瑞芬太尼对脓毒症诱导急性呼吸窘迫综合征大鼠的保护作用研究

doi:10.3877/cma.j.issn.1674-6880.2016.03.001

目的

观察瑞芬太尼对脓毒症诱导产生急性呼吸窘迫综合征（ARDS）大鼠的保护作用及机制。

方法

将40只SD大鼠分为对照组、ARDS组、瑞芬太尼对照组及瑞芬太尼治疗组，每组各10只。ARDS组与瑞芬太尼治疗组大鼠经股静脉注射7.5 mg/kg脂多糖以制备ARDS大鼠模型，对照组与瑞芬太尼对照组大鼠予以等体积生理盐水；而后瑞芬太尼对照组及治疗组在注射6 h后给予静脉注射瑞芬太尼0.04 μg/kg，ARDS组予以等体积生理盐水。所有大鼠于脂多糖注射后8 h处死。取右肺予以病理学检测，取左肺上叶进行髓过氧化物酶（MPO）水平、肺湿/干重（W/D）及肿瘤坏死因子α（TNF-α），白细胞介素1β（IL-1β）和IL-6水平的比较，并对支气管肺泡灌洗液（BALF）中蛋白含量及细胞计数进行检测。

结果

静脉注射脂多糖8 h后，肺组织病理切片提示肺内大量炎性细胞浸润，而给予瑞芬太尼处理的动物上述病理学改变明显减轻。ARDS组大鼠MPO水平[（1.98 ± 0.14）U/g vs.（0.89 ± 0.12）U/g]、肺W/D比值[（8.51 ± 0.13）vs.（3.83 ± 0.08）]、TNF-α[（1 141 ± 114）ng/L vs.（186 ± 8）ng/L]、IL-1β[（1 866 ± 291）ng/L vs.（201 ± 30）ng/L]、IL-6[（528 ± 61）ng/L vs.（246 ± 35）ng/L]、BALF中蛋白含量[（0.96 ± 0.02）g/L vs.（0.29 ± 0.01）g/L]及细胞计数[（11.57 ± 1.04）×10⁸/ml vs.（1.39 ± 0.29）× 10⁸/ml]均明显高于对照组（P均<0.05），而瑞芬太尼治疗组大鼠MPO水平为（1.01 ± 0.12）U/g，肺W/D比值4.05 ± 0.12，TNF-α为（573.8 ± 49.6）ng/L，IL-1β为（769.5 ± 49.8）ng/L，IL-6为（365.5 ± 35.8）ng/L，BALF中蛋白含量（0.53 ± 0.02）g/L，细胞计数为（7.57 ± 0.66）× 10⁸/ml，上述指标均明显低于ARDS组（P均<0.05）。

结论

瑞芬太尼对脓毒症诱导的ARDS大鼠具有保护作用。

关键词: 脓毒症, 瑞芬太尼, 急性呼吸窘迫综合征, 大鼠

Objective

To investigate the effects of remifentanil on sepsis induced acute respiratory distress syndrome (ARDS) in rats.

Methods

A total of 40 SD rats were randomly divided into four groups: control group, ARDS group, remifentanil control group, and remifentanil group. ARDS model was induced by administering 7.5 mg/kg lipopolysaccharide (LPS) via vein in the ARDS group and remifentanil group, and rats in the control group and remifentanil control group were injected with the same volume of saline. Then the rats in the remifentanil control group and remifentanil group were subcutaneously treated with 0.04 μg/kg remifentanil 6 hours after LPS administration. All rats were sacrificed at 8 h after LPS administration. Right lung tissue were used to examine lung pathology changes, the myeloperoxidase (MPO), wet/dry (W/D) ratio, tumor necrosis factor-α(TNF-α), interleukin-1β (IL-1β) and IL-6 levels in left upper lung were examined and compared. Moreover, protein content and cell count in bronchoalveolar lavage fluid (BALF) were detected.

Results

A large number of inflammatory cells infiltration at 8 h after LPS administration in the ARDS group and remifentanil control group, and above pathology changes were significantly alleviated in the remifentanil group. The levels of MPO [(1.98 ± 0.14) U/g vs. (0.89 ± 0.12) U/g], W/D ratio [(8.51 ± 0.13) vs. (3.83 ± 0.08)], TNF-α [(1 141 ± 114) ng/L vs. (186 ± 8) ng/L], IL-1β [(1 866 ± 291) ng/L vs. (201 ± 30) ng/L], IL-6 [(528 ± 61) ng/L vs. (246 ± 35) ng/L], protein content [(0.96 ± 0.02)g/L vs. (0.29 ± 0.01) g/L] and cell count [(11.57 ± 1.04) × 10⁸/ml vs. (1.39 ± 0.29) × 10⁸/ml] in the ARDS group were higher than those in the control group (all P<0.05). In the remifentanil group, the MPO level, W/D ratio, TNF-α, IL-1β, IL-6, protein content and cell count were (1.01 ± 0.12)U/g, 4.05 ± 0.12, (573.8 ± 49.6) ng/L, (769.5 ± 49.8) ng/L, (365.5 ± 35.8) ng/L, (0.53 ± 0.02) g/L and (7.57 ± 0.66) × 10⁸/ml, respectively. Above parameters were all lower than those in the ARDS group (all P<0.05).

Conclusion

Remifentanil could decrease the inflammation response and prevent the development of ARDS induced by LPS which plays a protective role in rats.

Key words: Remifentanil, Lipopolysaccharide, Acute lung injury, Cytokines

图1 各组大鼠肺脏病理学改变图。注：a~d图分别为对照组、急性呼吸窘迫综合症组、瑞芬太尼对照组、瑞芬太尼治疗组（HE ×400）

表1 各组ARDS大鼠肺组织MPO和肺湿干比重的变化（±s）

组别	例数	MPO水平（U/g）	肺湿干比重
对照组	10	0.89 ± 0.12	3.83 ± 0.08
ARDS组	10	1.98 ± 0.14^a	8.51 ± 0.13^a
瑞芬太尼对照组	10	0.82 ± 0.02	3.82 ± 0.10
瑞芬太尼治疗组	10	1.01 ± 0.12^b	4.05 ± 0.12^b
F值	?	24.45	59.63
P值	?	< 0.05	< 0.05

表1 各组ARDS大鼠肺组织MPO和肺湿干比重的变化（±s）

组别	例数	MPO水平（U/g）	肺湿干比重
对照组	10	0.89 ± 0.12	3.83 ± 0.08
ARDS组	10	1.98 ± 0.14^a	8.51 ± 0.13^a
瑞芬太尼对照组	10	0.82 ± 0.02	3.82 ± 0.10
瑞芬太尼治疗组	10	1.01 ± 0.12^b	4.05 ± 0.12^b
F值	?	24.45	59.63
P值	?	< 0.05	< 0.05

表2 各组ARDS大鼠肺泡灌洗液中TNF-α、IL-1β、IL-6比较ARDS大鼠（ng/L，±s）

组别	例数	TNF-α	IL-1β	IL-6
对照组	10	186 ± 18	201 ± 30	246 ± 35
ARDS组	10	1141 ± 114^a	1866 ± 291^a	528 ± 61^a
瑞芬太尼对照组	10	179 ± 16	195 ± 12	241 ± 44
瑞芬太尼治疗组	10	574 ± 50^b	770 ± 50^b	366 ± 36^b
F值	?	117.70	48.49	7.57
P值	?	< 0.05	< 0.05	< 0.05

表2 各组ARDS大鼠肺泡灌洗液中TNF-α、IL-1β、IL-6比较ARDS大鼠（ng/L，±s）

组别	例数	TNF-α	IL-1β	IL-6
对照组	10	186 ± 18	201 ± 30	246 ± 35
ARDS组	10	1141 ± 114^a	1866 ± 291^a	528 ± 61^a
瑞芬太尼对照组	10	179 ± 16	195 ± 12	241 ± 44
瑞芬太尼治疗组	10	574 ± 50^b	770 ± 50^b	366 ± 36^b
F值	?	117.70	48.49	7.57
P值	?	< 0.05	< 0.05	< 0.05

表3 各组ARDS大鼠肺泡灌洗液中蛋白含量和细胞计数比较（±s）

组别	例数	蛋白含量（g/L）	细胞计数（×10⁸/ml）
对照组	10	0.29 ± 0.01	1.39 ± 0.29
ARDS组	10	0.96 ± 0.02^a	11.57 ± 1.04^a
瑞芬太尼对照组	10	0.29 ± 0.01	1.49 ± 0.30
瑞芬太尼治疗组	10	0.53 ± 0.02^b	7.57 ± 0.66^b
F值	?	28.95	122.50
P值	?	< 0.05	< 0.05

表3 各组ARDS大鼠肺泡灌洗液中蛋白含量和细胞计数比较（±s）

组别	例数	蛋白含量（g/L）	细胞计数（×10⁸/ml）
对照组	10	0.29 ± 0.01	1.39 ± 0.29
ARDS组	10	0.96 ± 0.02^a	11.57 ± 1.04^a
瑞芬太尼对照组	10	0.29 ± 0.01	1.49 ± 0.30
瑞芬太尼治疗组	10	0.53 ± 0.02^b	7.57 ± 0.66^b
F值	?	28.95	122.50
P值	?	< 0.05	< 0.05

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Protective effects of remifentanil on sepsis induced acute respiratory distress syndrome in rats

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Protective effects of remifentanil on sepsis induced acute respiratory distress syndrome in rats