Effects of Tiotropium Bromide on Airway Inflammation in a Rat Model with COPD_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

HE Mudan , RONG Ling ,  ZHOU Xin

Department of Respiratory Disease, First People’s Hospital Affiliated to Shanghai Jiaotong University. Shanghai, 200080, China;

Corresponding author：

ZHOU Xin, Email: xzhou53@163.com

Keywords：

Chronic obstructive pulmonary disease; TiotropiumBromide; Airway inflammation; Airway resistance; Interleukin-8; Leukotriene B4

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Objective To investigate the effects of TiotropiumBromide on airway inflammation in a rat model of chronic obstructive pulmonary disease( COPD) . Methods Thirty Wistar rats were randomly divided into three groups. Group A received normal breeding as normal control. Group B and group C received LPS( 200 μg, intratracheally injected at the 1st and the 14th day) and tobacco exposure( from the 2nd day to the 30th day except the 14th day) to establish COPD model. And group C received a nebulized dose of Tiotropium Bromide( 0. 12 mmol / L, 10 minutes) 30 minutes before the tobacco exposure each time. Airway resistance and compliance were measured before sacrificed. Histological examination was performed with Hematoxylin-Eosin staining. The concentrations of IL-8 and LTB4 , total and differential cells counts in bronchoalveolar lavage fluid( BALF) were examined, and the concentrations of IL-8 and LTB4 in blood serum were also examined by ELISA. Results Severe lung inflammation and decreased lung function were demonstrated in the rats in the group B compared with those in the group A. The inflammatory cell counts in BALF, and the levels of IL-8 and LTB4 in BALF and serum were significantly increased in the group B compared with those in the group A. Tiotropium Bromide administration improved the parameters above. Conclusions The results suggest that Tiotropium Bromide can alleviate the lung inflammation and improve the lung function in a rat COPD model. These effects may be exerted through reducing the mediators of inflammation.

Citation： HE Mudan,RONG Ling,ZHOU Xin. Effects of Tiotropium Bromide on Airway Inflammation in a Rat Model with COPD. Chinese Journal of Respiratory and Critical Care Medicine, 2009, 09(3): 212-215. doi: Copy

1.	Sato E, Koyama S, Okubo Y, et al. Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol, 1998 , 274 : L970 -L979.
2.	Tashkin DP, Celli B, Senn S, et al. A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med, 2008 , 359 :1543-1554.
3.	王长征. 药物治疗能改变慢性阻塞性肺疾病患者肺功能的下降速率吗? 中国呼吸与危重监护杂志, 2009, 8: 1-2.
4.	Saito Y, Azuma A, Morimoto T, et al. Tiotropium ameliorates symptoms in patients with chronic airway mucus hypersecretion which is resistant to Macrolide therapy. Intern Med,2008, 47: 585-591.
5.	张弛, 林如平, 刘洪, 等. 鱼腥草注射液对慢性阻塞性肺疾病患者炎症细胞因子与肺功能影响. 中国中医药科技, 2006, 13: 294-295.
6.	Profita M, Bonanno A, Siena L, et al. Acetylcholine mediates the release of IL-8 in human bronchial cells by a NFκB/ ERKdependent mechanism. Eur J Pharmacol, 2008, 582: 145-153.
7.	Bühling F, Lieder N, Kuhlmann UC, et al Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro.Respir Med, 2007, 101: 2386-2394.
8.	宋一平, 崔德健, 茅培英, 等. 慢性阻塞性肺疾病大鼠模型气道重塑及生长因子的研究. 中华结核和呼吸杂志, 2001, 24: 283-287.
9.	Gosens R, Bos IS, Zaagsma J, et al. Protective effects of tiotropium bromide in the progression of airway smooth muscle remodeling. Am J Respir Crit Care Med, 2005, 171: 1096-1102.
10.	张永, 程德云, 王慧, 等. 慢性阻塞性肺疾病大鼠肺内白细胞介素-8 和肿瘤坏死因子-α与气道炎症的关系研究. 中国呼吸与危重监护杂志, 2003, 2: 553-558.
11.	谢静. 重症急性呼吸综合征患者血浆细胞因子水平的动态改变. 中华内科杂志, 2003, 42: 643-645.
12.	Keatings VM, Collins PD, Scott DM, etal. Differences ininterleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med, 1996, 153: 530-534.
13.	Crooks SW, Bayley DL, Hill SL, et al. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur Respir J, 2000, 15: 274-280.
14.	Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med, 1999, 160: 893-898.
15.	Turner CR, Breslow R, Conklyn MJ, et al. In vitro and in vivo effects of leukotrien B4 antagonism in a primate model of asthma. J Clin Invest, 1996, 97: 381-387.
16.	Profita M, Giorgi RD, Sala A, et al. Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients.Allergy, 2005, 60: 1361-1369.
17.	Jiménez E, Montiel M. Activation of MAP kinase by muscarinic cholinergic receptors induces cell proliferation and protein synthesis in human breast cancer cells. J Cell Physiol, 2005, 204: 678-686.。.

1. Sato E, Koyama S, Okubo Y, et al. Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol, 1998 , 274 : L970 -L979.
2. Tashkin DP, Celli B, Senn S, et al. A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med, 2008 , 359 :1543-1554.
3. 王长征. 药物治疗能改变慢性阻塞性肺疾病患者肺功能的下降速率吗? 中国呼吸与危重监护杂志, 2009, 8: 1-2.
4. Saito Y, Azuma A, Morimoto T, et al. Tiotropium ameliorates symptoms in patients with chronic airway mucus hypersecretion which is resistant to Macrolide therapy. Intern Med,2008, 47: 585-591.
5. 张弛, 林如平, 刘洪, 等. 鱼腥草注射液对慢性阻塞性肺疾病患者炎症细胞因子与肺功能影响. 中国中医药科技, 2006, 13: 294-295.
6. Profita M, Bonanno A, Siena L, et al. Acetylcholine mediates the release of IL-8 in human bronchial cells by a NFκB/ ERKdependent mechanism. Eur J Pharmacol, 2008, 582: 145-153.
7. Bühling F, Lieder N, Kuhlmann UC, et al Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro.Respir Med, 2007, 101: 2386-2394.
8. 宋一平, 崔德健, 茅培英, 等. 慢性阻塞性肺疾病大鼠模型气道重塑及生长因子的研究. 中华结核和呼吸杂志, 2001, 24: 283-287.
9. Gosens R, Bos IS, Zaagsma J, et al. Protective effects of tiotropium bromide in the progression of airway smooth muscle remodeling. Am J Respir Crit Care Med, 2005, 171: 1096-1102.
10. 张永, 程德云, 王慧, 等. 慢性阻塞性肺疾病大鼠肺内白细胞介素-8 和肿瘤坏死因子-α与气道炎症的关系研究. 中国呼吸与危重监护杂志, 2003, 2: 553-558.
11. 谢静. 重症急性呼吸综合征患者血浆细胞因子水平的动态改变. 中华内科杂志, 2003, 42: 643-645.
12. Keatings VM, Collins PD, Scott DM, etal. Differences ininterleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med, 1996, 153: 530-534.
13. Crooks SW, Bayley DL, Hill SL, et al. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur Respir J, 2000, 15: 274-280.
14. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med, 1999, 160: 893-898.
15. Turner CR, Breslow R, Conklyn MJ, et al. In vitro and in vivo effects of leukotrien B4 antagonism in a primate model of asthma. J Clin Invest, 1996, 97: 381-387.
16. Profita M, Giorgi RD, Sala A, et al. Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients.Allergy, 2005, 60: 1361-1369.
17. Jiménez E, Montiel M. Activation of MAP kinase by muscarinic cholinergic receptors induces cell proliferation and protein synthesis in human breast cancer cells. J Cell Physiol, 2005, 204: 678-686.。.

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