BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor and bronchoconstrictor but it has been shown to have also proinflammatory properties. Its ability to attract inflammatory cells in its site of production, upregulates the synthesis of adhesion molecules and stimulates the release of cytokines. The fact that cytokines have the ability to induce its synthesis and release, creates a dynamic loop for self-preservation and augmentation of the airway inflammation in Chronic Obstructive Pulmonary Disease (COPD), even after the ceasing of the noxious stimulus, i.e., cigarette smoke. Therefore, functional polymorphisms that may lead to increased levels of ET-1 may also cause an increased susceptibility to COPD development. MATERIALS AND METHODS: We analyzed the longitudinal effect on lung function of two ET-1 gene polymorphisms in a population of 190 smokers (95 non-COPD and 95 COPD smokers). The two polymorphisms involved an insertion polymorphism (+138 adenine insertion 3A/4A, 138bp downstream from the transcription start site, exon 1) and a single nucleotide transversion polymorphism on exon 5 (G/T, Lys198Asn). A total of 190 subjects were enrolled in the study for each polymorphism and were followed for 3 years by annual spirometry sessions. RESULTS: The adjusted annual decline of forced expiratory volume in 1 second (dFEV1) was greater for those having at least one copy of the mutated gene ins/delA compared to those with the wild type allele both in the non-COPD smokers group (mean difference in dFEV, of 19.4 ml/year, p = 0.004) and COPD smokers (mean difference in dFEV1 of 11.15 ml/year, p = 0.003). On the contrary, those heterozygous for the Lys198Asn polymorphism were found to have a slower decline in FEV1 compared to those homozygous for the wild type allele. The non-COPD smokers group had a gain-in-loss of 11,24 ml/year (p < 0.001) while the COPD-smokers group had a slower decline of 11.42 ml/year (p = 0.002). Those homozygous for the polymorphisms examined show an even greater deviation from those with the wild type allele but due to the small number comprising their group, the results don't have enough statistical power. Though, they still show the trend of the effect the polymorphisms have on annual FEV1 decline. CONCLUSIONS: The present data shows that ET-1 and its functional polymorphisms may be implicated in COPD phenotype and severity.
BACKGROUND:Endothelin-1 (ET-1) is a potent vasoconstrictor and bronchoconstrictor but it has been shown to have also proinflammatory properties. Its ability to attract inflammatory cells in its site of production, upregulates the synthesis of adhesion molecules and stimulates the release of cytokines. The fact that cytokines have the ability to induce its synthesis and release, creates a dynamic loop for self-preservation and augmentation of the airway inflammation in Chronic Obstructive Pulmonary Disease (COPD), even after the ceasing of the noxious stimulus, i.e., cigarette smoke. Therefore, functional polymorphisms that may lead to increased levels of ET-1 may also cause an increased susceptibility to COPD development. MATERIALS AND METHODS: We analyzed the longitudinal effect on lung function of two ET-1 gene polymorphisms in a population of 190 smokers (95 non-COPD and 95 COPD smokers). The two polymorphisms involved an insertion polymorphism (+138 adenine insertion 3A/4A, 138bp downstream from the transcription start site, exon 1) and a single nucleotide transversion polymorphism on exon 5 (G/T, Lys198Asn). A total of 190 subjects were enrolled in the study for each polymorphism and were followed for 3 years by annual spirometry sessions. RESULTS: The adjusted annual decline of forced expiratory volume in 1 second (dFEV1) was greater for those having at least one copy of the mutated gene ins/delA compared to those with the wild type allele both in the non-COPD smokers group (mean difference in dFEV, of 19.4 ml/year, p = 0.004) and COPD smokers (mean difference in dFEV1 of 11.15 ml/year, p = 0.003). On the contrary, those heterozygous for the Lys198Asn polymorphism were found to have a slower decline in FEV1 compared to those homozygous for the wild type allele. The non-COPD smokers group had a gain-in-loss of 11,24 ml/year (p < 0.001) while the COPD-smokers group had a slower decline of 11.42 ml/year (p = 0.002). Those homozygous for the polymorphisms examined show an even greater deviation from those with the wild type allele but due to the small number comprising their group, the results don't have enough statistical power. Though, they still show the trend of the effect the polymorphisms have on annual FEV1 decline. CONCLUSIONS: The present data shows that ET-1 and its functional polymorphisms may be implicated in COPD phenotype and severity.
Authors: Jia W Tan; Tina Gupta; Worapaka Manosroi; Tham M Yao; Paul N Hopkins; Jonathan S Williams; Gail K Adler; Jose R Romero; Gordon H Williams Journal: JCI Insight Date: 2017-12-07