产前使用硫酸特布他林对早产大鼠肺液吸收的促进作用及其机制探讨

发布时间：2018-06-09 21:18

本文选题：早产大鼠 + 肺液转运　；参考：《山西医科大学》2012年硕士论文

【摘要】：研究背景孕产妇高龄、异常胎盘(胎盘早剥、前置)、出血、感染、先兆子痫、宫内生长迟缓、异常的产前征象、胎儿脑积水等诸多因素均可导致早产儿出生率明显增高。近年来,早产儿的病死率和患病率明显高于足月儿,而呼吸道疾病是较为常见的并发症。因此,治疗及预防早产儿呼吸系统疾病已经成为临床上需要解决的主要问题之一。 1966年,Avery首次报道：早产儿肺液吸收延迟可导致早产儿湿肺或早产儿呼吸窘迫综合征,主要表现为出生后气促、呼吸困难甚至呼吸衰竭。胎儿时期肺泡内充满液体,在正常生产过程中需要通过狭窄的产道,当头部娩出而胸廓受挤压时约有1/2-2/3的肺泡液经口、鼻排出体外,其余部分由肺间质毛细血管和淋巴管吸收自行吸收。然而,近年来随着孕妇孕产期合并症的增加,使胎儿未足月行剖宫产娩出大量增多,生后肺泡内及间质内液体过多,吸收延迟,或有液体运转困难,以致出生24小时内肺泡存留较多液体而影响气体交换,这就使呼吸窘迫综合征的发生率大大增加。临床上早已在产前使用地塞米松来预防早产儿呼吸窘迫综合征的发生。然而,经产前地塞米松治疗虽然在很大程度上达到预防呼吸窘迫综合征的目的,但尚不能完全预防,且可能对胎儿会产生远期影响。因此还需寻求更积极的方法来预防早产儿的呼吸系统疾病。由于β2-AR激动剂能特异性兴奋p2-AR,发挥松弛气道平滑肌、降低气道阻力、增强黏液纤毛清除、抑制气道神经、降低血管通透性、抑制肥大细胞、炎性细胞释放介质。目前,临床上主要联合吸入皮质激素与β2-肾上腺素受体(β2-Adrenergic receptor, β2-AR)激动剂治疗小儿呼吸道与肺部疾病。已有研究发现：硫酸特布他林可增强急性肺损伤后大鼠肺泡上皮液体清除功能,减轻肺水肿,从而改善气体交换功能。然而,产前使用硫酸特布他林是否可以促进早产儿肺液吸收并不清楚。目的观察β2-AR激动剂硫酸特布他林对早产新生大鼠肺液吸收的影响,并分析其作用机制。方法本研究将孕鼠随机分为以下5组：受孕后第16天开始干预,药物均采用灌胃方法,1日2次,连用3天。大鼠孕19天杀鼠取材,每组取新生鼠10只,进行肺组织湿重/干重之比、Na+,K+-ATP酶活性和环磷酸腺苷(cAMP)浓度测定。结果 1.硫酸特布他林促进大鼠肺组织湿重/干重比值降低本研究发现：单纯早产组大鼠肺组织湿重/干重比值高于正常对照组(4.12±0.75vs.2.47±0.16,P0.01),提示单纯早产组肺液吸收延迟；0.013mg/kg硫酸特布他林可以降低早产大鼠肺组织湿重/干重比值(3.71±0.31vs.4.12±0.75,P0.01)；0.025mg/kg硫酸特布他林使得大鼠肺组织湿重/干重比值低于0.013mg/kg剂量组(2.50±0.09vs.3.71±0.31,P0.01),且与正常对照组相比无显著性差异(2.50±0.09vs.2.47±0.16,P0.05)；与地塞米松组(0.03mg/kg)相比,0.025mg/kg硫酸特布他林的效果略好(2.50±0.09vs.3.61±0.24,P0.01)。以上结果提示：硫酸特布他林可以促进早产大鼠肺液吸收延迟,且效果可能略优于地塞米松(见表1)。 2.硫酸特布他林促进大鼠肺组织Na+,K+-ATP酶活性增加本研究发现：单纯早产大鼠肺组织中的Na+,K+-ATP酶活性显著低于正常对照组(61.45±6.02vs.103.58±10.47,P0.01)；0.013mg/kg硫酸特布他林可以增加早产大鼠肺组织Na+,K+-ATP酶活性(71.0±4.22vs.61.45±6.02,P0.01)；0.025mg/kg硫酸特布他林可使早产大鼠肺组织Na+,K+-ATP酶活性与正常对照组之间无统计学差异(103.58±10.47vs.103.58±10.47,P0.05),表明硫酸特布他林组2(0.025mg/kg) Na+, K+-ATP酶活性已接近正常；与地塞米松组(100.06±10.78)相比,0.025mg/kg硫酸特布他林增加早产大鼠肺组织中Na+,K--ATP酶活力的能力略强(110.9±11.60vs.100.06±10.78,P0.05)。以上结果提示：硫酸特布他林可能通过增加大鼠肺组织中Na+,K+-ATP酶活性来促进大鼠肺组织湿重/干重比值降低(见表2)。 3.硫酸特布他林促进大鼠肺组织cAMP浓度增加本研究通过观察硫酸特布他林是否通过增加早产大鼠肺组织中cAMP浓度来激活Na+,K+-ATP酶活性。结果发现：单纯早产组肺组织cAMP浓度明显低于正常对照组(1.87±0.09vs.6.11±0.32, P0.01):0.013mg/kg硫酸特布他林可以增加早产大鼠肺组织Na+,K+-ATP酶活性(3.07±0.09vs.6.11±0.32,P0.01)；0.025mg/kg特布他林可使肺组织cAMP浓度与正常对照组相比无统计学差异(6.11±0.32vs.6.20±0.11,P0.05)；与地塞米松组(0.03mg/kg)相比,0.025mg/kg硫酸特布他林增加早产大鼠肺组织中cAMP浓度的能力更强(6.110.32vs.4.45±0.18)。以上结果提示：硫酸特布他林可能通过增加早产大鼠肺组织中cAMP浓度来激活Na+,K+-ATP酶活性。结论本研究发现：产前使用β2-AR激动剂硫酸特布他林,可以降低早产新生大鼠肺组织湿重/干重之比,即促进早产新生大鼠肺液吸收；该效应可能是硫酸特布他林通过升高肺组织中cAMP浓度进而增加Na+,K+-ATP酶活性引起的。这一研究结果为临床预防早产儿发生肺液吸收延迟提供了新的思路和实验依据。
[Abstract]:Research background
Maternal age, abnormal placenta (placenta abruption, preposition), bleeding, infection, preeclampsia, intrauterine growth retardation, abnormal antenatal signs, fetal hydrocephalus and many other factors can lead to a significant increase in the birth rate of preterm infants. In recent years, the mortality and prevalence of premature infants are significantly higher than those in the full-term infants, and respiratory diseases are more common complications. Therefore, the treatment and prevention of respiratory diseases in premature infants has become one of the major problems that need to be solved clinically.
In 1966, Avery first reported that the delayed absorption of pulmonary fluid in preterm infants could lead to premature infant wet lung or premature infant respiratory distress syndrome, mainly manifested in postnatal, respiratory and respiratory failure. In the fetal period, the alveoli are filled with liquid and need to pass through a narrow birth canal in normal production, when the head is delivered and the chest is squeezed. About 1/2-2/3 of the alveolar fluid is passed through the mouth, the nose is discharged from the body, the rest is absorbed by the pulmonary capillary capillary and the lymphatic vessels. However, in recent years, with the increase of pregnancy and birth complications in pregnant women, there is a large increase in the childbirth of the fetus without full term cesarean section, excessive fluid in the alveoli and interstitial fluid after birth, delayed absorption, or difficult fluid operation. That is to say, the presence of more fluid in alveoli and gas exchange during the 24 hours of birth will increase the incidence of respiratory distress syndrome.
Dexamethasone has long been used to prevent the occurrence of premature infant respiratory distress syndrome. However, prepartum dexamethasone is not fully prevented and may have a long effect on the fetus, although it is to a large extent the purpose of preventing respiratory distress syndrome. Prevention of respiratory diseases in preterm infants.
Due to the specific excitatory effect of beta 2-AR agonist on p2-AR, it relaxes airway smooth muscle, reduces airway resistance, enhances mucociliary clearance, inhibits airway nerve, reduces vascular permeability, inhibits mast cells, and releases mediators of inflammatory cells. At present, the main clinical combination of inhaled skin hormone and beta 2- adrenergic receptor (Beta 2-Adrenergic receptor) Beta 2-AR) agonists have been used to treat respiratory and pulmonary diseases in children. It has been found that terbutaline sulfate can enhance the fluid clearance function of alveolar epithelium in rats after acute lung injury, reduce pulmonary edema, and improve gas exchange function. However, it is not clear whether prenatal use of terbutaline can promote the absorption of pulmonary fluid in premature infants.
objective
To observe the effect of terbutaline sulfate, a beta 2-AR agonist, on the absorption of pulmonary fluid in preterm newborn rats and analyze its mechanism.
Method
In this study, pregnant rats were randomly divided into 5 groups: the intervention of sixteenth days after pregnancy and the use of gavage, 1 days 2 times and 3 days. The rats were selected for 19 days of pregnancy and 10 newborn rats in each group were selected, and the ratio of wet weight / dry weight of lung tissue, the activity of Na+, K+-ATP enzyme and the concentration of cAMP were measured.
Result
1. terbutaline sulfate increased the ratio of wet weight to dry weight of lung tissue in rats.
The study found that the ratio of wet weight / dry weight of lung tissue in preterm preterm rats was higher than that of normal control group (4.12 + 0.75vs.2.47 + 0.16, P0.01), suggesting that pulmonary fluid absorption delayed in preterm labor group; 0.013mg/kg sulfate terbutaline could reduce the ratio of wet weight / dry weight (3.71 + 0.31vs.4.12 + 0.75, P0.01) in preterm rats and 0.025mg/kg sulphate. The ratio of wet weight / dry weight of rat lung tissue was lower than that of 0.013mg/kg dose group (2.50 + 0.09vs.3.71 + 0.31, P0.01), and there was no significant difference compared with the normal control group (2.50 + 0.09vs.2.47 + 0.16, P0.05). Compared with dexamethasone group (0.03mg/kg), the effect of 0.025mg/kg terbutaline was slightly better than that of 0.025mg/kg (2.50 + 0.09vs.3.61 + 0.24, P0.01). The results suggest that terbutaline sulfate can promote the delayed absorption of lung fluid in premature rats, and the effect may be slightly better than that of dexamethasone (see Table 1).
2. terbutaline sulfate increased the activity of Na+ and K+-ATP in lung tissue of rats.
This study found that the Na+, K+-ATP enzyme activity in the lung tissue of preterm rats was significantly lower than that in the normal control group (61.45 + 6.02vs.103.58 + 10.47, P0.01); 0.013mg/kg sulfate terbutaline could increase the Na+, K+-ATP enzyme activity (71 + 4.22vs.61.45 + 6.02, P0.01) of the lung tissue of preterm rats; 0.025mg/kg sulfate terbutaline could make the lung of premature rats lung There was no statistical difference between the tissue Na+, K+-ATP enzyme activity and normal control group (103.58 + 10.47vs.103.58 + 10.47, P0.05), indicating that the activity of 2 (0.025mg/kg) Na+, K+-ATP enzyme activity of the terbutaline sulfate group was close to normal; compared with the dexamethasone group (100.06 + 10.78), 0.025mg/ kg sulfate terbutaline increased Na+, K--ATP enzyme activity in the lung tissue of preterm rats The ability of force was slightly stronger (110.9 + 11.60vs.100.06 + 10.78, P0.05). The above results suggest that terbutaline sulfate may promote the decrease of wet weight / dry weight ratio of lung tissue in rat lung by increasing the activity of Na+ and K+-ATP in rat lung tissue (see Table 2).
3. terbutaline sulfate increased cAMP concentration in lung tissue of rats
The purpose of this study was to observe whether terbutaline sulfate activated Na+ and K+-ATP enzyme activity by increasing the concentration of cAMP in the lung tissue of preterm rats. The results showed that the concentration of cAMP in the lung tissue in the simple preterm group was significantly lower than that of the normal control group (1.87 + 0.09vs.6.11 + 0.32, P0.01): 0.013mg/kg sulfate terbutaline could increase the Na+ of the lung tissue of the preterm rats, K+-AT The activity of P enzyme (3.07 + 0.09vs.6.11 + 0.32, P0.01); 0.025mg/kg in terbutaline could make the cAMP concentration of lung tissue have no statistical difference (6.11 + 0.32vs.6.20 + 0.11, P0.05). Compared with dexamethasone group (0.03mg/kg), 0.025mg/kg sulfate terbutaline increased the ability of cAMP concentration in the lung tissue of premature rats (6.110.32vs.4) .45 + 0.18). These results suggest that terbutaline sulfate may activate Na+ and K+-ATP enzyme activities by increasing the cAMP concentration in the lung tissue of premature rats.
conclusion
This study found that prenatal use of terbutaline, a beta 2-AR agonist, can reduce the ratio of wet weight / dry weight of lung tissue in premature newborn rats, that is, promoting pulmonary fluid absorption in premature newborn rats; this effect may be caused by the increase of the concentration of cAMP in the lung tissue by terbutaline sulfate and the increase of the activity of Na+ and K+-ATP enzyme. It provides a new idea and experimental basis for clinical prevention of premature pulmonary fluid absorption delay.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R722.6

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