药学学报

Group	Dose/mg·kg^-1	Temperature difference after injecting LPS at different time points/℃
Normal	–	0.05 ± 0.13	0.08 ± 0.20	0.06 ± 0.17	0.05 ± 0.29	0.08 ± 0.20	0.09 ± 0.12	0.04 ± 0.29
Model	–	0.98 ± 0.10^##	1.66 ± 0.13^##	1.53 ± 0.17^##	2.16 ± 0.14^##	1.93 ± 0.16^##	1.69 ± 0.15^##	1.05 ± 0.19^##
Xiyanping injection	12.5	0.99 ± 0.12	1.41 ± 0.11^**	1.28 ± 0.16^*	1.71 ± 0.26^**	1.59 ± 0.26^*	1.38 ± 0.19^**	0.86 ± 0.24
	25	0.98 ± 0.14	1.28 ± 0.23^**	1.05 ± 0.25^**	1.63 ± 0.33^**	1.49 ± 0.34^**	1.26 ± 0.33^**	0.78 ± 0.27^*
	50	0.95 ± 0.15	1.21 ± 0.39^*	0.94 ± 0.39^**	1.55 ± 0.43^**	1.39 ± 0.41^**	1.19 ± 0.43^**	0.71 ± 0.29^*
Analgin injection	50	1.03 ± 0.14	1.19 ± 0.19^**	1.00 ± 0.25^**	1.53 ± 0.18^**	1.36 ± 0.19^**	1.16 ± 0.24^**	0.66 ± 0.18^**

Group	Dose/mg·kg^-1	Temperature difference after injecting LPS at different time points/℃
Normal	–	0.05 ± 0.13	0.08 ± 0.20	0.06 ± 0.17	0.05 ± 0.29	0.08 ± 0.20	0.09 ± 0.12	0.04 ± 0.29
Model	–	0.98 ± 0.10^##	1.66 ± 0.13^##	1.53 ± 0.17^##	2.16 ± 0.14^##	1.93 ± 0.16^##	1.69 ± 0.15^##	1.05 ± 0.19^##
Xiyanping injection	12.5	0.99 ± 0.12	1.41 ± 0.11^**	1.28 ± 0.16^*	1.71 ± 0.26^**	1.59 ± 0.26^*	1.38 ± 0.19^**	0.86 ± 0.24
	25	0.98 ± 0.14	1.28 ± 0.23^**	1.05 ± 0.25^**	1.63 ± 0.33^**	1.49 ± 0.34^**	1.26 ± 0.33^**	0.78 ± 0.27^*
	50	0.95 ± 0.15	1.21 ± 0.39^*	0.94 ± 0.39^**	1.55 ± 0.43^**	1.39 ± 0.41^**	1.19 ± 0.43^**	0.71 ± 0.29^*
Analgin injection	50	1.03 ± 0.14	1.19 ± 0.19^**	1.00 ± 0.25^**	1.53 ± 0.18^**	1.36 ± 0.19^**	1.16 ± 0.24^**	0.66 ± 0.18^**

Time after injecting LPS/h	Group	Dose/mg·kg^-1	PLA2/ng·mL^-1	PGE2/pg·mL^-1	IL-1β/pg·mL^-1	TNF-α/pg·mL^-1
1	Normal	–	18.46 ± 7.23	64.72 ± 28.88	15.05 ± 1.71	9.42 ± 2.60
	Model	–	59.95 ± 10.44^##	229.04 ± 41.85^##	60.29 ± 11.06^##	112.73 ± 43.36^##
	Xiyanping injection	12.5	46.29 ± 13.54^*	174.07 ± 58.29^*	40.98 ± 12.11^*	85.50 ± 16.90
		25	38.35 ± 6.88^**	138.17 ± 27.47^**	31.35 ± 10.63^**	66.80 ± 22.63^*
		50	32.50 ± 5.06^**	90.70 ± 40.05^**	22.33 ± 5.52^**	42.54 ± 17.65^**
	Analgin injection	50	28.55 ± 8.10^**	86.18 ± 46.34^**	20.72 ± 3.11^**	40.76 ± 15.08^**
2	Normal	–	25.57 ± 4.48	65.13 ± 39.11	19.69 ± 7.09	12.40 ± 5.55
	Model	–	77.82 ± 24.86^##	280.94 ± 84.66^##	57.98 ± 13.20^##	145.38 ± 30.95^##
	Xiyanping injection	12.5	51.28 ± 14.38^*	184.44 ± 79.47^*	42.17 ± 13.89^*	122.96 ± 30.42
		25	41.43 ± 11.48^**	139.90 ± 60.89^**	33.42 ± 14.88^**	75.58 ± 28.54^**
		50	31.33 ± 4.88^**	87.14 ± 31.36^**	24.53 ± 6.61^**	55.80 ± 38.54^**
	Analgin injection	50	28.98 ± 3.83^**	79.12 ± 30.63^**	22.12 ± 12.40^**	59.71 ± 34.71^**
3	Normal	–	32.47 ± 6.57	49.12 ± 21.45	26.13 ± 7.87	13.94 ± 5.71
	Model	–	93.71 ± 22.74^##	296.76 ± 153.65^##	74.53 ± 9.16^##	172.83 ± 58.61^##
	Xiyanping injection	12.5	67.44 ± 20.66^*	173.55 ± 45.52	64.53 ± 7.13^*	130.99 ± 45.68
		25	50.82 ± 15.10^**	88.29 ± 47.96^**	49.10 ± 9.75^**	82.90 ± 40.21^**
		50	42.18 ± 10.32^**	64.96 ± 21.41^**	38.13 ± 8.26^**	42.15 ± 17.85^**
	Analgin injection	50	40.66 ± 17.07^**	58.30 ± 20.60^**	35.01 ± 8.33^**	37.88 ± 15.94^**
8.5	Normal	–	33.87 ± 8.97	34.84 ± 9.40	24.96 ± 6.00	13.74 ± 6.56
	Model	–	78.51 ± 19.99^##	88.73 ± 33.70^##	46.72 ± 8.65^##	74.14 ± 29.22^##
	Xiyanping injection	12.5	68.96 ± 18.05	66.72 ± 16.64	36.28 ± 10.95	63.06 ± 20.18
		25	58.98 ± 12.50^*	56.16 ± 20.79	31.46 ± 8.90^**	44.39 ± 10.62^*
		50	49.41 ± 14.91^**	49.77 ± 18.36^*	26.57 ± 10.93^**	37.38 ± 18.71^*
	Analgin injection	50	46.19 ± 11.89^**	42.46 ± 17.15^**	25.15 ± 9.67^**	34.34 ± 5.47^**

Time after injecting LPS/h	Group	Dose/mg·kg^-1	PLA2/ng·mL^-1	PGE2/pg·mL^-1	IL-1β/pg·mL^-1	TNF-α/pg·mL^-1
1	Normal	–	18.46 ± 7.23	64.72 ± 28.88	15.05 ± 1.71	9.42 ± 2.60
	Model	–	59.95 ± 10.44^##	229.04 ± 41.85^##	60.29 ± 11.06^##	112.73 ± 43.36^##
	Xiyanping injection	12.5	46.29 ± 13.54^*	174.07 ± 58.29^*	40.98 ± 12.11^*	85.50 ± 16.90
		25	38.35 ± 6.88^**	138.17 ± 27.47^**	31.35 ± 10.63^**	66.80 ± 22.63^*
		50	32.50 ± 5.06^**	90.70 ± 40.05^**	22.33 ± 5.52^**	42.54 ± 17.65^**
	Analgin injection	50	28.55 ± 8.10^**	86.18 ± 46.34^**	20.72 ± 3.11^**	40.76 ± 15.08^**
2	Normal	–	25.57 ± 4.48	65.13 ± 39.11	19.69 ± 7.09	12.40 ± 5.55
	Model	–	77.82 ± 24.86^##	280.94 ± 84.66^##	57.98 ± 13.20^##	145.38 ± 30.95^##
	Xiyanping injection	12.5	51.28 ± 14.38^*	184.44 ± 79.47^*	42.17 ± 13.89^*	122.96 ± 30.42
		25	41.43 ± 11.48^**	139.90 ± 60.89^**	33.42 ± 14.88^**	75.58 ± 28.54^**
		50	31.33 ± 4.88^**	87.14 ± 31.36^**	24.53 ± 6.61^**	55.80 ± 38.54^**
	Analgin injection	50	28.98 ± 3.83^**	79.12 ± 30.63^**	22.12 ± 12.40^**	59.71 ± 34.71^**
3	Normal	–	32.47 ± 6.57	49.12 ± 21.45	26.13 ± 7.87	13.94 ± 5.71
	Model	–	93.71 ± 22.74^##	296.76 ± 153.65^##	74.53 ± 9.16^##	172.83 ± 58.61^##
	Xiyanping injection	12.5	67.44 ± 20.66^*	173.55 ± 45.52	64.53 ± 7.13^*	130.99 ± 45.68
		25	50.82 ± 15.10^**	88.29 ± 47.96^**	49.10 ± 9.75^**	82.90 ± 40.21^**
		50	42.18 ± 10.32^**	64.96 ± 21.41^**	38.13 ± 8.26^**	42.15 ± 17.85^**
	Analgin injection	50	40.66 ± 17.07^**	58.30 ± 20.60^**	35.01 ± 8.33^**	37.88 ± 15.94^**
8.5	Normal	–	33.87 ± 8.97	34.84 ± 9.40	24.96 ± 6.00	13.74 ± 6.56
	Model	–	78.51 ± 19.99^##	88.73 ± 33.70^##	46.72 ± 8.65^##	74.14 ± 29.22^##
	Xiyanping injection	12.5	68.96 ± 18.05	66.72 ± 16.64	36.28 ± 10.95	63.06 ± 20.18
		25	58.98 ± 12.50^*	56.16 ± 20.79	31.46 ± 8.90^**	44.39 ± 10.62^*
		50	49.41 ± 14.91^**	49.77 ± 18.36^*	26.57 ± 10.93^**	37.38 ± 18.71^*
	Analgin injection	50	46.19 ± 11.89^**	42.46 ± 17.15^**	25.15 ± 9.67^**	34.34 ± 5.47^**

Examination site	Group	Dose/mg·kg^-1	PGE2/pg·mL^-1	cAMP/nmol·L^-1	AVP/ng·L^-1
Hypothalamus	Normal	–	264.91 ± 26.62	9.33 ± 1.68	28.17 ± 3.37
	Model	–	986.88 ± 212.97^##	33.42 ± 0.70^##	99.06 ± 7.53^##
	Xiyanping injection	12.5	759.95 ± 115.45^*	27.77 ± 2.99^**	89.76 ± 5.54
		25	410.63 ± 168.20^**	17.89 ± 5.75^**	65.24 ± 18.80^**
		50	322.07 ± 30.00^**	14.45 ± 2.55^**	41.46 ± 10.06^**
	Analgin injection	50	210.76 ± 64.44^**	13.74 ± 3.40^**	44.86 ± 6.71^**
Cerebrospinal fluid	Normal	–	270.88 ± 39.07	5.96 ± 0.83	11.15 ± 3.26
	Model	–	793.54 ± 105.46^##	17.77 ± 4.09^##	17.74 ± 6.08^#
	Xiyanping injection	12.5	626.06 ± 96.28^*	13.55 ± 2.12	21.26 ± 6.44
		25	456.62 ± 134.73^**	9.91 ± 3.69^**	32.27 ± 6.52^**
		50	324.77 ± 33.81^**	9.37 ± 1.64^**	49.07 ± 10.01^**
	Analgin injection	50	325.00 ± 77.91^**	7.99 ± 0.99^**	54.55 ± 11.75^**

Examination site	Group	Dose/mg·kg^-1	PGE2/pg·mL^-1	cAMP/nmol·L^-1	AVP/ng·L^-1
Hypothalamus	Normal	–	264.91 ± 26.62	9.33 ± 1.68	28.17 ± 3.37
	Model	–	986.88 ± 212.97^##	33.42 ± 0.70^##	99.06 ± 7.53^##
	Xiyanping injection	12.5	759.95 ± 115.45^*	27.77 ± 2.99^**	89.76 ± 5.54
		25	410.63 ± 168.20^**	17.89 ± 5.75^**	65.24 ± 18.80^**
		50	322.07 ± 30.00^**	14.45 ± 2.55^**	41.46 ± 10.06^**
	Analgin injection	50	210.76 ± 64.44^**	13.74 ± 3.40^**	44.86 ± 6.71^**
Cerebrospinal fluid	Normal	–	270.88 ± 39.07	5.96 ± 0.83	11.15 ± 3.26
	Model	–	793.54 ± 105.46^##	17.77 ± 4.09^##	17.74 ± 6.08^#
	Xiyanping injection	12.5	626.06 ± 96.28^*	13.55 ± 2.12	21.26 ± 6.44
		25	456.62 ± 134.73^**	9.91 ± 3.69^**	32.27 ± 6.52^**
		50	324.77 ± 33.81^**	9.37 ± 1.64^**	49.07 ± 10.01^**
	Analgin injection	50	325.00 ± 77.91^**	7.99 ± 0.99^**	54.55 ± 11.75^**

喜炎平注射液对细菌内毒素脂多糖致热家兔的解热作用

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郑晨 ¹ , 蒋春红 ² , 曾君南 ² , 戴岳 ¹ , 魏志凤 ¹^,^*

药学学报 | 研究论文 2020,55(8): 1836-1840

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药学学报 | 研究论文 2020, 55(8): 1836-1840

喜炎平注射液对细菌内毒素脂多糖致热家兔的解热作用

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郑晨¹, 蒋春红², 曾君南², 戴岳¹, 魏志凤¹^,^*

作者信息

1.中国药科大学中药学院, 江苏南京 210000

2.江西青峰药业有限公司创新天然药物与中药注射剂国家重点实验室, 江西赣州 341000

通讯作者:

*魏志凤, Tel:86-25-86185143, E-mail:zhifeng-wei@hotmail.com

Antipyretic effect of Xiyanping injection on bacterial endotoxin lipopolysaccharide-induced fever in rabbits

Chen ZHENG¹, Chun-hong JIANG², Jun-nan ZENG², Yue DAI¹, Zhi-feng WEI¹^,^*

Affiliations

1. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210000, China

2. State Key Laboratory of Innovative Natural Medicine and TCM Injections, Jiangxi Qingfeng Pharmaceutical, Ganzhou 341000, China

出版时间: 2020-08-12 doi: 10.16438/j.0513-4870.2019-1069

文章导航

摘要

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本文主要研究喜炎平注射液对细菌内毒素脂多糖（lipopolysaccharide，LPS）诱导的家兔发热的解热作用，并初步探讨机制，为其临床应用提供药理学依据。以LPS为诱导剂建立家兔发热模型，测定直肠温度变化；测定血清中前列腺素E2（prostaglandin E2，PGE2）、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素（interleukin-1β，IL-1β）和磷脂酶A2（phospholipaseA2，PLA2）水平；测定下丘脑和脑脊液中PGE2、环磷酸腺苷（cyclic adenosine monophosphate，cAMP）和精氨酸加压素（arginine vasopressin，AVP）水平。本文中动物福利和实验过程均遵循中国药科大学动物伦理委员会的规定。结果显示：喜炎平注射液（12.5、25和50 mg·kg^-1）可显著降低LPS所致发热家兔的体温，作用持续时间可达5.5~8.5 h。在剂量为25和50 mg·kg^-1时，喜炎平注射液的退热作用与安乃近注射液（50 mg·kg^-1）相当。深入研究发现，喜炎平注射液和安乃近注射液均不同程度地降低发热家兔血清中PGE2、IL-1β、TNF-α和PLA2水平。此外，喜炎平注射液亦显著降低发热家兔下丘脑中PGE2、cAMP、AVP水平和脑脊液中PGE2、cAMP水平，升高脑脊液中AVP水平。本研究发现喜炎平注射液可显著改善LPS所致家兔发热，其机制与调节血清、下丘脑和脑脊液中PGE2、TNF-α、IL-1β、PLA2、cAMP和AVP水平密切相关。

关键词

喜炎平注射液 / 穿心莲内酯 / 内毒素脂多糖 / 发热 / 解热作用

Abstract

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This paper mainly studied the effect of Xiyanping injection on the bacterial endotoxin lipopolysaccharide (LPS)-induced fever in rabbits, preliminarily investigated the mechanisms, and provided pharmacological basis for the clinical application. The rabbit model of endotoxin-induced fever was established by using LPS as the inducer; The changes of rectal temperature were measured; The levels of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and phospholipaseA2 (PLA2) in the serum were measured; The levels of PGE2, cyclic adenosine monophosphate (cAMP), and arginine vasopressin (AVP) in cerebrospinal fluid as well as hypothalamus were detected. The animal welfare and experimental process are in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University in this study. The results showed that Xiyanping injection (12.5, 25, and 50 mg·kg^-1) could significantly reduce LPS-upregulated body temperature of rabbits, and the duration of action could reach 5.5-8.5 h. At the doses of 25 and 50 mg·kg^-1, the antipyretic effect of Xiyanping injection was comparable to that of analgin injection (50 mg·kg^-1). Furthermore, Xiyanping injection and analgin injection both reduced the levels of PGE2, IL-1β, TNF-α, and PLA2 in the serum of febrile rabbits to the varying degrees. In addition, Xiyanping injection also down-regulated the levels of PGE2, cAMP, and AVP in the hypothalamus, and PGE2 and cAMP in the cerebrospinal fluid. The level of AVP in the cerebrospinal fluid was up-regulated. This study indicated that Xiyanping injection could significantly improve the endotoxin-induced fever in rabbits, and mechanisms were closely related to the regulation of the levels of PGE2, TNF-α, IL-1β, PLA2, cAMP, and AVP in serum, hypothalamus, and cerebrospinal fluid.

Key words

Xiyanping injection / andrographolide / bacterial endotoxin lipopolysaccharide / fever / antipyretic effect

引用本文

郑晨, 蒋春红, 曾君南, 戴岳, 魏志凤. 喜炎平注射液对细菌内毒素脂多糖致热家兔的解热作用. 药学学报, 2020 , 55 (8) : 1836 -1840 . DOI: 10.16438/j.0513-4870.2019-1069

Chen ZHENG, Chun-hong JIANG, Jun-nan ZENG, Yue DAI, Zhi-feng WEI. Antipyretic effect of Xiyanping injection on bacterial endotoxin lipopolysaccharide-induced fever in rabbits[J]. Acta Pharmaceutica Sinica, 2020 , 55 (8) : 1836 -1840 . DOI: 10.16438/j.0513-4870.2019-1069

正文

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维持体温的相对恒定是机体进行新陈代谢和正常生命活动的必要条件。然而在致热源的作用下, 体温调定点上移, 引起调节性体温升高(超过0.5 ℃), 机体呈现发热症状。临床中, 发热并非独立的疾病, 而多为相关疾病的临床表现或病理过程, 亦为多种疾病发生的重要信号^[1]。致热源分为外源性和内源性两类。外源性致热源主要包括细菌、病毒和抗原-抗体复合物等, 多为大分子物质, 通过促进机体释放内源性致热源如白细胞介素1β (interleukin-1β, IL-1β)和肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)等发挥作用。有研究表明, 发热与核因子NF-κB p65和环氧合酶-2等表达水平的升高密切相关^[2]。此外, 大鼠致热后下丘脑视前区(preoptic anterior hypothalamus, PO/AH)体温调定点上移, 产热增加。内源性致热源通过引起中枢体温正性调节介质前列腺素E2 (prostaglandin E2, PGE2)的释放, 进而作用于PO/AH, 最终引起发热^[3]。因此, 抑制内源性致热源和中枢体温正性调节介质的释放为解热药物发挥作用的重要途径。

喜炎平注射液为淡黄色至黄绿色的澄明液体, 其主要成分为水溶性穿心莲内酯总酯磺化物, 含量约为25 mg·mL^-1。临床应用喜炎平注射液对儿童社区获得性肺炎及急性支气管炎发热具有显著退热作用^{[4, 5]}。然而, 喜炎平注射液的解热作用机制尚不明确。本文采用静脉注射细菌内毒素脂多糖(lipopolysaccharide, LPS)的方法建立家兔发热模型^[6], 考察喜炎平注射液的解热作用, 并通过测定PGE2、IL-1β、TNF-α、磷脂酶A2 (phospholipase A2, PLA2)、环磷酸腺苷(cyclic adenosine monophosphate, cAMP)和精氨酸加压素(arginine vasopressin, AVP)水平展开初步机制探索。

材料与方法

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药品与试剂 喜炎平注射液(批号2016073103, 江西青峰药业有限公司); 安乃近注射液(批号15092801, 西安安健药业有限公司); LPS (批号046M4045V, Sigma-Aldrich公司); 氯化钠注射液(批号160417, 安徽双鹤药业有限公司); 家兔TNF-α酶联免疫吸附测定(enzyme linked immunosorbent assay, ELISA)试剂盒(批号DRE95136)、家兔IL-1β ELISA试剂盒(批号DRE95011)、家兔PGE2 ELISA试剂盒(批号DRE95027)、家兔PLA2 ELISA试剂盒(批号DRE95028)、家兔cAMP ELISA试剂盒(批号201811)和家兔AVP ELISA试剂盒(批号201811) (上海哈灵生物科技有限公司)。

实验仪器 双蒸纯水仪(美国Milipore密理博公司); 超高速冷冻离心机(湖南湘西仪器装备有限公司); 酶标仪[赛默飞世尔科技(中国)有限公司]。

实验动物 雄性家兔, 2.0~2.5 kg, 南京市江宁区青龙山动物繁殖场提供[SCXK (苏) 2012~0008; SYXK (苏) 2016~0017]。饲养于22 ± 2 ℃环境, 自由摄食和饮水, 适应3天后用于后续实验。本文中动物福利和实验过程均遵循中国药科大学动物伦理委员会的相关规定。

LPS致热家兔解热作用检测 每天测定雄性家兔体温2次, 剔除体温不正常及体温变化大(> 0.3 ℃)的家兔。实验前禁食12 h, 但可自由饮水。实验当日检测体温2~3次, 取均值作为基础体温。除正常组外, 其余家兔均按1 mL·kg^-1经耳缘静脉注射LPS (2 mg·L^-1); 正常组按1 mL·kg^-1经耳缘静脉给予氯化钠注射液。LPS注射30 min后, 测定家兔直肠温度, 并根据体温(剔除体温升高值≤0.8 ℃的家兔), 将LPS家兔分为模型组、喜炎平注射液(12.5、25和50 mg·kg^-1)组和安乃近注射液(50 mg·kg^-1)组, 每组8只。其中, 正常组和模型组(即仅注射LPS组)家兔均给予相应体积的氯化钠注射液; 给药组家兔除注射LPS外, 还需给予相应体积的受试药液。随后, 分别测定给药后0.5、1.5、2.5、3.5、5和8 h (即LPS注射后1、2、3、4、5.5和8.5 h)家兔的肛温, 将不同时间点肛温与基础肛温的差值(升温值)作为体温变化的指标。

LPS致热家兔血清PGE2、TNF-α、IL-1β和PLA2水平的检测 各组家兔均分别在LPS注射后1、2、3和8.5 h (即给药后0.5、1.5、2.5和8 h)取血。方法如下:将兔仰卧固定于手术台, 剪去心脏部位被毛, 皮肤消毒后, 选择心搏最明显处穿刺, 针头刺入心脏后即有血液涌入注射器, 取得所需血量后, 迅速将针头拔出。静置后于3 000 r·min^-1离心15 min获得血清。按照ELISA试剂盒检测方法测定血清中PGE2、TNF-α、IL-1β和PLA2水平, 加样于酶标板孔底部, 封板膜封板, 于37 ℃温育30 min。弃去液体, 甩干, 加入洗涤液, 洗涤5次。除空白孔外, 每孔加入酶标试剂50 μL, 37 ℃温育30 min, 洗涤5次。显色剂显色后, 加入终止液终止反应, 450 nm波长测量各孔的吸光度值。

LPS致热家兔下丘脑和脑脊液PGE2、cAMP和AVP水平的检测 根据LPS致热家兔解热作用检测方法建立LPS致热家兔模型, 分为正常组、模型组、喜炎平注射液(12.5、25和50 mg·kg^-1)组和安乃近注射液(50 mg·kg^-1)组。LPS注射后1 h, 麻醉家兔, 暴露出枕骨大孔, 用注射器从第四脑室抽取脑脊液。随后解剖取下丘脑, 采用ELISA试剂盒测定PGE2、cAMP和AVP水平。

数据统计 所有数据均用均值±标准差($\bar x$± s)表示。两组比较采用t检验方法; 多组比较采用One-way ANOVA方法。若方差非齐性, 进一步采用非参数检验。P < 0.05表示具有显著性差异。所用统计软件为IBM SPSS Statistics 22。

结果

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1 喜炎平注射液对发热家兔升温值的影响

如表 1所示, 与正常组相比, 模型组家兔给予LPS 0.5~8.5 h后体温显著升高(P < 0.01), 且分别在给予LPS后的1和3 h时2次达体温高峰, 呈现出典型的双相热。与模型组比较, 喜炎平注射液(12.5 mg·kg^-1)在给药后1~5.5 h可显著降低家兔升温值(P < 0.05或P < 0.01), 与已报道结果类似^[7]; 喜炎平注射液(25和50 mg·kg^-1)和安乃近注射液(50 mg·kg^-1)在给药后1~8.5 h均可显著降低家兔升温值(P < 0.05或P < 0.01), 且二者对发热家兔的降温作用相当。

2 喜炎平注射液对发热家兔血清PGE2、TNF-α、IL-1β和PLA2水平的影响

如表 2所示, 与正常组相比, 模型组家兔注射LPS后1~8.5 h血清PLA2、PGE2、IL-1β和TNF-α水平均明显升高(P < 0.01), 在给予LPS后3 h均处于高峰水平。与模型组比较, 喜炎平注射液(12.5 mg·kg^-1)能明显抑制家兔注射LPS后1~3 h时相中血清PLA2、PGE2和IL-1β水平的升高(P < 0.05或P < 0.01), 喜炎平注射液(25和50 mg·kg^-1)和安乃近注射液(50 mg·kg^-1)能显著抑制家兔注射LPS后1~8.5 h时相中血清PLA2、PGE2、IL-1β和TNF-α水平的升高(P < 0.05或P < 0.01)。

3 喜炎平注射液对发热家兔下丘脑和脑脊液PGE2、cAMP和AVP水平的影响

如表 3所示, 与正常组比较, 模型组家兔注射LPS 1 h后下丘脑和脑脊液中致热介质PGE2和cAMP水平均明显升高(P < 0.01)。与模型组比较, 喜炎平注射液(12.5、25和50 mg·kg^-1)和安乃近注射液(50 mg·kg^-1)均可明显抑制给予LPS 1 h后家兔下丘脑和脑脊液中PGE2和cAMP水平的升高(P < 0.05或P < 0.01)。

家兔注射LPS 1 h后下丘脑和脑脊液中解热介质AVP水平明显升高(P < 0.01或P < 0.05), 提示机体在抗LPS致热作用中存在体温负调节机制, 通过促进AVP合成抑制体温升高。静脉注射喜炎平注射液(25和50 mg·kg^-1)明显降低下丘脑中AVP水平(P < 0.01), 促进下丘脑AVP的释放, 升高脑脊液中AVP水平(P < 0.01)。

讨论

收起

发热是感染性或非感染性疾病所触发的一种保守系统反应, 通过上调体温调定点引起机体体温升高^[8]。在研究解热作用时, 常以家兔或大鼠为实验对象, 而家兔体温变化灵敏、易产生发热反应、且发热表现较为恒定, 故最为常用。LPS是革兰阴性菌内毒素的活性成分, 当细菌死亡自溶或黏附于其他细胞时释出内毒素, 展现其毒性^[9]。LPS自身为外源性致热源, 其大量进入血液后可导致“热源反应”, 促进单核细胞和巨噬细胞等分泌大量的PGE2、TNF-α和IL-1β等发挥作用。此外, LPS可形成LPS-LPS-binding protein-soluble CD14 (LPS-LBP-sCD14)三联复合物, 其作用于Toll样受体4, 激活髓样分化因子, 后者可募集白介素-1受体相关激酶-1和白介素-1受体相关激酶-2, 介导丝裂原活化蛋白激酶和核因子κB信号通路的活化, 亦为其介导发热的重要机制^[10]。因此, LPS诱导的家兔发热模型常被用作评价清热药的解热作用, 本研究中亦以此建模。

LPS所诱发的内源性致热源主要包括PGE2、PLA2、TNF-α和IL-1β等^[11]。其中, PGE2为介导炎症发热过程的重要脂质介质, 经由花生四烯酸途径释放, 受到PLA2、环加氧酶-2和PGE2合酶等的调控。有研究表明, PGE2主要通过与下丘脑视前区的前列腺素E3受体结合, 引起发热^[12]。TNF-α和IL-lβ为2种关键的内源性致热源, TNF-α可与TNF Ⅰ型受体和TNF Ⅱ型受体发生相互作用, 参与机体体温调控过程^[13]; IL-lβ则与Toll样受体结合, 上调体温调定点诱导发热^[14]。

此外, 下丘脑作为体温调节中枢, 是体温调控的关键节点, 影响多种中枢介质的合成与释放。在LPS作用下, 下丘脑释放的发热介质cAMP增多, 产热增加。cAMP是另一种广泛研究的中枢致热介质, 作用于PO/AH温敏神经元, 改变其放电频率, 提高体温调定点, 在发热性体温调节中具有正调节作用。而AVP作为中枢解热介质在发热时体温的负调节中具有重要作用, 它由下丘脑神经元合成, 由神经纤维传递至脑腹中隔区, 通过作用于隔区V1受体兴奋热敏神经元和抑制冷敏神经元而致体温降低, 刺激AVP的内源性释放并抑制发热^[15]。

本文研究结果显示, 喜炎平注射液以12.5、25和50 mg·kg^-1剂量静脉给药, 在给药后1 h开始即有明显降低内毒素LPS致热家兔体温升高的作用, 降温作用持续时间可达5.5~8.5 h; 且喜炎平注射液(25和50 mg·kg^-1)对发热家兔的降温作用与安乃近注射液(50 mg·kg^-1)的效果相当, 表明喜炎平注射液有显著且持久的退热作用, 并呈一定的剂量相关性, 降温持续时间随剂量增加而延长。深入研究发现, 喜炎平注射液(25和50 mg·kg^-1)和安乃近注射液(50 mg·kg^-1)可显著抑制家兔注射LPS后1~8.5 h时相中血清PLA2、PGE2、IL-1β和TNF-α水平的升高。此外, 通过检测下丘脑和脑脊液中PGE2、cAMP和AVP水平, 发现喜炎平注射液(12.5、25和50 mg·kg^-1)可显著降低发热家兔下丘脑中PGE2、cAMP、AVP水平和脑脊液中PGE2、cAMP水平, 明显升高脑脊液中AVP水平, 提示其解热作用的发挥与抑制中枢致热介质PGE2和cAMP的合成以及促进中枢解热介质AVP释放相关。

作者贡献:郑晨负责完成实验和论文撰写工作; 蒋春红和曾君南负责数据采集和数据分析工作; 戴岳参与实验指导工作; 魏志凤负责实验指导和论文修改工作。

利益冲突:本研究与任何组织和个人均无利益冲突。

基金

收起

国家“重大新药创制”科技重大专项(2014ZX09201025)

参考文献

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2020年第55卷第8期

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文章信息

doi: 10.16438/j.0513-4870.2019-1069

接收时间：2019-12-30
首发时间：2026-01-21
出版时间：2020-08-12

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文章信息

作者

出版历史

收稿日期：2019-12-30
修回日期：2020-01-29

基金

国家“重大新药创制”科技重大专项(2014ZX09201025)

作者信息

1.中国药科大学中药学院, 江苏南京 210000

2.江西青峰药业有限公司创新天然药物与中药注射剂国家重点实验室, 江西赣州 341000

通讯作者:

*魏志凤, Tel:86-25-86185143, E-mail:zhifeng-wei@hotmail.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Group	Dose/mg·kg^-1	Temperature difference after injecting LPS at different time points/℃
Normal	–	0.05 ± 0.13	0.08 ± 0.20	0.06 ± 0.17	0.05 ± 0.29	0.08 ± 0.20	0.09 ± 0.12	0.04 ± 0.29
Model	–	0.98 ± 0.10^##	1.66 ± 0.13^##	1.53 ± 0.17^##	2.16 ± 0.14^##	1.93 ± 0.16^##	1.69 ± 0.15^##	1.05 ± 0.19^##
Xiyanping injection	12.5	0.99 ± 0.12	1.41 ± 0.11^**	1.28 ± 0.16^*	1.71 ± 0.26^**	1.59 ± 0.26^*	1.38 ± 0.19^**	0.86 ± 0.24
	25	0.98 ± 0.14	1.28 ± 0.23^**	1.05 ± 0.25^**	1.63 ± 0.33^**	1.49 ± 0.34^**	1.26 ± 0.33^**	0.78 ± 0.27^*
	50	0.95 ± 0.15	1.21 ± 0.39^*	0.94 ± 0.39^**	1.55 ± 0.43^**	1.39 ± 0.41^**	1.19 ± 0.43^**	0.71 ± 0.29^*
Analgin injection	50	1.03 ± 0.14	1.19 ± 0.19^**	1.00 ± 0.25^**	1.53 ± 0.18^**	1.36 ± 0.19^**	1.16 ± 0.24^**	0.66 ± 0.18^**

Group

Dose/mg·kg^-1

Temperature difference after injecting LPS at different time points/℃

0.5 h

1 h

2 h

3 h

4 h

5.5 h

8.5 h

Normal

–

0.05 ± 0.13

0.08 ± 0.20

0.06 ± 0.17

0.05 ± 0.29

0.08 ± 0.20

0.09 ± 0.12

0.04 ± 0.29

Model

–

0.98 ± 0.10^##

1.66 ± 0.13^##

1.53 ± 0.17^##

2.16 ± 0.14^##

1.93 ± 0.16^##

1.69 ± 0.15^##

1.05 ± 0.19^##

Xiyanping injection

12.5

0.99 ± 0.12

1.41 ± 0.11^**

1.28 ± 0.16^*

1.71 ± 0.26^**

1.59 ± 0.26^*

1.38 ± 0.19^**

0.86 ± 0.24

0.98 ± 0.14

1.28 ± 0.23^**

1.05 ± 0.25^**

1.63 ± 0.33^**

1.49 ± 0.34^**

1.26 ± 0.33^**

0.78 ± 0.27^*

0.95 ± 0.15

1.21 ± 0.39^*

0.94 ± 0.39^**

1.55 ± 0.43^**

1.39 ± 0.41^**

1.19 ± 0.43^**

0.71 ± 0.29^*

Analgin injection

1.03 ± 0.14

1.19 ± 0.19^**

1.00 ± 0.25^**

1.53 ± 0.18^**

1.36 ± 0.19^**

1.16 ± 0.24^**

0.66 ± 0.18^**

Time after injecting LPS/h	Group	Dose/mg·kg^-1	PLA2/ng·mL^-1	PGE2/pg·mL^-1	IL-1β/pg·mL^-1	TNF-α/pg·mL^-1
1	Normal	–	18.46 ± 7.23	64.72 ± 28.88	15.05 ± 1.71	9.42 ± 2.60
	Model	–	59.95 ± 10.44^##	229.04 ± 41.85^##	60.29 ± 11.06^##	112.73 ± 43.36^##
	Xiyanping injection	12.5	46.29 ± 13.54^*	174.07 ± 58.29^*	40.98 ± 12.11^*	85.50 ± 16.90
		25	38.35 ± 6.88^**	138.17 ± 27.47^**	31.35 ± 10.63^**	66.80 ± 22.63^*
		50	32.50 ± 5.06^**	90.70 ± 40.05^**	22.33 ± 5.52^**	42.54 ± 17.65^**
	Analgin injection	50	28.55 ± 8.10^**	86.18 ± 46.34^**	20.72 ± 3.11^**	40.76 ± 15.08^**
2	Normal	–	25.57 ± 4.48	65.13 ± 39.11	19.69 ± 7.09	12.40 ± 5.55
	Model	–	77.82 ± 24.86^##	280.94 ± 84.66^##	57.98 ± 13.20^##	145.38 ± 30.95^##
	Xiyanping injection	12.5	51.28 ± 14.38^*	184.44 ± 79.47^*	42.17 ± 13.89^*	122.96 ± 30.42
		25	41.43 ± 11.48^**	139.90 ± 60.89^**	33.42 ± 14.88^**	75.58 ± 28.54^**
		50	31.33 ± 4.88^**	87.14 ± 31.36^**	24.53 ± 6.61^**	55.80 ± 38.54^**
	Analgin injection	50	28.98 ± 3.83^**	79.12 ± 30.63^**	22.12 ± 12.40^**	59.71 ± 34.71^**
3	Normal	–	32.47 ± 6.57	49.12 ± 21.45	26.13 ± 7.87	13.94 ± 5.71
	Model	–	93.71 ± 22.74^##	296.76 ± 153.65^##	74.53 ± 9.16^##	172.83 ± 58.61^##
	Xiyanping injection	12.5	67.44 ± 20.66^*	173.55 ± 45.52	64.53 ± 7.13^*	130.99 ± 45.68
		25	50.82 ± 15.10^**	88.29 ± 47.96^**	49.10 ± 9.75^**	82.90 ± 40.21^**
		50	42.18 ± 10.32^**	64.96 ± 21.41^**	38.13 ± 8.26^**	42.15 ± 17.85^**
	Analgin injection	50	40.66 ± 17.07^**	58.30 ± 20.60^**	35.01 ± 8.33^**	37.88 ± 15.94^**
8.5	Normal	–	33.87 ± 8.97	34.84 ± 9.40	24.96 ± 6.00	13.74 ± 6.56
	Model	–	78.51 ± 19.99^##	88.73 ± 33.70^##	46.72 ± 8.65^##	74.14 ± 29.22^##
	Xiyanping injection	12.5	68.96 ± 18.05	66.72 ± 16.64	36.28 ± 10.95	63.06 ± 20.18
		25	58.98 ± 12.50^*	56.16 ± 20.79	31.46 ± 8.90^**	44.39 ± 10.62^*
		50	49.41 ± 14.91^**	49.77 ± 18.36^*	26.57 ± 10.93^**	37.38 ± 18.71^*
	Analgin injection	50	46.19 ± 11.89^**	42.46 ± 17.15^**	25.15 ± 9.67^**	34.34 ± 5.47^**

Time after injecting LPS/h

Group

Dose/mg·kg^-1

PLA2/ng·mL^-1

PGE2/pg·mL^-1

IL-1β/pg·mL^-1

TNF-α/pg·mL^-1

Normal

–

18.46 ± 7.23

64.72 ± 28.88

15.05 ± 1.71

9.42 ± 2.60

Model

–

59.95 ± 10.44^##

229.04 ± 41.85^##

60.29 ± 11.06^##

112.73 ± 43.36^##

Xiyanping injection

12.5

46.29 ± 13.54^*

174.07 ± 58.29^*

40.98 ± 12.11^*

85.50 ± 16.90

38.35 ± 6.88^**

138.17 ± 27.47^**

31.35 ± 10.63^**

66.80 ± 22.63^*

32.50 ± 5.06^**

90.70 ± 40.05^**

22.33 ± 5.52^**

42.54 ± 17.65^**

Analgin injection

28.55 ± 8.10^**

86.18 ± 46.34^**

20.72 ± 3.11^**

40.76 ± 15.08^**

Normal

–

25.57 ± 4.48

65.13 ± 39.11

19.69 ± 7.09

12.40 ± 5.55

Model

–

77.82 ± 24.86^##

280.94 ± 84.66^##

57.98 ± 13.20^##

145.38 ± 30.95^##

Xiyanping injection

12.5

51.28 ± 14.38^*

184.44 ± 79.47^*

42.17 ± 13.89^*

122.96 ± 30.42

41.43 ± 11.48^**

139.90 ± 60.89^**

33.42 ± 14.88^**

75.58 ± 28.54^**

31.33 ± 4.88^**

87.14 ± 31.36^**

24.53 ± 6.61^**

55.80 ± 38.54^**

Analgin injection

28.98 ± 3.83^**

79.12 ± 30.63^**

22.12 ± 12.40^**

59.71 ± 34.71^**

Normal

–

32.47 ± 6.57

49.12 ± 21.45

26.13 ± 7.87

13.94 ± 5.71

Model

–

93.71 ± 22.74^##

296.76 ± 153.65^##

74.53 ± 9.16^##

172.83 ± 58.61^##

Xiyanping injection

12.5

67.44 ± 20.66^*

173.55 ± 45.52

64.53 ± 7.13^*

130.99 ± 45.68

50.82 ± 15.10^**

88.29 ± 47.96^**

49.10 ± 9.75^**

82.90 ± 40.21^**

42.18 ± 10.32^**

64.96 ± 21.41^**

38.13 ± 8.26^**

42.15 ± 17.85^**

Analgin injection

40.66 ± 17.07^**

58.30 ± 20.60^**

35.01 ± 8.33^**

37.88 ± 15.94^**

8.5

Normal

–

33.87 ± 8.97

34.84 ± 9.40

24.96 ± 6.00

13.74 ± 6.56

Model

–

78.51 ± 19.99^##

88.73 ± 33.70^##

46.72 ± 8.65^##

74.14 ± 29.22^##

Xiyanping injection

12.5

68.96 ± 18.05

66.72 ± 16.64

36.28 ± 10.95

63.06 ± 20.18

58.98 ± 12.50^*

56.16 ± 20.79

31.46 ± 8.90^**

44.39 ± 10.62^*

49.41 ± 14.91^**

49.77 ± 18.36^*

26.57 ± 10.93^**

37.38 ± 18.71^*

Analgin injection

46.19 ± 11.89^**

42.46 ± 17.15^**

25.15 ± 9.67^**

34.34 ± 5.47^**

Examination site	Group	Dose/mg·kg^-1	PGE2/pg·mL^-1	cAMP/nmol·L^-1	AVP/ng·L^-1
Hypothalamus	Normal	–	264.91 ± 26.62	9.33 ± 1.68	28.17 ± 3.37
	Model	–	986.88 ± 212.97^##	33.42 ± 0.70^##	99.06 ± 7.53^##
	Xiyanping injection	12.5	759.95 ± 115.45^*	27.77 ± 2.99^**	89.76 ± 5.54
		25	410.63 ± 168.20^**	17.89 ± 5.75^**	65.24 ± 18.80^**
		50	322.07 ± 30.00^**	14.45 ± 2.55^**	41.46 ± 10.06^**
	Analgin injection	50	210.76 ± 64.44^**	13.74 ± 3.40^**	44.86 ± 6.71^**
Cerebrospinal fluid	Normal	–	270.88 ± 39.07	5.96 ± 0.83	11.15 ± 3.26
	Model	–	793.54 ± 105.46^##	17.77 ± 4.09^##	17.74 ± 6.08^#
	Xiyanping injection	12.5	626.06 ± 96.28^*	13.55 ± 2.12	21.26 ± 6.44
		25	456.62 ± 134.73^**	9.91 ± 3.69^**	32.27 ± 6.52^**
		50	324.77 ± 33.81^**	9.37 ± 1.64^**	49.07 ± 10.01^**
	Analgin injection	50	325.00 ± 77.91^**	7.99 ± 0.99^**	54.55 ± 11.75^**

Examination site

Group

Dose/mg·kg^-1

PGE2/pg·mL^-1

cAMP/nmol·L^-1

AVP/ng·L^-1

Hypothalamus

Normal

–

264.91 ± 26.62

9.33 ± 1.68

28.17 ± 3.37

Model

–

986.88 ± 212.97^##

33.42 ± 0.70^##

99.06 ± 7.53^##

Xiyanping injection

12.5

759.95 ± 115.45^*

27.77 ± 2.99^**

89.76 ± 5.54

410.63 ± 168.20^**

17.89 ± 5.75^**

65.24 ± 18.80^**

322.07 ± 30.00^**

14.45 ± 2.55^**

41.46 ± 10.06^**

Analgin injection

210.76 ± 64.44^**

13.74 ± 3.40^**

44.86 ± 6.71^**

Cerebrospinal fluid

Normal

–

270.88 ± 39.07

5.96 ± 0.83

11.15 ± 3.26

Model

–

793.54 ± 105.46^##

17.77 ± 4.09^##

17.74 ± 6.08^#

Xiyanping injection

12.5

626.06 ± 96.28^*

13.55 ± 2.12

21.26 ± 6.44

456.62 ± 134.73^**

9.91 ± 3.69^**

32.27 ± 6.52^**

324.77 ± 33.81^**

9.37 ± 1.64^**

49.07 ± 10.01^**

Analgin injection

325.00 ± 77.91^**

7.99 ± 0.99^**

54.55 ± 11.75^**