Effects of smoking combined with intermittent hypoxia exposure on the lungs and vascular endothelial function in rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

BI Hong , HUANG Zhaoming , HE Xu , CHEN Min , HE Jian , HE Lewei , GUO Xiang , WANG Liyan , DU Junyi , ZHOU Kaihua , WANG Qing ,  JIN Zhixian

Department of Pneumology, the First Hospital of Kunming Almette Hospital, Kunming, Yunnan 650224, P. R. China;

Corresponding?author：

JIN Zhixian, Email: jzx666999@163.com

Keywords：

Smoking; Emphysema; Intermittent hypoxia; Obstruction; Sleep apnea hypopnea; Overlap; Endothelium; Rat

DOI：

10.7507/1671-6205.201809021

Video：

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Objective To investigate the effects of smoking combined with intermittent hypoxia on the pathophysiology of lung tissue and thoracic aorta, and the endothelial injury.Methods Twenty-four rats (SPF, female, six weeks old) were divided randomly into 4 groups (n=6). The control group was given false smoking and normal oxygen exposure, the smoking-exposed group was exposed in smoking, the intermittent hypoxia group was exposed in intermittent hypoxia environment, and the overlap group was exposed to smoking and intermittent hypoxia. After 8 weeks, body weight, right ventricular hypertrophy index (RVHI), the pathological changes of lung tissue and thoracic aorta were measured, and the level of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) in serum of rats were evaluated.Results RVHI of rats in the smoking-exposed group, intermittent hypoxia group, overlap group were higher than that in the control group. In addition, RVHI in the overlap group was higher than that in the smoking-exposed group, intermittent hypoxia group (all P<0.05). The levels of ET-1, VEGF and SDF-1α in the serum of the smoking-exposed group, intermittent hypoxia group and overlap group were higher than those in the control group, while the level of eNOS was lower than that in the control group, (all P<0.05), the most significant difference was between control group and the overlap group. Pathological observation of lung tissue and thoracic aorta showed obvious emphysema in the smoking-exposed group and overlap group, which was more obvious in the overlap group than that in the smoking-exposed group (all P<0.05). Lung interstitial inflammatory infiltration, bronchial wall lymphocyte hyperplasia and pulmonary fibrosis were shown in different degrees in the smoking-exposed group, intermittent hypoxia group and overlap group, and the pulmonary arteriole wall showed thickening, fibrosis and peripheral inflammatory infiltration also were found in these groups. Thoracic aorta in the smoking-exposed group, intermittent hypoxia group and overlap group showed different degrees of endothelial cell injury, middle membrane thickening, and collagen fiber hyperplasia. The pathological features of the overlap group were most obvious compared to the other two groups.Conclusions Smoking and intermittent hypoxia exposure can lead to different degrees of lung tissue and vascular endothelial injury and decrease of vascular endothelial protective factors in rats, resulting in dysfunction of vascular endothelial cells, which leads to the structural remodeling of pulmonary arterioles and aorta, such as thickening, fibrosis, etc. Combined smoking and intermittent hypoxia exposure can lead to more serious pathological damage.

Citation： BI Hong, HUANG Zhaoming, HE Xu, CHEN Min, HE Jian, HE Lewei, GUO Xiang, WANG Liyan, DU Junyi, ZHOU Kaihua, WANG Qing, JIN Zhixian. Effects of smoking combined with intermittent hypoxia exposure on the lungs and vascular endothelial function in rats. Chinese Journal of Respiratory and Critical Care Medicine, 2019, 18(6): 560-566. doi: 10.7507/1671-6205.201809021 Copy

1.	Thomashow MA, Shimbo D, Parikh MA, et al. Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study. Am J Respir Crit Care Med, 2013, 188(1): 60-68.
2.	Feng J, Wang QS, Chiang A, et al. The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats. PLoS One, 2010, 5(10): e13201.
3.	馮靖, 陳寶元, 郭美南, 等. 間歇低氧氣體環境模型的建立. 天津醫科大學學報, 2006, 12(4): 509-515.
4.	陳敏, 黃照明, 何劍, 等. 通過煙熏和間歇低氧構建大鼠 COPD-OSAHS 重疊綜合征模型. 中國實驗動物學報, 2019, 27(1): 59-64.
5.	李秀, 呂芳. 慢性阻塞性肺疾病血清內皮素及其臨床意義. 安徽醫學, 2000, 21(2): 39-40.
6.	張超, 歐敏. 瘦素在間歇低氧致肺動脈內皮損傷中的作用. 海南醫學雜志, 2018, 29(14): 1935-1937.
7.	蔣光峰, 張金慧, 李薇. OSAHS 患者血清 NO、VEGF、HIF-1α 水平的變化及臨床意義. 臨床耳鼻咽喉頭頸外科雜志, 2012, 26(18): 807-810.
8.	Zychowski KE, Sanchez B, Pedrosa RP, et al. Serum from obstructive sleep apnea patients induces inflammatory responses in coronary artery endothelial cells. Atherosclerosis, 2016, 254: 59-66.
9.	McNicholas WT. Chronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular disease. Am J Respir Crit Care Med, 2009, 180(8): 692-700.
10.	Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med, 1985, 6(4): 651-661.
11.	Sanders MH, Newman AB, Haggerty CL, et al. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med, 2003, 167(1): 7-14.
12.	Marin JM, Soriano JB, Carrizo SJ, et al. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med, 2010, 182(3): 325-331.
13.	Neilan TG, Bakker JP, Sharma B, et al. T1 measurements for detection of expansion of the myocardial extracellular volume in chronic obstructive pulmonary disease. Can J Cardiol, 2014, 30(12): 1668-1675.
14.	Sharma B, Neilan TG, Kwong RY, et al. Evaluation of right ventricular remodeling using cardiac magnetic resonance imaging in co-existent chronic obstructive pulmonary disease and obstructive sleep apnea. COPD, 2013, 10(1): 4-10.
15.	Serban KA, Rezania S, Petrusca DN, et al. Structural and functional characterization of endothelial microparticles released by cigarette smoke. Sci Rep, 2016, 6: 31596.
16.	陳云芳, 王勝, 錢自亮. 香煙煙霧法肺動脈高壓小鼠模型肺組織 HIF-1α 和 Nrf2 表達. 江西師范大學學報(自然科學版), 2017, 41(2): 155-159.
17.	Sajkov D, Wang T, Saunders NA, et al. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med, 1999, 159(5 Pt 1): 1518-1526.
18.	畢虹, 金志賢, 周開華, 等. 重疊綜合征患者血管內皮損傷機制及靶向治療進展. 天津醫藥, 2017, 45(11): 1228-1232.
19.	Kai S, Tanaka T, Daijo H, et al. Hydrogen sulfide inhibits hypoxia-but not a anoxia-induced hypoxia-inducible factor 1 activation in a von Hippel-Lindau-and mitochondria-dependent manner. Antioxid Redox Signal, 2012, 16(3): 203-216.
20.	Paradis A, Zhang L. Role of endothelin in uteroplacental circulation and fetal vascular function. Curr Vasc Pharmacol, 2013, 11(5): 594-605.
21.	羅美蓉, 王正偉, 安志星. 人血管內皮生長因子研究進展. 中國老年學雜志, 2012, 32(17): 3835-3837.
22.	Janssens R, Mortier A, Boff D, et al. Natural nitration of CXCL12 reduces its signaling capacity and chemotactic activity in vitro and abrogates intra-articular lymphocyte recruitment in vivo. Oncotarget, 2016, 7(38): 62439-62459.
23.	Yu Y, Wu RX, Gao LN, et al. Stromal cell-derived factor-1-directed bone marrow mesenchymal stem cell migration in response to inflammatory and/or hypoxic stimuli. Cell Adh Migr, 2016, 10(4): 342-359.
24.	王英, 李亞, 李建生. 慢性阻塞性肺疾病肺血管重塑研究進展. 中醫學報, 2012, 27(02): 143-145.
25.	孫艾琦, 孫麗丹, 白麗華, 等. 慢性阻塞性肺疾病與阻塞性睡眠呼吸暫停低通氣綜合征及重疊綜合征患者血管內皮生長因子表達差異. 中華實用診斷與治療雜志, 2017, 31(3): 262-263.
26.	曹娟, 王濱, 張秀偉, 等. 老年重疊綜合征患者血管內皮功能的觀察. 中國醫藥科學, 2011, 1(23): 20-22.

1. Thomashow MA, Shimbo D, Parikh MA, et al. Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study. Am J Respir Crit Care Med, 2013, 188(1): 60-68.
2. Feng J, Wang QS, Chiang A, et al. The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats. PLoS One, 2010, 5(10): e13201.
3. 馮靖, 陳寶元, 郭美南, 等. 間歇低氧氣體環境模型的建立. 天津醫科大學學報, 2006, 12(4): 509-515.
4. 陳敏, 黃照明, 何劍, 等. 通過煙熏和間歇低氧構建大鼠 COPD-OSAHS 重疊綜合征模型. 中國實驗動物學報, 2019, 27(1): 59-64.
5. 李秀, 呂芳. 慢性阻塞性肺疾病血清內皮素及其臨床意義. 安徽醫學, 2000, 21(2): 39-40.
6. 張超, 歐敏. 瘦素在間歇低氧致肺動脈內皮損傷中的作用. 海南醫學雜志, 2018, 29(14): 1935-1937.
7. 蔣光峰, 張金慧, 李薇. OSAHS 患者血清 NO、VEGF、HIF-1α 水平的變化及臨床意義. 臨床耳鼻咽喉頭頸外科雜志, 2012, 26(18): 807-810.
8. Zychowski KE, Sanchez B, Pedrosa RP, et al. Serum from obstructive sleep apnea patients induces inflammatory responses in coronary artery endothelial cells. Atherosclerosis, 2016, 254: 59-66.
9. McNicholas WT. Chronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular disease. Am J Respir Crit Care Med, 2009, 180(8): 692-700.
10. Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med, 1985, 6(4): 651-661.
11. Sanders MH, Newman AB, Haggerty CL, et al. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med, 2003, 167(1): 7-14.
12. Marin JM, Soriano JB, Carrizo SJ, et al. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med, 2010, 182(3): 325-331.
13. Neilan TG, Bakker JP, Sharma B, et al. T1 measurements for detection of expansion of the myocardial extracellular volume in chronic obstructive pulmonary disease. Can J Cardiol, 2014, 30(12): 1668-1675.
14. Sharma B, Neilan TG, Kwong RY, et al. Evaluation of right ventricular remodeling using cardiac magnetic resonance imaging in co-existent chronic obstructive pulmonary disease and obstructive sleep apnea. COPD, 2013, 10(1): 4-10.
15. Serban KA, Rezania S, Petrusca DN, et al. Structural and functional characterization of endothelial microparticles released by cigarette smoke. Sci Rep, 2016, 6: 31596.
16. 陳云芳, 王勝, 錢自亮. 香煙煙霧法肺動脈高壓小鼠模型肺組織 HIF-1α 和 Nrf2 表達. 江西師范大學學報(自然科學版), 2017, 41(2): 155-159.
17. Sajkov D, Wang T, Saunders NA, et al. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med, 1999, 159(5 Pt 1): 1518-1526.
18. 畢虹, 金志賢, 周開華, 等. 重疊綜合征患者血管內皮損傷機制及靶向治療進展. 天津醫藥, 2017, 45(11): 1228-1232.
19. Kai S, Tanaka T, Daijo H, et al. Hydrogen sulfide inhibits hypoxia-but not a anoxia-induced hypoxia-inducible factor 1 activation in a von Hippel-Lindau-and mitochondria-dependent manner. Antioxid Redox Signal, 2012, 16(3): 203-216.
20. Paradis A, Zhang L. Role of endothelin in uteroplacental circulation and fetal vascular function. Curr Vasc Pharmacol, 2013, 11(5): 594-605.
21. 羅美蓉, 王正偉, 安志星. 人血管內皮生長因子研究進展. 中國老年學雜志, 2012, 32(17): 3835-3837.
22. Janssens R, Mortier A, Boff D, et al. Natural nitration of CXCL12 reduces its signaling capacity and chemotactic activity in vitro and abrogates intra-articular lymphocyte recruitment in vivo. Oncotarget, 2016, 7(38): 62439-62459.
23. Yu Y, Wu RX, Gao LN, et al. Stromal cell-derived factor-1-directed bone marrow mesenchymal stem cell migration in response to inflammatory and/or hypoxic stimuli. Cell Adh Migr, 2016, 10(4): 342-359.
24. 王英, 李亞, 李建生. 慢性阻塞性肺疾病肺血管重塑研究進展. 中醫學報, 2012, 27(02): 143-145.
25. 孫艾琦, 孫麗丹, 白麗華, 等. 慢性阻塞性肺疾病與阻塞性睡眠呼吸暫停低通氣綜合征及重疊綜合征患者血管內皮生長因子表達差異. 中華實用診斷與治療雜志, 2017, 31(3): 262-263.
26. 曹娟, 王濱, 張秀偉, 等. 老年重疊綜合征患者血管內皮功能的觀察. 中國醫藥科學, 2011, 1(23): 20-22.

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