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PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/15957913PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/15957913 with the analysis of variance (ANOVA) (Bonferroni-Dunn) with values of p < 0.05 sufficient to reject the null hypothesis for all analyses. All experiments were designed with matched control conditions within each experiment to enable statistical comparison as paired samples.ResultsFormoterol inhibits basal and thrombin-, but not PDGF-induced human PAVSM cell proliferationBecause formoterol inhibits proliferation of human bronchus fibroblasts and airway smooth 2-Amino-3-methoxypyridine muscle cells [9,14], we examined the effects of formoterol and its enantiomers on the proliferation of human PAVSM cells under serumdepleted conditions and in the presence of thrombin and PDGF, confirmed PAVSM mitogens that are involved in PH pathogenesis [20,39,40]. Consistent with our published data [20], serum-deprived PAVSM cells had modest levels of DNA synthesis that were significantly increased by treatment with PDGF and thrombin (Figure 1A). Racemic formoterol inhibited DNA synthesis in serum-deprived human PAVSM cells in a concentration-dependent manner (Figure 1B). (R,R) formoterol had a greater inhibitory effect on human PAVSM cell proliferation compared to racemic formoterol (IC50 1 M and 4 M, respectively). (S,S)formoterol had modest inhibitory effect (IC50 20 M)Goncharova et al. Respiratory Research 2012, 13:109 http://respiratory-research.com/content/13/1/Page 4 ofABCDFigure 1 Formoterol inhibits basal and thrombin-, but not PDGF-induced DNA synthesis in human PAVSM cells. A: Cells serum-deprived for 48 h were treated for 18 h with 1 U/ml thrombin, 10 ng/ml PDGF, or diluent followed by DNA synthesis analysis using the BrdU incorporation assay. Data represent a percentage of BrdU-positive cells per total number of cells taken as 100 . Data are mean values ?SE from three independent experiments. A minimum of 200 cells per each condition were analyzed in each experiment. B-D: Cells serum-deprived for 48 h were treated with 0.2, 2, 20 M (R,R)-, (S,S)-, racemic formoterol, or diluent PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/4155310 in the presence of vehicle (B), 1 U/ml thrombin (C) or 10 ng/ml PDGF (D) followed by DNA synthesis analysis using the BrdU incorporation assay. Data are means ?SE from three separate experiments, 3-((4-Iodophenoxy)methyl)pyridine n = 3 for each experimental condition. *p < 0.001 for formoterol vs. diluent and for thrombin + (R,R) formoterol vs. thrombin by ANOVA (Bonferroni-Dunn). A minimum of 200 cells per condition were analyzed in each experiment.and attenuated DNA synthesis only when used in maximal dose. (R,R) and, to a lesser extent, racemic formoterol significantly inhibited thrombin-induced human PAVSM cell proliferation (IC50 for (R,R) formoterol 20 M), and (S,S) formoterol had no significant effect (Figure 1C). Both racemic and (S,S) formoterol did not provide 50 inhibition of cell proliferation even when administrated in high doses (20 M). Interestingly, racemic formoterol and both formoterol enantiomers had no effect on PDGF-induced proliferation of human PAVSM cells (Figure 1D). These data demonstrate that formoterol inhibits basal and thrombin-induced, but not PDGF-stimulated human PAVSM cell proliferation and suggest that growth inhibitory effects of formoterol depend predominantly on its (R,R), but not (S,S) enantiomer.Formoterol inhibits PAVSM cell proliferation caused by chronic hypoxia exposureBecause chronic hypoxia is one of the confirmed triggers of PAVSM cell proliferation and pulmonary vascular remodeling in PH [2,4.