活性维生素D<sub>3</sub>对老年慢性阻塞性肺疾病维生素D缺乏患者气道重塑的保护作用

何瀚夫; 聂晓红; 金宇; 罗立; 赖晓蓉; 朱鹏飞

doi:10.16766/j.cnki.issn.1674-4152.002413

活性维生素D₃对老年慢性阻塞性肺疾病维生素D缺乏患者气道重塑的保护作用

doi: 10.16766/j.cnki.issn.1674-4152.002413

1.
成都医学院第二附属医院呼吸与危重症医学科，四川成都 610051
2.
成都医学院第二附属医院检验医学科，四川成都 610051

基金项目:

四川省科技计划项目 2019YJ0649

详细信息

通讯作者:
聂晓红, E-mail: xhnie1226@sina.com

中图分类号: R563 R977.24
计量
- 文章访问数: 235
- HTML全文浏览量: 160
- PDF下载量: 3
- 被引次数: 0
出版历程
- 收稿日期: 2021-01-20
- 网络出版日期: 2022-08-20

Protective effect of active vitamin D₃ on airway remodelling in elderly patients with chronic obstructive pulmonary disease and vitamin D deficiency

1.
Department of Pulmonary and Critical Care Medicine, the Second Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610051, China

摘要

摘要: 目的探讨活性维生素D₃(阿法骨化醇)对老年慢性阻塞性肺疾病(简称慢阻肺)维生素D缺乏者气道重塑的保护作用。方法选取成都医学院第二附属医院2019年1月—2020年1月健康人群(健康对照组)40例及年龄≥60岁的25羟维生素D[25(OH)D]水平低于20 ng/mL的稳定期慢阻肺患者146例。慢阻肺患者采用随机数字法分为3组，分别为高剂量组(48例)、低剂量组(49例)及对照组(49例)，在入组时、3个月及6个月后分别测定患者的血液25(OH)D、基质金属蛋白酶9(MMP-9)、转化生长因子-β1(TGF-β1)、金属蛋白酶组织抑制因子-1(TIMP-1)，高分辨率CT测量支气管管壁厚度与外径比值(T/D)及气道壁面积占气道总截面积百分比(WA%)。结果慢阻肺组患者25(OH)D水平[(13.47±5.32)ng/mL]明显低于健康对照组[(20.35±8.34)ng/mL，P＜0.05]；而MMP-9、TGF-β1、TIMP-1、T/D、WA%显著高于健康对照组(均P＜0.05)。低剂量组补充3个月后25(OH)D、MMP-9、TGF-β1及WA%较补充前有明显改善(均P＜0.05)，补充6个月后TIMP-1和T/D较补充前也有改善(均P＜0.05)。高剂量组补充3个月及6个月治疗后，患者的25(OH)D水平及上述气道重塑指标均较治疗前有显著改善(均P＜0.05)，其中补充6个月后的25(OH)D、TGF-β1及WA%与同期的低剂量组比较差异有统计学意义(均P＜0.05)。25(OH)D水平与MMP-9、TGF-β1、WA%呈负相关(r值分别为-0.287、-0.311、-0.389，均P＜0.05)。结论老年慢阻肺维生素D缺乏者每天补充阿法骨化醇对25(OH)D水平的提升及气道重塑有较好的保护作用，高剂量连续补充6个月效果更佳。
- 25-羟维生素D /
- 缺乏 /
- 慢性阻塞性肺疾病 /
- 基质金属蛋白酶9 /
- 转化生长因子β1 /
- 气道重塑
Abstract: Objective To explore the protective effect of active vitamin D3 (alfacalcidol) on airway remodelling in elderly patients with chronic obstructive pulmonary disease (COPD) and vitamin D deficiency. Methods Forty healthy people (healthy control group) and 146 stable COPD patients with 25(OH)D level lower than 20 ng/mL were selected from January 2019 to January 2020. Patients with chronic obstructive pulmonary disease were randomly divided into three groups: high-dose group (n=48), low-dose group (n=49) and control group (n=49). The levels of 25(OH)D, matrix metalloproteinase-9 (MMP-9), transforming growth factor β1 (TGF-β1), tissue inhibitor of metallo-proteinase-1 (TIMP-1) in blood and HRCT were measured. The ratio of bronchial wall thickness to outer diameter (T/D) and the percentage of airway wall area to total airway cross-sectional area (WA%) were measured at the time of admission and at 3 and 6 months later. Results The 25(OH)D level in the COPD group was (13.47±5.32) ng/mL, which was significantly lower than that in the healthy control group [(20.35±8.34) ng/mL], P < 0.05. Meanwhile, the levels of MMP-9, TGF β-1, TIMP-1, T/D and WA% were significantly higher in the COPD group than in the healthy control group (P < 0.05). The levels of 25(OH)D, MMP-9, TGF-β1 and WA% in the low-dose group significantly improved after 3 months of supplementation (P < 0.05), and the levels of TIMP-1 and T/D in the low-dose group significantly improved after 6 months of supplementation (P < 0.05). The level of 25(OH)D and all airway remodelling indexes in the high-dose group after 3 and 6 months of treatment improved (all P < 0.05). The levels of 25(OH)D, TGF-β1 and WA% after 6 months of treatment were different from those in the low-dose group (P < 0.05). The 25(OH)D level negatively correlated with MMP-9, TGF-β1 and WA% (r=-0.287, -0.311, -0.389, respectively, all P < 0.05). Conclusion In elderly patients with COPD vitamin D deficiency, daily supplement of alfacalcidol exerts a better protective effect on the improvement of 25(OH)D level and airway remodelling, and high-dose supplement for 6 months exerts a better effect.
- 25-hydroxyvitamin D /
- Deficiency /
- Chronic obstructive pulmonary disease /
- Matrix metalloproteinase 9 /
- Transforming growth factor β1 /
- Airway remodelling

HTML全文

表 1 健康对照组与慢阻肺组25(OH)D水平及气道重塑指标比较(x±s)

Table 1. Comparison of 25(OH)D levels and airway remodeling indexes between healthy control group and COPD group (x±s)

组别	例数	年龄(岁)	25(OH)D(ng/mL)	MMP-9(μg/L)	TGF-β1(μg/L)	TIMP-1(μg/L)	T/D	WA%
健康对照组	40	72.74±7.49	20.35±8.34	7.31±2.26	10.37±3.69	49.31±16.10	0.17±0.03	31.41±10.56
慢阻肺组	146	74.58±7.11	13.47±5.32	11.52±3.85	15.42±5.65	66.02±20.35	0.35±0.04	57.80±12.29
t值		1.623	8.892	9.735	8.312	8.526	11.706	9.847
P值		0.131	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001

下载: 导出CSV

表 2 各指标组间、时间及组间与时间的交互作用

Table 2. Between groups, time, and interaction between groups and time

项目	组间		时间点		交互作用
项目	F值	P值	F值	P值	F值	P值
25(OH)D	10.304	< 0.001	10.453	0.005	77.525	< 0.001
MMP-9	8.082	< 0.001	22.045	< 0.001	43.443	< 0.001
TGF-β1	2.326	0.101	19.136	< 0.001	18.069	< 0.001
TIMP-1	8.132	< 0.001	12.726	0.002	24.628	< 0.001
T/D	3.153	0.257	8.935	0.009	15.247	< 0.001
WA%	9.031	< 0.001	17.388	< 0.001	51.345	< 0.001
多变量	6.844	< 0.001	87.739	< 0.001	60.309	< 0.001

下载: 导出CSV

表 3 3组慢阻肺患者不同时间点25(OH)D水平及气道重塑指标比较(x±s)

Table 3. Comparison of 25(OH)D levels and airway remodeling indexes at different time points in patients with chronic obstructive pulmonary disease in three groups(x±s)

组别	例数	25(OH)D(ng/mL)			MMP-9(pg/mL)			TGF-β1(pg/mL)
组别	例数	治疗前	治疗3个月	治疗6个月	治疗前	治疗3个月	治疗6个月	治疗前	治疗3个月	治疗6个月
对照组	49	13.47±5.32	13.41±5.75	13.59±5.49	11.52±3.85	11.36±3.57	12.03±3.86	15.42±5.65	15.65±6.02	14.97±5.73
低剂量组	49	13.58±5.95	16.32±5.60^ad	17.24±6.21^ad	11.91±4.02	9.93±4.10^ad	9.05±3.21^ad	16.03±5.27	14.12±4.98^ad	13.06±4.31^ad
高剂量组	48	13.36±5.43	18.09±6.38^abd	19.15±6. 02^acde	11.35±3.68	9.30±3.43^ad	8.85±2.92^ad	15.78±5.53	13.36±4.72^ad	12.01±3. 88^ade
F值		1.033	3.812	4.719	0.943	2.965	3.315	0.898	1.523	1.747
P值		0.437	0.017	0.008	0.466	0.046	0.024	0.461	0.284	0.217

组别	例数	TIMP-1(pg/mL)			T/D			WA%
组别	例数	治疗前	治疗3个月	治疗6个月	治疗前	治疗3个月	治疗6个月	治疗前	治疗3个月	治疗6个月
对照组	49	66.02±20.35	64.27±19.03	65.56±20.32	0.34±0.04	0.33±0.04	0.35±0.04	57.59±12.21	55.45±13.15	57.11±12.07
低剂量组	49	65.58±21.02	58.33±21.45	55.41±20.33^ad	0.36±0.06	0.30±0.04	0.27±0.04^ad	59.37±12.69	51.26±10.64^ad	47.05±10.11^ad
高剂量组	48	64.67±22.76	53.55±18.58^ad	52.90±19.72^ad	0.35±0.05	0.29±0.04^a	0.25±0.04^ad	56.85±13.57	49.62±11.36^ad	43.75±9.85^ade
F值		0.936	1.853	3.018	0.895	1.928	3.152	1.140	2.631	2.864
P值		0.423	0.201	0.035	0.511	0.185	0.021	0.396	0.047	0.038
注：与对照组3个月及6个月时比较, ^aP < 0.05;与低剂量组3个月时比较, ^bP < 0.05;与低剂量组6个月比较, ^cP < 0.05;与同组内治疗前比较, ^dP < 0.05;与同组3个月时比较, ^eP < 0.05。

下载: 导出CSV

表 4 25(OH)D水平与气道重塑指标相关性分析

Table 4. Correlation analysis between 25(OH)D level and airway remodeling indexes

统计量	MMP-9	TGF-β1	TIMP-1	T/D	WA%
r值	-0.287	-0.311	-0.115	-0.109	-0.389
P值	0.035	0.021	0.253	0.421	0.008

下载: 导出CSV

参考文献(26)

[1]	WANG C, XU J Y, YANG L, et al. Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health[CPH] study): A national cross-sectional study[J]. The Lancet, 2018, 391(10131): 1706-1717. doi: 10.1016/S0140-6736(18)30841-9
[2]	KÖKTÜRK N, KOÇ E M, KÖRLÜ A T, et al. Vitamin D status in hospitalized patients with chronic obstructive pulmonary disease[J]. Tuberk Toraks, 2020, 68(1): 25-34. doi: 10.5578/tt.66351
[3]	高蕾, 王曦, 王楠, 等. 维生素D对支气管哮喘气道重塑的治疗作用及意义[J]. 中华临床医师杂志(电子版), 2019, 13(12): 943-946. doi: 10.3877/cma.j.issn.1674-0785.2019.12.014 GAO L, WANG X, WANG N, et al. Effect of vitamin D on airway remodeling in asthma[J]. Chinese Journal of Clinicians (Electronic Edition), 2019, 13(12): 943-946. doi: 10.3877/cma.j.issn.1674-0785.2019.12.014
[4]	FÆRK G, ÇOLAK Y, AFZAL S, et al. Low concentrations of 25-hydroxy vitamin D and long-term prognosis of COPD: A prospective cohort study[J]. Eur J Epidemiol, 2018, 33(6): 567-577. doi: 10.1007/s10654-018-0393-9
[5]	SALEEM A, SHARIF S, JARVIS S, et al. A comprehensive review on vitamin D as a novel therapeutic agent in chronic obstructive pulmonary disease[J]. Cureus, 2021, 13(2): e13095.
[6]	SINGH D, AGUSTI A, ANZUETO A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: The GOLD science committee report 2019[J]. Eur Respir J, 2019, 53(5): 1900164. doi: 10.1183/13993003.00164-2019
[7]	蒋凌志, 许丹媛, 杨志雄. 支气管哮喘患者血清25-(OH)D3、TGF-β1水平与气道重塑的关系[J]. 山东医药, 2018, 58(12): 54-56. doi: 10.3969/j.issn.1002-266X.2018.12.016 JIANG L Z, XU D Y, YANG Z X, et al. Relationship between serum levels of 25-(OH)D3, TGF-β1 and airway remodeling in asthmatic patients[J]. Shandong Medical Journal, 2018, 58(12): 54-56. doi: 10.3969/j.issn.1002-266X.2018.12.016
[8]	RITCHIE A I, WEDZICHA J A. Definition, causes, pathogenesis, and consequences of chronic obstructive pulmonary disease exacerbations[J]. Clin Chest Med, 2020, 41(3): 421-438. doi: 10.1016/j.ccm.2020.06.007
[9]	庞才双, 曾妮, 申永春. 慢性阻塞性肺疾病气道重塑机制及其研究进展[J]. 西部医学, 2017, 29(1): 135-140. doi: 10.3969/j.issn.1672-3511.2017.01.031 PANG Z S, ZENG N, SHEN Y C, et al. Mechanism and advance of airway remolding in chronic obstructive pulmonary disease[J]. Medical Journal of West China, 2017, 29(1): 135-140. doi: 10.3969/j.issn.1672-3511.2017.01.031
[10]	弋可, 黄玲. 基质蛋白酶9与慢性阻塞性肺疾病的研究进展[J/CD]. 中华肺部疾病杂志(电子版), 2018, 11(3): 366-369. YI K, HUANG L, et al. Research progress of matrix proteinase 9 and chronic obstructive pulmonary disease[J/CD]. Chinese Journal of Lung Diseases (Electronic Edition), 2018, 11(3): 366-369.
[11]	ARBANINGSIH S R, SYARANI F, GANIE R A, et al. The levels of vitamin D, metalloproteinase-9 and tissue inhibitor metalloproteinase-1 in COPD patients, healthy smokers and non-smokers of indonesian citizens[J]. Open Access Maced J Med Sci, 2019, 7(13): 2123-2126. doi: 10.3889/oamjms.2019.612
[12]	UYSAL P, UZUN H. Relationship between circulating serpina3g, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 and -2 with chronic obstructive pulmonary disease Severity[J]. Biomolecules, 2019, 9(2): 62. doi: 10.3390/biom9020062
[13]	OJIAKU C A, YOO E J, PANETTIERI R A J R. Transforming growth factor beta1 function in airway remodeling and hyperresponsiveness[J]. Am J Respir Cell Mol Biol, 2017, 56(4): 432-442. doi: 10.1165/rcmb.2016-0307TR
[14]	MAHMOOD M Q, REID D, WARD C, et al. Transforming growth factor(TGF)beta (1)and Smad signalling pathways: A likely key to EMT-associated COPD pathogenesis[J]. Respirology, 2017, 22(1): 133-140. doi: 10.1111/resp.12882
[15]	SANDERS K J C, KLOOSTER K, VANFLETEREN L E G W, et al. CT-derived muscle remodelling after bronchoscopic lung volume reduction in advanced emphysema[J]. Thorax, 2019, 74(2): 206-207. doi: 10.1136/thoraxjnl-2018-211931
[16]	宁志伟, 王鸥, 邢小平. 维生素D的研究历史[J]. 中华骨质疏松和骨矿盐疾病杂志, 2018, 11(1): 39-43. doi: 10.3969/j.issn.1674-2591.2018.01.005 NING Z W, WANG O, XING X P, et al. History review of vitamin D[J]. Chinese Journal of Osteoporosis and Bone Mineral Research, 2018, 11(1): 39-43. doi: 10.3969/j.issn.1674-2591.2018.01.005
[17]	AHMAD S, ARORA S, KHAN S, et al. Vitamin D and its therapeutic relevance in pulmonary diseases[J]. J Nutr Biochem, 2021, 90: 108571. doi: 10.1016/j.jnutbio.2020.108571
[18]	刘魁, 钱会, 韩可兴, 等. 135例COPD急性加重患者营养状况及其与急性加重的关系分析[J]. 中华全科医学, 2020, 18(8): 1313-1315, 1347. doi: 10.16766/j.cnki.issn.1674-4152.001495 LIU K, QIAN H, HAN K X, et al. Analysis of nutritional status in 135 patients with acute exacerbation of COPD and its relationship with acute exacerbation[J]. Chinese Journal of General Practice, 2020, 18(8): 1313-1315, 1347. doi: 10.16766/j.cnki.issn.1674-4152.001495
[19]	沈魏, 郭忠良. AECOPD患者25-羟维生素D水平与IL-6、IgA的相关性研究[J]. 中华全科医学, 2015, 13(10): 1606-1607, 1634. https://www.cnki.com.cn/Article/CJFDTOTAL-SYQY201510017.htm SHEN W, GUO Z L, et al. A correlational study between the level of 25-hydroxy vitamin D and IL-6 and IgA in patients with acute exacerbation of chronic obstructive pulmonary disease[J]. Chinese Journal of General Practice, 2015, 13(10): 1606-1607, 1634. https://www.cnki.com.cn/Article/CJFDTOTAL-SYQY201510017.htm
[20]	FERRARI R, CARAM L M O, TANNI S E, et al. The relationship between vitamin D status and exacerbation in COPD patients-a literature review[J]. Respir Med, 2018, 139: 34-38. doi: 10.1016/j.rmed.2018.04.012
[21]	吴春婷, 赵佳晖, 肖瑶, 等. 慢性阻塞性肺疾病患者血清维生素D水平与肺功能的相关性研究[J]. 心肺血管病杂志, 2018, 37(5): 410-414. doi: 10.3969/j.issn.1007-5062.2018.05.008 WU C T, ZHAO J H, XIAO Y, et al. The correlation study of serum vitamin D levels and chronic obstructive pulmonary disease[J]. Journal of Cardiovascular and Pulmonary Diseases, 2018, 37(5): 410-414. doi: 10.3969/j.issn.1007-5062.2018.05.008
[22]	KHAN D M, ULLAH A, RANDHAWA F A, et al. Role of Vitamin D in reducing number of acute exacerbations in Chronic Obstructive Pulmonary Disease (COPD) patients[J]. Pak J Med Sci, 2017, 33(3): 610-614.
[23]	王青青, 荣令. 补充维生素D对慢性阻塞性肺疾病患者的影响[J]. 安徽理工大学学报(自然科学版), 2019, 39(6): 83-86. https://www.cnki.com.cn/Article/CJFDTOTAL-HLGB201906016.htm WANG Q Q, RONG L, et al. Effects of Vitamin D supplementation on patients with chronic obstructive pulmonary disease[J]. Journal of Anhui University of Science and Technology: Natural Science Edition, 2019, 39(6): 83-86. https://www.cnki.com.cn/Article/CJFDTOTAL-HLGB201906016.htm
[24]	HAMMAMI M M, YUSUF A. Differential effects of vitamin D₂ and D₃ supplements on 25-hydroxy vitamin D level are dose, sex, and time dependent: A randomized controlled trial[J]. BMC Endocr Disord, 2017, 17(1): 12.
[25]	MARTINEAU A R, THUMMEL K E, WANG Z, et al. Differential effects of oral boluses of vitamin D₂ vs vitamin D₃ on vitamin D metabolism: A randomized controlled trial[J]. J Clin Endocrinol Metab, 2019, 104(12): 5831-5839.
[26]	TRIPKOVIC L, WILSON L R, HART K, et al. Daily supplementation with 15 μg vitamin D₂ compared with vitamin D₃ to increase wintertime 25-hydroxy vitamin D status in healthy South Asian and white European women: A 12-wk randomized, placebo-controlled food-fortification trial[J]. Am J Clin Nutr, 2017, 106(2): 481-490.