基于GnRH探讨升浮药麻黄、沉降药葶苈子干预肺水肿作用差异

Differential Effects of Shengfu(升浮)Medicine Ephedrae Herba and Chenjiang(沉降)Medicine Descurainiae Semen Lepidii Semen on Pulmonary Edema Based on GnRH

目的:基于促性腺激素释放激素(GnRH)探究升浮药麻黄、沉降药葶苈子干预肺水肿的作用差异,为研究升降浮沉药性的本质提供新思路。方法:选择56只雄性SD大鼠,通过胸膜腔注射1%角叉菜胶2 mL/kg建立肺水肿模型,检测肺水肿评价指标(胸腔渗出液量、肺湿质量/干质量比、肺含水量及肺通透性),检测GnRH相关指标(GnRH、黄体生成素以及睾酮含量),检测与机体气机调节密切相关的五大系统(呼吸系统、中枢系统、循环系统、消化系统、泌尿系统)相关指标,评价麻黄和葶苈子的升降浮沉药性干预肺水肿的作用差异。结果:与正常对照组比较,模型对照组胸腔积液量、肺含水量以及肺通透指数显著升高,气道黏膜出现充血和水肿,喘息潜伏时间减少,喘息次数增加(P<0.01),肺组织中凋亡细胞以及ROS水平显著升高(P<0.01),肺泡灌洗液中IL-4、IgE的含量显著升高,IFN-γ的含量显著降低(P<0.01),排汗量和尿量明显降低(P<0.05或P<0.01),小肠推进率显著降低,胃残留率显著升高(P<0.01),睡眠时间显著降低(P<0.01),每搏输出量、短轴缩短率、射血分数及心输出量显著降低(P<0.01),血压显著升高(P<0.01);麻黄和葶苈子均显著抑制肺水肿大鼠肺组织炎症细胞浸润和杯状细胞增生,抑制胶原和细胞外基质沉积;葶苈子显著降低胸腔积液量、肺含水量以及肺通透指数(LPI)(P<0.01),麻黄能够降低LPI(P<0.01);麻黄能够显著增加肺水肿大鼠GnRH和睾酮的含量(P<0.01),葶苈子对GnRH相关指标没有影响;对于呼吸系统,葶苈子的止咳平喘作用优于麻黄,麻黄和葶苈子均可减少大鼠咳嗽次数,增加大鼠咳嗽潜伏时间,降低肺组织细胞凋亡水平(P<0.01),降低肺泡灌洗液(BALF)中IL-4和IgE的含量(P<0.01),而葶苈子的沉降药性还能降低肺组织原代细胞活性氧(ROS)水平(P<0.01),升高IFN-γ的含量(P<0.01);对于泌尿系统,麻黄的升浮之性可显著增加大鼠汗点数而宣发肺气(P<0.01),对大鼠尿量没有显著影响,而葶苈子可以显著增加大鼠尿量而肃降泻肺(P<0.01),对于大鼠发汗没有显著影响;对于消化系统,葶苈子能增加小肠推进率,抑制胃残留率(P<0.05),促进胃排空,但麻黄一定程度抑制小肠推进率;对于中枢系统,葶苈子能显著减少大鼠活动次数,增加大鼠睡眠时间(P<0.01),麻黄一定程度增加活动次数,降低睡眠时间;对于循环系统,葶苈子对心功能具有保护作用,能显著升高每搏输出量、短轴缩短率、射血分数以及心输出量(P<0.05或P<0.01),降低肺水肿大鼠血压(P<0.01),麻黄能够显著升高大鼠短轴缩短率和射血分数(P<0.01),升高肾脏血流量(P<0.01)。合并GnRH拮抗剂西曲瑞克后,麻黄的改善效果消失(P<0.01),葶苈子的作用不受影响。结论:葶苈子通过泻水逐饮,促肺肃降而改善肺水肿,是其沉降药性的体现,且不受GnRH拮抗剂影响,说明葶苈子的沉降药性与GnRH无关;麻黄能改善肺水肿咳喘症状,可能与其宣肺平喘相关,是其升浮药性的体现,且作用被GnRH拮抗剂所拮抗,说明麻黄的升浮药性与GnRH有关。

Objective:To investigate the differential effects of Shengfu(升浮)medicine Ephedrae Herba and Chenjiang(沉降)medicine Descurainiae Semen Lepidii Semen in the intervention of pulmonary edema based on gonadotropin-releasing hormone(GnRH)to provide new insights into the property of Shengfu medicines and Chenjiang medicines.Methods:Fifty-six male SD rats were selected,and a pulmonary edema model was established by injecting 1%carrageenan(2 mL/kg)into the pleural cavity.Various parameters related to pulmonary edema[pleural effusion volume,lung wet-to-dry weight ratio,lung water content,and lung permeability index(LPI)],GnRH-related indicators(GnRH,luteinizing hormone,and testosterone levels),and indicators related to five major systems closely related to the Qi(气)movement in the body(respiratory system,central nervous system,circulatory system,digestive system,and urinary system)were measured to assess the differential effects of Ephedrae Herba and Descurainiae Semen Lepidii Semen on pulmonary edema.Results:Compared with the normal control group,the model control group showed significantly increased pleural effusion volume,lung water content,and LPI,along with congestion and edema of the airway mucosa,reduced apnea latency,increased apnea frequency(P<0.01),elevated apoptotic cells and reactive oxygen species(ROS)levels in lung tissue(P<0.01),increased levels of IL-4 and IgE in bronchoalveolar lavage fluid(BALF),decreased level of IFN-γ(P<0.01),reduced sweat and urine output(P<0.05 or P<0.01),reduced intestinal transit rate,increased gastric residue rate(P<0.01),shortened sleep time(P<0.01),reduced stroke volume,fractional shortening,ejection fraction,and cardiac output(P<0.01),and increased blood pressure(P<0.01).Both Ephedrae Herba and Descurainiae Semen Lepidii Semen significantly inhibited the infiltration of inflammatory cells and goblet cell proliferation and reduced collagen and extracellular matrix deposition.Descurainiae Semen Lepidii Semen significantly decreased pleural effusion volume,lung water content,and LPI(P<0.01),while Ephedrae Herba reduced LPI to some extent(P<0.01).Regarding GnRH-related indicators,Ephedrae Herba significantly increased GnRH and testosterone levels in rats with pulmonary edema(P<0.01),while Descurainiae Semen Lepidii Semen had no effect on GnRH-related indicators.In terms of the respiratory system,Descurainiae Semen Lepidii Semen had a better antitussive and antiasthmatic effect than Ephedrae Herba.Both Ephedrae Herba and Descurainiae Semen Lepidii Semen reduced cough frequency,increased cough latency in rats,reduced apoptosis levels in lung tissue(P<0.01),and reduced the levels of IL-4 and IgE in BALF(P<0.01).Additionally,Descurainiae Semen Lepidii Semen with its Chenjiang property,could reduce the level of ROS in lung tissue(P<0.01)and increase the level of IFN-γ(P<0.01).For the urinary system,Ephedrae Herba by virtue of Shengfu property,significantly increased sweat spots and promoted lung Qi(P<0.01)without significantly affecting urine output,while Descurainiae Semen Lepidii Semen significantly increased urine output and purged lung Qi(P<0.01)without significantly affecting sweating.For the digestive system,Descurainiae Semen Lepidii Semen increased intestinal transit rate,inhibited gastric residue(P<0.05),and promoted gastric emptying,whereas Ephedrae Herba had a certain degree of inhibitory effect on intestinal transit rate.For the central nervous system,Descurainiae Semen Lepidii Semen significantly reduced the activity frequency of rats and prolonged sleep time(P<0.01),while Ephedrae Herba increased activity frequency to some extent and shortened sleep time.Regarding the circulatory system,Descurainiae Semen Lepidii Semen had a protective effect on heart function,significantly increasing stroke volume,fractional shortening,ejection fraction,and cardiac output(P<0.01 or P<0.05)and reducing blood pressure in rats with pulmonary edema(P<0.01).Ephedrae Herba significantly increased stroke volume and fractional shortening(P<0.01)and increased renal blood flow(P<0.01).After the administration of the GnRH antagonist Cetrorelix,the improvement effect of Ephedrae Herba disappeared(P<0.01),while the effect of Descurainiae Semen Lepidii Semen remained unaffected.Conclusion:Descurainiae Semen Lepidii Semen improves pulmonary edema through Xieshuizhuyin(泻水逐饮)and Cufeisujiang(促肺肃降),which reflects its Chenjiang property,and its action is not influenced by GnRH,indicating that the Chenjiang property of Descurainiae Semen Lepidii Semen is unrelated to GnRH.Ephedrae Herba can improve cough and asthma symptoms of pulmonary edema,which may be related to Xuanfeipingchuan(宣肺平喘),reflecting its Shengfu property.Its effect is antagonized by GnRH,indicating a relationship between the Shengfu property of Ephedrae Herba and GnRH.