雾化吸入一氧化氮供体硝普钠治疗新生猪急性呼吸窘迫综合征的实验研究

doi:10.3877/cma.j.issn.1673-5250.2012.02.020

目的

探讨雾化吸入(neb)一氧化氮(NO)供体硝普钠(SNP) (neb－SNP)对新生猪急性呼吸窘迫综合征(ARDS)的疗效、安全性及实验依据。

方法

采用生理盐水(NS)肺泡灌洗法复制ARDS新生猪模型(n＝30)。造模成功后将其随机分成5组(n＝6×5)。对照组：仅机械通气治疗；NS组：机械通气治疗＋neb－NS 30 min治疗；A，B和C组为实验组，分别进行机械通气治疗＋neb－SNP 1 mg/mL，5 mg/mL和10 mg/mL 30 min治疗。对5组分别于不同时点进行动态平均股动脉压(MAP)、平均肺动脉压(MPAP)、全血高铁血红蛋白(MetHb)含量监测及动脉血气分析和细胞因子[肿瘤坏死因子(TNF)－α与白细胞介素(IL)－10，－12]水平测定。

结果

造模成功时，NS组及A，B，C组MPAP均显著高于对照组，差异有统计学意义(P<0.01)；neb结束时，B及C组MPAP较NS组显著下降，差异有统计学意义(P<0.05)。在相同时点，5组MAP比较，差异无统计学意义(P>0.05)。neb结束时，5组全血MetHb含量比较，差异无统计学意义(P> 0.05)。A，B及C组neb结束后30 min，未发现反跳性肺动脉高压。neb结束后不同时点，A，B及C组与对照组及NS组IL－10，－12，TNF－α比较，差异有统计学意义(P<0.05)，而B与C组比较，差异无统计学意义(P>0.05)。

结论

neb－SNP可选择性降低ARDS模型肺动脉高压，同时具有调节炎症介质和抗炎因子等作用，可抑制炎症因子表达，从而减轻ARDS症状。

关键词: 急性呼吸窘迫综合征, 一氧化氮供体, 雾化吸入硝普钠, 肺动脉高压, 细胞因子, 新生猪

Objective

To observe the effects of nebulized(neb) nitrogen monoxidum(NO) donors sodium nitroprusside (SNP)(neb-SNP)on acute respiratory distress syndrome(ARDS) in newborn piglets.

Methods

Thirty anesthetized and mechanically ventilated piglets were randomly divided into five groups (n=6×5): ①Control group; ②Group NS, receiving neb normal sodium(NS) after ARDS ; ③ Group A, B, and C(neb-SNP), receiving 1 mg/mL, 5 mg/mL and 10 mg/mL neb-SNP after ARDS, respectively. Mean arterial pressure(MAP) and mean pulmonary arterial pressure (MPAP) were monitored continuously. Arterial blood gas analysis was determined at baseline, termination of neb-SNP and 30 min, 60 min, 120 min after neb, and blood methemoglobin (MetHb) were monitored.Tumor necrosis factor(TNF)-α, interleukin (IL)-10, -12 concentration in serum at 30 min, 60 min and 120 min after neb were measured.

Results

ARDS resulted in a significant increase in MPAP, MPAP in group NS, group A, B and C were significantly higher than that in control group (P<0.01). After neb, MPAP in group B and C were significantly lower than that in group NS(P<0.05). There was no significant difference in MAP among five groups at the same time points (P>0.05). After neb, there were no significant differences in blood MetHb level among five groups. No rebound pulmonary hypertension was observed after withdrawal of neb. Serum concentrations of TNF-α and IL-12 in group A, B and C (the neb-SNP treated group) were more decreased than those in control group and group NS, and serum IL-10 concentration was obviously increased in group A, B and C.

Conclusions

neb-SNP could be used as a selective pulmonary vasodilator for acute pulmonary hypertension induced by ARDS in newborn piglets. Reduced lung injury induced by ARDS through lowering and inhibiting expression of harmful inflammatory cytokines.

Key words: acute respiratory distress syndrome, nitrogen monoxidum donor, nebulized sodium nitroprusside, pulmonary hypertension, cytokine, newborn piglet

表1 5组平均肺动脉压与平均股动脉压的动态变化比较(mm Hg，±s)

Table 1 Comparison of dynamic variation of mean pulmonary arterial pressure and mean femoral artery pressure among 5 groups (mm Hg，±s)

组别		n	基础状态	造模成功时	neb结束时	neb结束后(min)
组别		n	基础状态	造模成功时	neb结束时	30	60	120
MPAP		?	?	?	?	?	?	?
?	NS组	6	17.4±1.1^a	37.3±1.3^b	39.0±3.3^b	38.7±4.6^b	39.8±4.7^b	42.9±5.1^b
?	A组	6	18.7±1.8^ad	37.7±3.1^bd	31.3±3.2^bc	34.0±4.0^bc	33.3±6.4^bc	37.5±4.1^bc
?	B组	6	17.8±1.2^ad	35.0±2.4^bd	23.3±7.0^bc	24.1±3.7^bc	26.2±3.8^bc	28.7±4.6^bc
?	C组	6	17.7±0.9^ad	36.4±2.7^bd	22.5±6.7^bc	23.6±4.1^bc	25.8±4.3^bc	29.1±4.9^bc
?	对照组	6	18.2±1.5	17.2±0.4	17.5±0.8	17.2±1.2	17.2±1.2	17.7±1.3
MAP		?	?	?	?	?	?	?
?	NS组	6	73.0± 5.6^a	75.6± 9.5^a	76.6±12.3^a	74.0±11.4^a	75.0±10.8^a	76.7±11.3^a
?	A组	6	76.7±11.0^a	77.8±14.7^a	71.3±16.8^a	69.8±10.1^a	70.8±11.1^a	75.2±11.7^a
?	B组	6	74.7± 7.5^a	77.8±12.8^a	78.3±14.1^a	76.2±14.8^a	74.2±13.9^a	76.2±17.2^a
?	C组	6	75.1± 6.6^a	76.2±11.7^a	80.0±15.3^a	78.3±14.6^a	76.3±12.7^a	72.9±10.6^a
?	对照组	6	75.7± 8.3	74.8±11.1	75.5± 9.7	77.6±11.9	77.8± 9.9	75.8± 8.7

表1 5组平均肺动脉压与平均股动脉压的动态变化比较(mm Hg，±s)

Table 1 Comparison of dynamic variation of mean pulmonary arterial pressure and mean femoral artery pressure among 5 groups (mm Hg，±s)

组别		n	基础状态	造模成功时	neb结束时	neb结束后(min)
组别		n	基础状态	造模成功时	neb结束时	30	60	120
MPAP		?	?	?	?	?	?	?
?	NS组	6	17.4±1.1^a	37.3±1.3^b	39.0±3.3^b	38.7±4.6^b	39.8±4.7^b	42.9±5.1^b
?	A组	6	18.7±1.8^ad	37.7±3.1^bd	31.3±3.2^bc	34.0±4.0^bc	33.3±6.4^bc	37.5±4.1^bc
?	B组	6	17.8±1.2^ad	35.0±2.4^bd	23.3±7.0^bc	24.1±3.7^bc	26.2±3.8^bc	28.7±4.6^bc
?	C组	6	17.7±0.9^ad	36.4±2.7^bd	22.5±6.7^bc	23.6±4.1^bc	25.8±4.3^bc	29.1±4.9^bc
?	对照组	6	18.2±1.5	17.2±0.4	17.5±0.8	17.2±1.2	17.2±1.2	17.7±1.3
MAP		?	?	?	?	?	?	?
?	NS组	6	73.0± 5.6^a	75.6± 9.5^a	76.6±12.3^a	74.0±11.4^a	75.0±10.8^a	76.7±11.3^a
?	A组	6	76.7±11.0^a	77.8±14.7^a	71.3±16.8^a	69.8±10.1^a	70.8±11.1^a	75.2±11.7^a
?	B组	6	74.7± 7.5^a	77.8±12.8^a	78.3±14.1^a	76.2±14.8^a	74.2±13.9^a	76.2±17.2^a
?	C组	6	75.1± 6.6^a	76.2±11.7^a	80.0±15.3^a	78.3±14.6^a	76.3±12.7^a	72.9±10.6^a
?	对照组	6	75.7± 8.3	74.8±11.1	75.5± 9.7	77.6±11.9	77.8± 9.9	75.8± 8.7

表2 5组氧合指数值的动态变化与全血高铁血红蛋白水平的监测结果比较(±s)

Table 2 Comparison of time course of oxygenation index and blood methemoglobin among 5 groups(±s)

组别	n	基础状态	造模成功时	neb结束时	neb结束后(min)			MetHb (%)
组别	n	基础状态	造模成功时	neb结束时	30	60	120	MetHb (%)
NS组	6	2.10±0.09	19.20±2.60^a	21.20±3.20^a	20.20±1.90	21.10±2.40	20.70±2.20	1.18±0.33
A组	6	2.50±0.06	21.90±3.70^a	14.40±2.10^ab	13.20±1.60^b	15.20±4.30^b	17.20±4.90	1.53±0.41
B组	6	2.30±0.02	23.20±3.20^a	10.30±1.90^ab	9.30±1.40^b	10.50±3.50^b	14.40±4.50	1.77±0.52
C组	6	2.30±0.04	24.10±2.80^a	11.20±2.20^ab	9.60±1.50^b	11.30±2.60^b	14.70±3.80	1.84±0.45
对照组	6	2.40±0.30	2.30±0.40	2.41±0.60	2.41±0.60	2.30±0.50	2.20±0.60	1.31±0.27

表2 5组氧合指数值的动态变化与全血高铁血红蛋白水平的监测结果比较(±s)

Table 2 Comparison of time course of oxygenation index and blood methemoglobin among 5 groups(±s)

组别	n	基础状态	造模成功时	neb结束时	neb结束后(min)			MetHb (%)
组别	n	基础状态	造模成功时	neb结束时	30	60	120	MetHb (%)
NS组	6	2.10±0.09	19.20±2.60^a	21.20±3.20^a	20.20±1.90	21.10±2.40	20.70±2.20	1.18±0.33
A组	6	2.50±0.06	21.90±3.70^a	14.40±2.10^ab	13.20±1.60^b	15.20±4.30^b	17.20±4.90	1.53±0.41
B组	6	2.30±0.02	23.20±3.20^a	10.30±1.90^ab	9.30±1.40^b	10.50±3.50^b	14.40±4.50	1.77±0.52
C组	6	2.30±0.04	24.10±2.80^a	11.20±2.20^ab	9.60±1.50^b	11.30±2.60^b	14.70±3.80	1.84±0.45
对照组	6	2.40±0.30	2.30±0.40	2.41±0.60	2.41±0.60	2.30±0.50	2.20±0.60	1.31±0.27

表3 血清白细胞介素－12水平比较(pg/mL, ±s)

Table 3 Comparison of blood serum interleukin－12 level among 5 groups (pg/mL，±s)

组别	n	neb结束后(min)
组别	n	30	60	120
NS组	6	24.27±11.34^a	33.57± 9.93^a	63.84±29.27^a
A组	6	19.83± 7.44^ab	26.53±12.63^ab	28.01±11.52^ab
B组	6	14.61± 4.79^abc	16.45± 6.48^abc	17.28± 8.76^abc
C组	6	15.37± 5.73^abc	17.44± 4.89^abc	19.46± 9.33^abc
对照组	6	10.76± 3.58	11.19± 3.56	10.12± 4.67

表3 血清白细胞介素－12水平比较(pg/mL, ±s)

Table 3 Comparison of blood serum interleukin－12 level among 5 groups (pg/mL，±s)

组别	n	neb结束后(min)
组别	n	30	60	120
NS组	6	24.27±11.34^a	33.57± 9.93^a	63.84±29.27^a
A组	6	19.83± 7.44^ab	26.53±12.63^ab	28.01±11.52^ab
B组	6	14.61± 4.79^abc	16.45± 6.48^abc	17.28± 8.76^abc
C组	6	15.37± 5.73^abc	17.44± 4.89^abc	19.46± 9.33^abc
对照组	6	10.76± 3.58	11.19± 3.56	10.12± 4.67

表4 血清中肿瘤坏死因子－α水平比较(pg/mL, ±s)

Table 4 Comparison of blood serum tumor necrosis factor－α level among 5 groups(pg/ mL, ±s)

组别	n	neb结束后(min)
组别	n	30	60	120
NS组	6	63.02±11.22^a	98.47±26.34^a	122.19±30.91^a
A组	6	55.33± 7.89^a	61.07±12.25^a	69.68±12.38^a
B组	6	49.36± 4.49^abc	56.45± 6.21^abc	55.28± 8.77^abc
C组	6	50.37± 5.48^abc	57.77± 4.91^abc	60.49± 9.54^abc
对照组	6	39.57±10.78	40.34±16.71	36.22± 8.95

表4 血清中肿瘤坏死因子－α水平比较(pg/mL, ±s)

Table 4 Comparison of blood serum tumor necrosis factor－α level among 5 groups(pg/ mL, ±s)

组别	n	neb结束后(min)
组别	n	30	60	120
NS组	6	63.02±11.22^a	98.47±26.34^a	122.19±30.91^a
A组	6	55.33± 7.89^a	61.07±12.25^a	69.68±12.38^a
B组	6	49.36± 4.49^abc	56.45± 6.21^abc	55.28± 8.77^abc
C组	6	50.37± 5.48^abc	57.77± 4.91^abc	60.49± 9.54^abc
对照组	6	39.57±10.78	40.34±16.71	36.22± 8.95

表5 血清中白细胞介素－10水平比较(pg/mL, ±s)

Table 5 Comparison of blood serum interleukin－10 level among 5 groups(pg/mL, ±s)

组别	n	neb结束后(min)
组别	n	30	60	120
NS组	6	18.78±3.09	34.62± 4.78^a	40.67±7.39^a
A组	6	33.43±7.54^a	55.82±10.80^a	64.30±9.38^a
B组	6	49.79±6.46^abc	88.45±11.29^abc	85.28±9.96^abc
C组	6	50.22±7.47^abc	89.11±10.35^abc	80.49±8.34^abc
对照组	6	10.19±3.12	11.37± 2.53	12.87±4.11

表5 血清中白细胞介素－10水平比较(pg/mL, ±s)

Table 5 Comparison of blood serum interleukin－10 level among 5 groups(pg/mL, ±s)

组别	n	neb结束后(min)
组别	n	30	60	120
NS组	6	18.78±3.09	34.62± 4.78^a	40.67±7.39^a
A组	6	33.43±7.54^a	55.82±10.80^a	64.30±9.38^a
B组	6	49.79±6.46^abc	88.45±11.29^abc	85.28±9.96^abc
C组	6	50.22±7.47^abc	89.11±10.35^abc	80.49±8.34^abc
对照组	6	10.19±3.12	11.37± 2.53	12.87±4.11

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Experimental Study on Nebulized Nitrogen Monoxidum Donator Sodium Nitroprusside on Acute Respiratory Distress Syndrome in Newborn Piglets

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Experimental Study on Nebulized Nitrogen Monoxidum Donator Sodium Nitroprusside on Acute Respiratory Distress Syndrome in Newborn Piglets