胃饥饿素对小鼠急性肺损伤的保护作用及其机制研究

doi:10.3877/cma.j.issn.2095-1221.2021.02.003

目的

探讨胃饥饿素对小鼠急性肺损伤的保护作用和机制。

方法

将60只小鼠采用随机数字表法分为6组：对照组、模型组、胃饥饿素低、中、高剂量组和地塞米松组。对照组和模型组腹腔注射0.2 mL生理盐水，胃饥饿素各组分别注射400、200、100 μg/kg溶液，地塞米松组注射2 mg/kg。给药后1 h，对照组滴注等体积生理盐水，其余各组鼻腔滴入10 μg （20 μL）脂多糖（LPS）。24 h后，测量肺湿/干重（W/D），ELISA测量支气管肺泡灌洗液（BALF）中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和血清中TNF-α、IL-6和IL-1β含量，苏木精-伊红染色检测肺组织病理学形态，蛋白免疫印迹法测量肺组织中IL-1β p17、半胱氨酸天冬氨酸蛋白酶-1 （caspase-1） p20、Nod样受体家族3 （NLRP3）和消皮素（GSDMD）蛋白表达。体外培养肺泡巨噬细胞，分为对照组、LPS+三磷酸腺苷（ATP）组、低、中和高剂量胃饥饿素组。碘化吡啶（PI）染色观察细胞焦亡，蛋白免疫印迹法检测细胞中IL-1β p17、caspase-1 p20、NLRP3和GSDMD蛋白表达。多组间比较采用单因素方差分析，组间两两比较采用LSD-t检验。

结果

与对照组比较，模型组肺W/D （4.03±0.46比12.71±0.68）、BALF中TNF-α （3.92±0.59比12.83±0.66）、IL-6 （23.94±3.51比159.03±5.21）、血清中TNF-α （2.67±0.29比13.23±0.76）、IL-6 （26.73±2.61比141.64±3.86）和IL-1β （43.89±4.19比249.03±5.38）含量升高，肺组织IL-1β p17 （0.67±0.02比0.93±0.02）、caspase-1 p20 （0.67±0.04比1.02±0.08）、NLRP3 （0.58±0.04比0.91±0.03）和GSDMD蛋白表达（0.46±0.06比1.06±0.09）上调，差异具有统计学意义（P均< 0.05）。与模型组比较，低、中和高剂量胃饥饿素组和地塞米松组肺W/D （12.71±0.68比11.13±0.53，7.56±0.31，6.12±0.32，6.14±0.34）、BALF中TNF-α （12.83±0.66比9.89±0.47，9.78±0.53，7.33±0.27，6.27±0.38）、IL-6 （159.03±5.21比130.32±2.49，122.87±3.31，67.42±1.70，56.45±3.33）以及血清中TNF-α （13.23±0.76比10.14±0.52，9.04±0.46，6.43±0.38，6.35±0.26）、IL-6 （141.64±3.86比121.89±3.34，116.42±2.68，71.23±3.02，78.54±5.13）和IL-1β含量（249.03±5.38比230.14±5.53，196.53±6.41，100.67±3.50，91.56±4.29）呈浓度依赖性减低，肺组织IL-1β p17 （0.93±0.02比0.84±0.01，0.71±0.02，0.61±0.04，0.60±0.02）、caspase-1 p20 （1.02±0.08比0.90±0.03，0.81±0.02，0.63±0.03，0.61±0.03）、NLRP3 （0.91±0.03比0.85±0.03，0.68±0.05，0.64±0.02，0.68±0.03）和GSDMD蛋白表达（1.06±0.09比0.71±0.02，0.75±0.02，0.67±0.03，0.61±0.01）呈浓度依赖性下调，差异具有统计学意义（P均< 0.05）。与对照组比较，LPS+ATP组PI阳性细胞数增加，细胞肿胀和膜破裂，肺泡巨噬细胞中IL-1β p17 （0.44±0.01比0.99±0.03）、caspase-1 p20（0.37±0.01比1.32±0.02）、NLRP3 （0.39±0.02比1.31±0.01）和GSDMD表达（0.39±0.01比0.83±0.02）上调，差异具有统计学意义（P均< 0.05）。与LPS+ATP组比较，低、中和高剂量胃饥饿素组PI阳性细胞数呈剂量依赖性减少，细胞肿胀和膜破裂缓解，肺泡巨噬细胞中IL-1β p17 （0.99±0.03比0.55±0.02，0.45±0.02，0.31±0.02）、caspase-1 p20 （1.32±0.02比0.45±0.02，0.42±0.02，0.09±0.01）、NLRP3 （1.31±0.01比0.90±0.02，0.82±0.02，0.33±0.01）和GSDMD （0.83±0.02比0.67±0.04，0.49±0.01，0.35±0.02）表达呈剂量依赖性下调，差异具有统计学意义（P均< 0.05）。

结论

胃饥饿素对小鼠急性肺损伤具有保护作用，该作用可能与NLRP3炎性小体介导炎症反应和肺泡巨噬细胞焦亡有关。

关键词: 胃饥饿素, 肺泡巨噬细胞, 炎性小体, 急性肺损伤

Objective

To explore the protective effect and mechanism of ghrelin on acute lung injury in mice.

Methods

Sixty mice were randomly divided into 6 groups, including control group, model group, low-dose ghrelin group, middle-dose group, high-dose group and dexamethasone group. The mice in control group and model group were intraperitoneally injected with 0.2 mL normal saline, the mice in ghrelin group were injected with 400 μg/kg, 200 μg/kg and 100 μg/kg respectively, and the mice in dexamethasone group were injected with 2 mg/kg. One hour after administration, 10 μg (20 μL) lipopolysaccharide (LPS) was instilled into the nasal cavity in model group as well as treatment groups, and the equal volume of saline was injected into the control group. After 24 hours, lung wet/dry weight (W/D) was detected. The contents of tumor necrosis factor-α (TNF-α) , interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) and the contents of TNF-α, IL-6 and IL-1β in serum were analyzed by ELISA. The pathological morphology of lung tissue was analyzed by HE staining. The expression of IL-1β p17, cysteinyl aspartate specific proteinase-1 (Caspase-1) p20, Nod-like receptor protein 3 (NLRP3) and GSDMD protein were detected by western blot. Alveolar macrophages were cultured in vitro and divided into control group, LPS+ATP group, low dose group, middle dose group and high dose group. The pyroptosis was analyzed by PI staining. And the expression of IL-1β p17, caspase-1 p20, NLRP3 and GSDMD proteins were observed by western blot. One-way analysis of variance was used for comparison between multiple groups, and LSD-t test was used for pairwise comparison between groups.

Results

Compared with the control group, the lung W/D (4.03±0.46 vs 12.71±0.68) , TNF-α in BALF (3.92±0.59 vs 12.83±0.66) , IL-6 (23.94±3.51 vs 159.03±5.21) , serum levels of TNF-α (2.67±0.29 vs 13.23±0.76) , IL-6 (26.73±2.61 vs 141.64±3.86) and IL-1β (43.89±4.19 vs 249.03±5.38) in lung tissue of model group were increased, and IL-1β p17 (0.67±0.02 vs 0.93±0.02) , caspase-1 p20 (0.67±0.04 vs 1.02±0.08) , NLRP3 (0.58±0.04 vs 0.91±0.03) and GSDMD (0.46±0.06 vs 1.06±0.09) proteins expression were up-regulated significantly (P < 0.05) . Compared with the model group, W/D (12.71±0.68 vs 11.13±0.53, 7.56±0.31, 6.12±0.32, 6.14±0.34) and the contents of TNF-α (12.83±0.66 vs 9.89±0.47, 9.78±0.53, 7.33±0.27, 6.27±0.38) , IL-6 (159.03±5.21 vs 130.32±2.49, 122.87±3.31, 67.42±1.70, 56.45±3.33) in BALF and the contents of TNF-α (13.23±0.76 vs 10.14±0.52, 9.04±0.46, 6.43±0.38, 6.35±0.26) , IL-6 (141.64±3.86 vs 121.89±3.34, 116.42±2.68, 71.23±3.02, 78.54±5.13) and IL-1β (249.03±5.38 vs 230.14±5.53, 196.53±6.41, 100.67±3.50, 91.56±4.29) were dose-dependently decreased in serum in low dose group, middle dose group, high dose group and dexamethasone group, and the expression of IL-1β p17 (0.93±0.02 vs 0.84±0.01, 0.71±0.02, 0.61±0.04, 0.60±0.02) , caspase-1 p20 (1.02±0.08 vs 0.90±0.03, 0.81±0.02, 0.63±0.03, 0.61±0.03) , NLRP3 (0.91±0.03 vs 0.85±0.03, 0.68±0.05, 0.64±0.02, 0.68±0.03) and GSDMD (1.06±0.09 vs 0.71±0.02, 0.75±0.02, 0.67±0.03, 0.61±0.01) protein in lung tissue was dose-dependently downregulated (P < 0.05) . Compared with the control group, the number of PI-positive cells in the LPS+ATP group was increased, the cells were swelled and the membrane was ruptured, and IL-1β p17 (0.44±0.01 vs 0.99±0.03) and caspase-1 p20 (0.37±0.01 vs 1.32±0.02) , NLRP3 (0.39±0.02 vs 1.31±0.01) and GSDMD (0.39±0.01 vs 0.83±0.02) in alveolar macrophages were significantly up-regulated, and the difference was statistically significant (P < 0.05) . Compared with LPS+ATP group, the number of PI positive cells in low, middle and high dose groups was dose-dependently decreased, cell swelling and membrane rupture were relieved, and the expression of IL-1β p17 (0.99±0.03 vs 0.55±0.02, 0.45±0.02, 0.31±0.02) , caspase-1 p20 (1.32±0.02 vs 0.45±0.02, 0.42±0.02, 0.09±0.01) , NLRP3 (1.31±0.01 vs 0.90±0.02, 0.82±0.02, 0.33±0.01) and GSDMD (0.83±0.02 vs 0.67±0.04, 0.49±0.01, 0.35±0.02) in alveolar macrophages was dose-dependently downregulated (P < 0.05) .

Conclusions

Ghrelin has protective effect on acute lung injury in mice, which may be related to NLRP3 inflammasome mediated inflammatory response and pyroptosis in alveolar macrophages.

Key words: Ghrelin, Alveolar macrophages, Inflammasome, Acute lung injury

表1 胃饥饿素对小鼠W/D、BALF中IL-6和TNF-α含量的影响（±s）

分组	动物数	W/D	IL-6 （ng/mL）	TNF-α （ng/mL）
对照	10	4.03±0.46	23.94±3.51	3.92 ±0.59
模型	10	12.71±0.68^a	159.03±5.21^a	12.83±0.66^a
低剂量	10	11.13±0.53^b	130.32±2.49^b	9.89±0.47^b
中剂量	10	7.56±0.31^bc	122.87±3.31^bc	9.78±0.53^b
高剂量	10	6.12±0.32^bcd	67.42±1.70 ^bcd	7.33±0.27 ^bcd
地塞米松	10	6.14±0.34 ^bcd	56.45±3.33 ^bcde	6.27±0.38 ^bcd
F值		234.812	912.027	162.991
P值		0.021	0.013	0.032

表1 胃饥饿素对小鼠W/D、BALF中IL-6和TNF-α含量的影响（±s）

分组	动物数	W/D	IL-6 （ng/mL）	TNF-α （ng/mL）
对照	10	4.03±0.46	23.94±3.51	3.92 ±0.59
模型	10	12.71±0.68^a	159.03±5.21^a	12.83±0.66^a
低剂量	10	11.13±0.53^b	130.32±2.49^b	9.89±0.47^b
中剂量	10	7.56±0.31^bc	122.87±3.31^bc	9.78±0.53^b
高剂量	10	6.12±0.32^bcd	67.42±1.70 ^bcd	7.33±0.27 ^bcd
地塞米松	10	6.14±0.34 ^bcd	56.45±3.33 ^bcde	6.27±0.38 ^bcd
F值		234.812	912.027	162.991
P值		0.021	0.013	0.032

表2 胃饥饿素对小鼠血清中IL-1β、IL-6和TNF-α含量的影响（±s）

分组	动物数	IL-1β （pg/mL）	IL-6 （ng/mL）	TNF-α （ng/mL）
对照	10	43.89±4.19	26.73±2.61	2.67±0.29
模型	10	249.03±5.38^a	141.64±3.86^a	13.23±0.76^a
低剂量	10	230.14±5.53^b	121.89±3.34^b	10.14±0.52^b
中剂量	10	196.53±6.41b^c	116.42±2.68^b	9.04±0.46^bc
高剂量	10	100.67±3.50^bcd	71.23±3.02^bcd	6.43±0.38^bcd
地塞米松	10	91.56±4.29^bcd	78.54±5.13^bcd	6.35±0.26^bcd
F值		1139.024	546.521	239.511
P值		0.012	0.015	0.023

表2 胃饥饿素对小鼠血清中IL-1β、IL-6和TNF-α含量的影响（±s）

分组	动物数	IL-1β （pg/mL）	IL-6 （ng/mL）	TNF-α （ng/mL）
对照	10	43.89±4.19	26.73±2.61	2.67±0.29
模型	10	249.03±5.38^a	141.64±3.86^a	13.23±0.76^a
低剂量	10	230.14±5.53^b	121.89±3.34^b	10.14±0.52^b
中剂量	10	196.53±6.41b^c	116.42±2.68^b	9.04±0.46^bc
高剂量	10	100.67±3.50^bcd	71.23±3.02^bcd	6.43±0.38^bcd
地塞米松	10	91.56±4.29^bcd	78.54±5.13^bcd	6.35±0.26^bcd
F值		1139.024	546.521	239.511
P值		0.012	0.015	0.023

图1 倒置显微镜下观察胃饥饿素对小鼠肺组织病理形态的影响（苏木精-伊红染色，×40）

表3 胃饥饿素对肺组织中IL-1β p17、caspase-1 p20、NLRP3和GSDMD蛋白表达的影响（±s）

分组	动物数	IL-1β p17	caspase-1 p20	NLRP3	GSDMD
对照	10	0.67±0.02	0.67±0.04	0.58±0.04	0.46±0.06
模型	10	0.93±0.02^a	1.02±0.08^a	0.91±0.03^a	1.06±0.09^a
低剂量	10	0.84±0.01^b	0.90±0.03^b	0.85±0.03^b	0.71±0.02^b
中剂量	10	0.71±0.02^bc	0.81±0.02^b	0.68±0.05^bc	0.75±0.02^b
高剂量	10	0.61±0.04^bcd	0.63±0.03^bcd	0.64±0.02^bc	0.67±0.03^bd
地塞米松	10	0.60±0.02^bcd	0.61±0.03^bcd	0.68±0.03^bc	0.61±0.01^bd
F值		69.562	87.265	19.792	24.863
P值		0.048	0.032	0.037	0.012

表3 胃饥饿素对肺组织中IL-1β p17、caspase-1 p20、NLRP3和GSDMD蛋白表达的影响（±s）

分组	动物数	IL-1β p17	caspase-1 p20	NLRP3	GSDMD
对照	10	0.67±0.02	0.67±0.04	0.58±0.04	0.46±0.06
模型	10	0.93±0.02^a	1.02±0.08^a	0.91±0.03^a	1.06±0.09^a
低剂量	10	0.84±0.01^b	0.90±0.03^b	0.85±0.03^b	0.71±0.02^b
中剂量	10	0.71±0.02^bc	0.81±0.02^b	0.68±0.05^bc	0.75±0.02^b
高剂量	10	0.61±0.04^bcd	0.63±0.03^bcd	0.64±0.02^bc	0.67±0.03^bd
地塞米松	10	0.60±0.02^bcd	0.61±0.03^bcd	0.68±0.03^bc	0.61±0.01^bd
F值		69.562	87.265	19.792	24.863
P值		0.048	0.032	0.037	0.012

图2 胃饥饿素干预后小鼠肺组织内IL-1β p17、caspase-1 p20、NLRP3和GSDMD蛋白表达

图3 胃饥饿素对肺泡巨噬细胞中碘化吡啶阳性细胞数的影响

表4 胃饥饿素对肺泡巨噬细胞中IL-1β p17、caspase-1 p20、NLRP3和GSDMD蛋白表达的影响（±s）

分组	动物数	IL-1β p17	caspase-1 p20	NLRP3	GSDMD
对照	10	0.44±0.01	0.37±0.01	0.39±0.02	0.39±0.01
LPS+ATP	10	0.99±0.03^a	1.32±0.02^a	1.31±0.01^a	0.83±0.02^a
低剂量	10	0.55±0.02^b	0.45±0.02^b	0.90±0.02^b	0.67±0.04^b
中剂量	10	0.45±0.02^b	0.42±0.02^b	0.82±0.02^b	0.49±0.01^bc
高剂量	10	0.31±0.02^bcd	0.09±0.01^bcd	0.33±0.01^bcd	0.35±0.02^bcd
F值		214.333	685.723	1009.023	200.316
P值		0.032	0.021	0.015	0.025

表4 胃饥饿素对肺泡巨噬细胞中IL-1β p17、caspase-1 p20、NLRP3和GSDMD蛋白表达的影响（±s）

分组	动物数	IL-1β p17	caspase-1 p20	NLRP3	GSDMD
对照	10	0.44±0.01	0.37±0.01	0.39±0.02	0.39±0.01
LPS+ATP	10	0.99±0.03^a	1.32±0.02^a	1.31±0.01^a	0.83±0.02^a
低剂量	10	0.55±0.02^b	0.45±0.02^b	0.90±0.02^b	0.67±0.04^b
中剂量	10	0.45±0.02^b	0.42±0.02^b	0.82±0.02^b	0.49±0.01^bc
高剂量	10	0.31±0.02^bcd	0.09±0.01^bcd	0.33±0.01^bcd	0.35±0.02^bcd
F值		214.333	685.723	1009.023	200.316
P值		0.032	0.021	0.015	0.025

图4 胃饥饿素对肺泡巨噬细胞中IL-1β p17、caspase-1 p20、NLRP3和GSDMD蛋白表达的影响

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The protective effect and mechanism of ghrelin on acute lung injury in mice

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The protective effect and mechanism of ghrelin on acute lung injury in mice