孟鲁司特对哮喘中白三烯B4代谢的影响

doi:10.3969/j.issn.1674-8115.2023.05.008

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (5): 580-591.doi: 10.3969/j.issn.1674-8115.2023.05.008

• 论著 · 基础研究 • 上一篇

孟鲁司特对哮喘中白三烯B4代谢的影响

胡煜¹^,²^,³(), 谢亮¹^,²^,⁴^,⁵, 邹丹³, 伏洪玲¹^,², 娄丽丽¹^,², 谢柯祺³, 刘瀚旻¹^,²^,⁴^,⁵()

^1.四川大学华西第二医院小儿呼吸免疫科，成都 610041
^2.四川大学华西第二医院肺发育与相关疾病联合实验室，成都 610041
^3.电子科技大学医学院附属绵阳医院·绵阳市中心医院儿科，绵阳 621000
^4.四川大学华西第二医院出生缺陷与相关妇儿疾病教育部重点实验室，成都 610041
^5.四川大学国家卫生健康委员会时间生物学重点实验室，成都 610041

收稿日期:2023-03-31 接受日期:2023-01-03 出版日期:2023-05-28 发布日期:2023-07-11
通讯作者: 刘瀚旻 E-mail:976700544@qq.com;liuhm@scu.edu.cn
作者简介:胡　煜（1982—），男，副主任医师，博士；电子信箱：976700544@qq.com。
基金资助:
国家自然科学基金(U21A20333);四川省中央引导地方科技发展专项项目(2021ZYD0105);中央高校基本科研业务费专项资金(SCU2022D022);四川省卫健委普及应用项目(20PJ254)

Effect of montelukast on leukotriene B4 metabolism in asthma

HU Yu¹^,²^,³(), XIE Liang¹^,²^,⁴^,⁵, ZOU Dan³, FU Hongling¹^,², LOU Lili¹^,², XIE Keqi³, LIU Hanmin¹^,²^,⁴^,⁵()

^1.Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
^2.The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University; West China Institute of Women and Children′s Health, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
^3.Department of Pediatrics, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, China
^4.Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China
^5.NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, 610041, China

Received:2023-03-31 Accepted:2023-01-03 Online:2023-05-28 Published:2023-07-11
Contact: LIU Hanmin E-mail:976700544@qq.com;liuhm@scu.edu.cn
Supported by:
National Natural Science Foundation of China-Joint Fund for Regional Innovation and Development(U21A20333);Central Government Funds of Guiding Local Scientific and Technological Development for Sichuan Province(2021ZYD0105);Fundamental Research Funds for the Central Universities(SCU2022D022);Popularization and application project of Sichuan Health Committee(20PJ254)

摘要/Abstract

摘要：

目的·观察孟鲁司特在哮喘治疗中对白三烯B4（leukotriene B4，LTB4）代谢途径关键分子表达的影响，探讨哮喘的潜在干预靶点。方法·卵清蛋白（ovalbumin，OVA）+Al（OH）₃致敏激发小鼠，建立以过敏性气道疾病（allergic airway disease，AAD）为特点的小鼠急性、亚急性和慢性哮喘模型并予孟鲁司特灌胃干预，然后再予OVA激发慢性哮喘模型。无约束全身体积描记仪测定小鼠肺功能，探究气道高反应性（airway hyperresponsiveness，AHR）的变化规律。苏木精-伊红（hematoxylin-eosin，HE）染色观察肺组织嗜酸性粒细胞（eosinophil，EOS）浸润及杯状细胞（goblet cell，GCL）增生情况，观察气道过敏性炎症的病理学特点。ELISA和液相芯片多因子检测试剂盒检测支气管肺泡灌洗液（bronchoalveolar lavage fluid，BALF）和血清的免疫球蛋白E（immunoglobulin E，IgE）、干扰素γ（interferon γ，IFN-γ）和白细胞介素（interleukin，IL）表达水平，观察2型辅助性T细胞（helper T cell type 2，Th2）炎症情况。RT-qPCR、Western blotting及免疫组织化学检测小鼠LTB4合成限速酶5-脂氧合酶激活蛋白（5-lipoxygenase activating protein，ALOX5AP）和白三烯A4水解酶（leukotriene A4 hydrolase，LTA4H）及LTB4受体1（leukotriene B4 receptor 1，BLT1）基因及蛋白表达，探究LTB4的代谢与哮喘的关系。结果·OVA+Al（OH）₃可建立以AAD为特征的小鼠哮喘模型，表现为以增强呼气间歇（enhanced pause，Penh）值升高为肺功能特点的AHR，以气道EOS浸润和GCL增生为病理学特点的嗜酸性炎症和黏液高分泌状态，及以BALF和血清中IgE、IL-4和IL-13升高且IFN-γ、IL-2和IL-12降低为免疫学特点的Th2型炎症反应；孟鲁司特可有效缓解AAD。ALOX5AP、LTA4H和BLT1基因及蛋白在哮喘中表达增强，孟鲁司特始终抑制ALOX5AP表达，但可促进LTA4H和BLT1在慢性期的表达。OVA再次激发后，孟鲁司特可使LTA4H和BLT1表达增强。结论·孟鲁司特具有缓解哮喘小鼠过敏性炎症的效应，但可刺激LTB4的生成和堆积并以慢性期显著；再次予OVA激发孟鲁司特持续干预的哮喘小鼠可使LTB4与BLT1的表达增强；孟鲁司特可能存在激活LTB4及其受体BLT1进而加重哮喘发作的风险，LTB4代谢限速酶LTA4H及受体BLT1可能是哮喘治疗的潜在靶点。

关键词: 哮喘, 5-脂氧合酶激活蛋白, 白三烯A4水解酶, 白三烯B4受体, 孟鲁司特

Abstract:

Objective ·To observe the effect of montelukast on the expressions of key genes in LTB4 (leukotriene B4) metabolic pathway in treating asthma and investigate the candidate intervene targets of asthma. Methods ·The acute, subacute, and chronic asthmatic mouse models characterizing by allergic airway disease (AAD) were set up by ovalbumin (OVA) and Al(OH)₃ sensitization and challenge and intervened by intragastric administration of montelukast and finally challenged by OVA for chronic asthma model. The pulmonary functions of mice were tested by unconstrained whole body plethysmograph, to quest the change patterns of airway hyperresponsiveness (AHR). The eosinophil (EOS) infiltration and goblet cell (GCL) hyperplasia in mouse lungs were detected by hematoxylin-eosin (HE) staining, to quest the pathologic features of airway allergic inflammation. The levels of immunoglobulin E (IgE), interferon γ (IFN-γ), and interleukin (IL) in bronchoalveolar lavage fluid (BALF) and serum were detected by ELISA and Milliplex kits, to quest the helper T cell type 2 (Th2) inflammation status. The transcription and protein levels of 5-lipoxygenase activating protein (ALOX5AP), leukotriene A4 hydrolase (LTA4H), and leukotriene B4 receptor 1 (BLT1) genes, which encoded the rate-limiting enzymes in LTB4 synthesis pathway, were detected by RT-qPCR, Western blotting and immunohistochemistry (IHC). Results ·The asthmatic mouse model could be set up by OVA and Al (OH)₃ and was presented as AHR characterized by increasing enhanced pause (Penh) value, eosinophilic inflammation and high mucous secretion pathologically characterized by airway EOS infiltration and GCL hyperplasia, Th2 inflammation immunologically characterized by the increasing levels of IgE, IL-4, and IL-13 as well as decreasing levels of IFN-γ, IL-2, and IL-12 in BALF and serum. Montelukast could alleviate AAD effectively. The transcription and protein levels of ALOX5AP, LTA4H, and BLT1 genes increased in asthma. Montelukast can inhibit the expression of ALOX5AP gene and promote the expressions of LTB4 and BLT1 genes in asthmatic chronic phase. When challenged by OVA once again, montelukast can induce the significantly high expressions of LTB4 and BLT1 genes. Conclusion ·Montelukast has the effect of relieving allergic inflammation in asthma mice, but it can stimulate the production and accumulation of LTB4 and is significant in chronic phase. When challenged by OVA a second time, LTB4 could be promoted to combine with BLT1 and attend in the pathogenesis of asthma. The results suggested that there was a potential risk of activation of LTB4 by montelukast. The rate-limiting enzyme LTA4H and its receptor BLT1 metabolism may be potential targets for asthma treatment.

Key words: asthma, 5-lipoxygenase activating protein (ALOX5AP), leukotriene A4 hydrolase (LTA4H), leukotriene B4 receptor, montelukast

中图分类号:

R562

胡煜, 谢亮, 邹丹, 伏洪玲, 娄丽丽, 谢柯祺, 刘瀚旻. 孟鲁司特对哮喘中白三烯B4代谢的影响[J]. 上海交通大学学报（医学版）, 2023, 43(5): 580-591.

HU Yu, XIE Liang, ZOU Dan, FU Hongling, LOU Lili, XIE Keqi, LIU Hanmin. Effect of montelukast on leukotriene B4 metabolism in asthma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(5): 580-591.

图/表 9

图1 哮喘小鼠模型建立Note： AAD was induced by intraperitoneal sensitization of Balb/c mice with 40 μg grade V OVA and 2 mg aluminum hydroxide in saline. Sensitization was delivered on Day 0 and 14 (acute and subacute models) or on Day 0, 7 and 14 (chronic model). Mice were then challenged by nebulization of 3% OVA in saline for 30 min on four consecutive days (acute), seven consecutive days (subacute), or 3 d/week for 6 weeks (chronic). Control mice were sensitized with 2 mg of aluminum hydroxide in 0.5 mL and challenged by nebulized saline. Treated AAD mice to montelukast by means of gavage every night on challenging days or Day 63 to 90 (chronic). Control mice were treated to gavage saline. AAD mice were challenged by nebulization of 3% OVA in saline for 30 min on three consecutive days by Day 91 to 93.

Fig 1 Setup of mice model with asthma

表1 引物列表

Tab 1 List of primers

Primer Name	Direction	Sequence (5′→3′)
ALOX5AP	Forward	TGTCGGCTATCTGGGAGAGAGA
ALOX5AP	Reverse	ATCCGCTTGCCGAAGATGTA
LTA4H	Forward	TTGATTGGAACACCTGGCTCTA
LTA4H	Reverse	TGTCAGAGTCACGTCGTAATTGG
BLT1	Forward	GGCACTAAGACAGATTCAAGGATT
BLT1	Reverse	ACATGCCACCAGGAGAAGAAG
Actin	Forward	TGGCTCCTAGCACCATGAAGA
Actin	Reverse	GCCACCGATCCACACAGAGT

图2 小鼠肺功能Penh值Note： A-C. The Penh values of acute (A), subacute (B) and chronic (C) models of control and AAD mice (n=8). D. The Penh values of each model of control and AAD mice at the concentration of Mch is 25 mg/mL (n=8). ①P=0.000.

Fig 2 Penh values of different mice groups

图3 小鼠肺组织HE染色及评分Note： A. The HE staining of acute, subacute and chronic models of control and AAD mice lung samples (×400). B. The EOS scores of control and AAD mice lung samples (n=8). C. The GCL scores of control and AAD mice lung samples (n=8). ①P=0.001, ②P=0.000, ③P=0.003.

Fig 3 HE staining and scores of mice lung samples

图4 小鼠BALF及血清IgE和细胞因子表达Note： A-F. The expression levels of IgE (A), IFN-γ (B), IL-2 (C), IL-12 (D), IL-4 (E) and IL-13 (F) in BALF and serum of control and AAD mice (n=4). ①P=0.000, ②P=0.004, ③P=0.002, ④P=0.007. ⑤P=0.001, ⑥P=0.006.

Fig 4 Expression levels of IgE and cytokines in BALF and serum of mice

图5 ALOX5AP 基因及蛋白表达Note： A. Immunohistochemical staining of ALOX5AP protein of control, AAD and AAD+ montelukast mice lung samples (×400). B. RT-qPCR transcription levels of ALOX5AP gene (n=4). C. IOD values of ALOX5AP protein in immunohistochemical staining (n=8). ①P=0.001, ②P=0.000, ③P=0.005.

Fig 5 Transcription and protein levels of ALOX5AP gene

图6 LTA4H 基因及蛋白表达Note： A. Immunohistochemical staining of LTA4H protein of control, AAD and AAD+ montelukast mice lung samples (×400). B. RT-qPCR transcription levels of LTA4H gene (n=4). C. IOD values of LTA4H protein in immunohistochemical staining (n=8). ①P=0.009, ②P=0.000, ③P=0.003.

Fig 6 Transcription and protein levels of LTA4H gene

图7 BLT1 基因及蛋白表达Note： A. Immunohistochemical staining of BLT1 protein of control, AAD and AAD+montelukast mice lung samples (×400). B. RT-qPCR transcription levels of BLT1 gene (n=4). C.IOD values of BLT1 protein in immunohistochemical staining (n=8). ①P=0.000, ②P=0.003.

Fig 7 Transcription and protein levels of BLT1 gene

图8 OVA再次激发哮喘小鼠后 ALOX5AP 、 LTA4H 和 BLT1 基因及蛋白表达Note： A. RT-qPCR transcription levels of ALOX5AP, LTA4H and BLT1 gene of control, AAD, AAD+montelukast and AAD+montelukast-NC mice (n=4). B. Immunohistochemical staining of ALOX5AP, LTA4H and BLT1 protein lung samples (×400) and the IOD values of each protein in immunohistochemical staining (n=8). C. Western blotting electrophoresis bands of ALOX5AP, LTA4H and BLT1 protein and the ratio values of each protein (n=4). ①P=0.000, ②P=0.007, ③P=0.011, ④P=0.012, ⑤P=0.009, ⑥P=0.017.

Fig 8 Transcription and protein levels of ALOX5AP, LTA4H and BLT1 genes after re-challenged by OVA in asthma mice models

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孟鲁司特对哮喘中白三烯B4代谢的影响

Effect of montelukast on leukotriene B4 metabolism in asthma

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