009; Howes et al., 2012). The fibrinolytic system and plasmin-mediated proteolysis are also intimately coupled to the axis of thrombus development and inflammation by controlling fibrin degradation, activation of matrix metalloproteinases, infiltration of monocytes/macrophages and other immune mediators, vessel wall remodeling, and ultimately thrombus resolution (Wakefield et al., 2008).