不同时间使用地塞米松对新生大鼠高氧肺损伤的影响
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摘要
目的
(1)观察不同日龄新生大鼠的肺形态发育,为研究高氧暴露会致新生大鼠发生肺形态变化提供基础;(2)观察高氧对新生大鼠的生长发育及肺组织病理形态变化的影响,建立支气管肺发育不良(bronchopulmonary dysplasia ,BPD)动物模型;(3)观察不同时间使用地塞米松对新生大鼠高氧肺损伤及生长发育的影响,以期为在BPD的防治过程中能否使用地塞米松提供理论依据。
方法
(1)将新生Wistar大鼠随机分为4个大组(Ⅰ~Ⅳ组),每组再分2个亚组(a、b组),共8个小组,每小组20只新生鼠,分别为:7日龄空气组(Ⅰa组)及14日龄空气组(Ⅰb组);7日龄高氧组(Ⅱa组)和14日龄高氧组(高氧7日+空气7日,Ⅱb组);早期地塞米松组(Ⅲa组)于吸氧第1天起给予腹腔内注射地塞米松,每天1次,共7天,初始剂量为1.5ug/g体重,3天后改为0.75ug/g体重,再使用4天,Ⅲb组为生理盐水对照组;晚期地塞米松组(Ⅳa组)于生后第8天,即吸氧结束后给予腹腔内注射地塞米松,注射剂量及方法同Ⅲa组,Ⅳb组为生理盐水对照组。(2)观察记录各组大鼠一般状况、体重及死亡情况。(3)观察各组大鼠肺组织大体病理变化、HE染色下肺组织病理形态学变化,计算肺系数、测定肺泡间隔厚度、进行放射状肺泡计数(radical alveolar counts, RAC)和肺纤维化Stocker评分,以判断肺水肿、肺泡化阻滞及肺纤维化程度。
结果
(1)空气组大鼠生长发育情况良好,7d时肺泡数量较少,肺间隔及肺泡壁较厚,至14 d时肺泡壁和肺间隔明显变薄,肺泡数量较多,RAC及肺泡间隔厚度与7d时相比,P<0.05。(2)高氧组大鼠在暴露于95%O23天后就出现氧依赖及呼吸功能不全症状,并逐渐加重,与空气组大鼠相比一般状况差,体重增长缓慢(P<0.05)。高氧暴露7d时即可见大鼠肺泡间隔水肿、增宽,肺间质细胞增加,肺泡内及肺间质中可见炎性细胞渗出,肺泡数目减少,并可见肺泡内出血,停止吸氧后有2只大鼠死亡,且肺损伤继续加重,14d时表现为肺泡间隔明显增宽,肺泡次级隔数目减少,肺泡结构相对简单化且大小不一,肺泡数目减少,炎性细胞浸润明显,RAC值较正常同日龄大鼠明显减少(P<0.05),肺纤维化的发生率及严重程度提高。(3)早期地塞米松组大鼠的一般状况最差,体重增长最为缓慢(P<0.05),且停氧后有8只大鼠出现抽搐发作,其中6只大鼠死亡,肺大体病理以Ⅲ、Ⅳ、Ⅴ级为主,其肺水肿、肺泡发育阻滞及肺纤维化程度最严重,肺系数、RAC值、肺间隔厚度与高氧组及对照组相比均差异显著(P<0.05),肺纤维化的发生率及严重程度明显提高。。(4)晚期地塞米松组大鼠一般状况较高氧组好转,体重增长率较高氧组及对照组快(P<0.05),肺大体病理以Ⅱ、Ⅲ级为主,似肺损伤程度相对较轻,但与高氧组及对照组大鼠比较,肺系数、RAC值、肺间隔厚度及肺纤维化评分差异无统计学意义(P>0.05)。
结论
(1)新生大鼠生后肺仍处于持续发育阶段,将其暴露于95%氧7d即可导致高氧肺损伤。在停止吸氧后肺损害程度继续加重。(2)早期使用地塞米松没有预防BPD的作用,且会加重高氧肺损伤,应避免使用。(3)晚期使用地塞米松虽未明显改善高氧肺损伤的肺结构异常,但使大鼠的一般状况及生长发育有所改善。(4)鉴于目前临床使用地塞米松的习惯剂量及使用次数,建议不要将地塞米松作为BPD的预防性用药,在使用地塞米松治疗BPD的过程中,应在晚期使用,并尽可能使用小剂量、短疗程。
Objectivs
(1) To provide basis for investigating chang of lung structure with prolonged hyperoxia by observing structural changes in neonatal rats with different age. (2) To observe the effects on the lung morphology changes and growth status of normal neonatal rats after prolonged hyperoxia-exposed for establishing bronchopulmonary dysplasia (BPD) model in neonatal rats. (3) To study the effects of used dexamethasone in different time on lung pathological morphology changes and growth development in neonatal rats which injury of hyperoxia , in order to providing the theoretical reference of whether can use dexamethasone to prevent and cure BPD.
Methods
The Wistar neonatal rats was designed in eight groups by random including:7st d and 14st d air group (Ⅰa andⅠb group);7st d hyperxia group which prolonged exposed 95%oxygen for 7 days (Ⅱa group)and 14st d hyperxia group which bred in the air for 7 days after hyperoxia-exposed for 7 days (Ⅱb group);hyperxia group with Early dexamethasone group which give dexamethasone from 1.5ug/g for 3 days to 0.75ug/g for 4 days i.p qd on the first day of oxygen (Ⅲa group) ,and NS group which use NS instead (Ⅲb group). Later dexamethasone group (Ⅳa group) which give dexamethasone from the day leave oxygen to 14st day, the doses as well as early dexamethasone group, and NS group which use NS instead (Ⅳb group). Body weight, general situation and the death number of rats were recorded. Observe the pulmonary general pathology classification and lung morphometric analysis were undertaken according to HE staining.Judge the degree of pulmonary edema, alveolarization block and pulmonary fibrosis from lung coefficient calculation , alveolar interval thickness ,radical alveoli count (RAC)and pulmonary fibrosis Stocker score.
Results
(1)The air group rats growth is good. The lung morphometric analysis in 7th day showed thick septa and walls of alveoli and fewer alveoli. In 14th day, the septa and walls of alveoli became thin, alveoli showing large. There have significant differences in RAC and alveolar interval thickness between the two air groups (P<0.05). (2) The hyperxia group rats showing progressive serious oxygen dependence and respiratory insufficiency symptoms after exposed 95% oxygen 3 days later. The general station is worse than that of the air group. The weight growth in the hyperxia group is slower and the rate of weight growth is obviously decrease than that of the air group (264.76±27.98% Vs 396.94±41.67%,P<0.05). The 7st d hyperxia group rats displayed the septa dedma and thicker walls of alveoli , alveolar interstitial cells increaed , there was a few inflammatory cells and blooding cells exuded out in the alveoli and interstitial. The lung injury was continue and there was two rats died after stop breathing oxygen. The 14st d hyperxia group rats showed alveolar septa was obviously thicker, and the secondary septum decreased , the alveolar structure showed simple and had fewer and larger alveoli. RAC of hyperxia group rats(8.36±1.28) was significantly lower than that of neonatal rats in air group(12.71±1.79), the degree and incidence of pulmonary fibrosis were obviously increased. (3) The general situation of early dexamethasone group rats was the worst and the weight growth is the slowest of all groups. There were eight rats happened convulsions after unexposed oxygen and six rats died. The pulmonary general pathology classification was the mostlyⅢ、Ⅳ、Ⅴlevel. The degree of pulmonary edema, alveolarization block and pulmonary fibrosis were the most serious. There have significant differences in lung coefficient calculation, RAC, alveolar interval thickness and pulmonary fibrosis Stocker score between the early dexamethasone group and the NS control group (P<0.05). (4) The general situation of the later dexamethasone group was better and the growth increased faster than hyperxia group and NS comtrol group. The pulmonary general pathology classification of the later dexamethasone group was the mostlyⅡ、Ⅲlevel. The later dexamethasone group seemly lung injury is lighter, but there have not significant differences in lung coefficient calculation, RAC, alveolar interval thickness and pulmonary fibrosis Stocker score between the later dexamethasone group and the NS control group (P>0.05).
Conclusions
(1) The lung of the neonatal rat is still in the continuous development stage after birth. Neonatal rats exposed to 95%oxygen for 7 days may cause hyperxia lung injury and the lung damage continue serious after stop oxygen (2) Early use dexamethasone has no action to prevent BPD happen, instead it may aggravated the hyperxia lung damage. (3) Although there was no significently change of pulmonary structured exception after use dexamethasone later, but the general situation and rat growth improved. (4) Because of the clinical habit of dexamethasone use dose and use frequency, we suggest don`t use dexamethasone as prophylaxis for BPD, we should use dexamethasone therapy BPD in the late stages, and during the treatment process,we should use dexamethasone as small doses and short treatment as possible.
(1)观察不同日龄新生大鼠的肺形态发育,为研究高氧暴露会致新生大鼠发生肺形态变化提供基础;(2)观察高氧对新生大鼠的生长发育及肺组织病理形态变化的影响,建立支气管肺发育不良(bronchopulmonary dysplasia ,BPD)动物模型;(3)观察不同时间使用地塞米松对新生大鼠高氧肺损伤及生长发育的影响,以期为在BPD的防治过程中能否使用地塞米松提供理论依据。
方法
(1)将新生Wistar大鼠随机分为4个大组(Ⅰ~Ⅳ组),每组再分2个亚组(a、b组),共8个小组,每小组20只新生鼠,分别为:7日龄空气组(Ⅰa组)及14日龄空气组(Ⅰb组);7日龄高氧组(Ⅱa组)和14日龄高氧组(高氧7日+空气7日,Ⅱb组);早期地塞米松组(Ⅲa组)于吸氧第1天起给予腹腔内注射地塞米松,每天1次,共7天,初始剂量为1.5ug/g体重,3天后改为0.75ug/g体重,再使用4天,Ⅲb组为生理盐水对照组;晚期地塞米松组(Ⅳa组)于生后第8天,即吸氧结束后给予腹腔内注射地塞米松,注射剂量及方法同Ⅲa组,Ⅳb组为生理盐水对照组。(2)观察记录各组大鼠一般状况、体重及死亡情况。(3)观察各组大鼠肺组织大体病理变化、HE染色下肺组织病理形态学变化,计算肺系数、测定肺泡间隔厚度、进行放射状肺泡计数(radical alveolar counts, RAC)和肺纤维化Stocker评分,以判断肺水肿、肺泡化阻滞及肺纤维化程度。
结果
(1)空气组大鼠生长发育情况良好,7d时肺泡数量较少,肺间隔及肺泡壁较厚,至14 d时肺泡壁和肺间隔明显变薄,肺泡数量较多,RAC及肺泡间隔厚度与7d时相比,P<0.05。(2)高氧组大鼠在暴露于95%O23天后就出现氧依赖及呼吸功能不全症状,并逐渐加重,与空气组大鼠相比一般状况差,体重增长缓慢(P<0.05)。高氧暴露7d时即可见大鼠肺泡间隔水肿、增宽,肺间质细胞增加,肺泡内及肺间质中可见炎性细胞渗出,肺泡数目减少,并可见肺泡内出血,停止吸氧后有2只大鼠死亡,且肺损伤继续加重,14d时表现为肺泡间隔明显增宽,肺泡次级隔数目减少,肺泡结构相对简单化且大小不一,肺泡数目减少,炎性细胞浸润明显,RAC值较正常同日龄大鼠明显减少(P<0.05),肺纤维化的发生率及严重程度提高。(3)早期地塞米松组大鼠的一般状况最差,体重增长最为缓慢(P<0.05),且停氧后有8只大鼠出现抽搐发作,其中6只大鼠死亡,肺大体病理以Ⅲ、Ⅳ、Ⅴ级为主,其肺水肿、肺泡发育阻滞及肺纤维化程度最严重,肺系数、RAC值、肺间隔厚度与高氧组及对照组相比均差异显著(P<0.05),肺纤维化的发生率及严重程度明显提高。。(4)晚期地塞米松组大鼠一般状况较高氧组好转,体重增长率较高氧组及对照组快(P<0.05),肺大体病理以Ⅱ、Ⅲ级为主,似肺损伤程度相对较轻,但与高氧组及对照组大鼠比较,肺系数、RAC值、肺间隔厚度及肺纤维化评分差异无统计学意义(P>0.05)。
结论
(1)新生大鼠生后肺仍处于持续发育阶段,将其暴露于95%氧7d即可导致高氧肺损伤。在停止吸氧后肺损害程度继续加重。(2)早期使用地塞米松没有预防BPD的作用,且会加重高氧肺损伤,应避免使用。(3)晚期使用地塞米松虽未明显改善高氧肺损伤的肺结构异常,但使大鼠的一般状况及生长发育有所改善。(4)鉴于目前临床使用地塞米松的习惯剂量及使用次数,建议不要将地塞米松作为BPD的预防性用药,在使用地塞米松治疗BPD的过程中,应在晚期使用,并尽可能使用小剂量、短疗程。
Objectivs
(1) To provide basis for investigating chang of lung structure with prolonged hyperoxia by observing structural changes in neonatal rats with different age. (2) To observe the effects on the lung morphology changes and growth status of normal neonatal rats after prolonged hyperoxia-exposed for establishing bronchopulmonary dysplasia (BPD) model in neonatal rats. (3) To study the effects of used dexamethasone in different time on lung pathological morphology changes and growth development in neonatal rats which injury of hyperoxia , in order to providing the theoretical reference of whether can use dexamethasone to prevent and cure BPD.
Methods
The Wistar neonatal rats was designed in eight groups by random including:7st d and 14st d air group (Ⅰa andⅠb group);7st d hyperxia group which prolonged exposed 95%oxygen for 7 days (Ⅱa group)and 14st d hyperxia group which bred in the air for 7 days after hyperoxia-exposed for 7 days (Ⅱb group);hyperxia group with Early dexamethasone group which give dexamethasone from 1.5ug/g for 3 days to 0.75ug/g for 4 days i.p qd on the first day of oxygen (Ⅲa group) ,and NS group which use NS instead (Ⅲb group). Later dexamethasone group (Ⅳa group) which give dexamethasone from the day leave oxygen to 14st day, the doses as well as early dexamethasone group, and NS group which use NS instead (Ⅳb group). Body weight, general situation and the death number of rats were recorded. Observe the pulmonary general pathology classification and lung morphometric analysis were undertaken according to HE staining.Judge the degree of pulmonary edema, alveolarization block and pulmonary fibrosis from lung coefficient calculation , alveolar interval thickness ,radical alveoli count (RAC)and pulmonary fibrosis Stocker score.
Results
(1)The air group rats growth is good. The lung morphometric analysis in 7th day showed thick septa and walls of alveoli and fewer alveoli. In 14th day, the septa and walls of alveoli became thin, alveoli showing large. There have significant differences in RAC and alveolar interval thickness between the two air groups (P<0.05). (2) The hyperxia group rats showing progressive serious oxygen dependence and respiratory insufficiency symptoms after exposed 95% oxygen 3 days later. The general station is worse than that of the air group. The weight growth in the hyperxia group is slower and the rate of weight growth is obviously decrease than that of the air group (264.76±27.98% Vs 396.94±41.67%,P<0.05). The 7st d hyperxia group rats displayed the septa dedma and thicker walls of alveoli , alveolar interstitial cells increaed , there was a few inflammatory cells and blooding cells exuded out in the alveoli and interstitial. The lung injury was continue and there was two rats died after stop breathing oxygen. The 14st d hyperxia group rats showed alveolar septa was obviously thicker, and the secondary septum decreased , the alveolar structure showed simple and had fewer and larger alveoli. RAC of hyperxia group rats(8.36±1.28) was significantly lower than that of neonatal rats in air group(12.71±1.79), the degree and incidence of pulmonary fibrosis were obviously increased. (3) The general situation of early dexamethasone group rats was the worst and the weight growth is the slowest of all groups. There were eight rats happened convulsions after unexposed oxygen and six rats died. The pulmonary general pathology classification was the mostlyⅢ、Ⅳ、Ⅴlevel. The degree of pulmonary edema, alveolarization block and pulmonary fibrosis were the most serious. There have significant differences in lung coefficient calculation, RAC, alveolar interval thickness and pulmonary fibrosis Stocker score between the early dexamethasone group and the NS control group (P<0.05). (4) The general situation of the later dexamethasone group was better and the growth increased faster than hyperxia group and NS comtrol group. The pulmonary general pathology classification of the later dexamethasone group was the mostlyⅡ、Ⅲlevel. The later dexamethasone group seemly lung injury is lighter, but there have not significant differences in lung coefficient calculation, RAC, alveolar interval thickness and pulmonary fibrosis Stocker score between the later dexamethasone group and the NS control group (P>0.05).
Conclusions
(1) The lung of the neonatal rat is still in the continuous development stage after birth. Neonatal rats exposed to 95%oxygen for 7 days may cause hyperxia lung injury and the lung damage continue serious after stop oxygen (2) Early use dexamethasone has no action to prevent BPD happen, instead it may aggravated the hyperxia lung damage. (3) Although there was no significently change of pulmonary structured exception after use dexamethasone later, but the general situation and rat growth improved. (4) Because of the clinical habit of dexamethasone use dose and use frequency, we suggest don`t use dexamethasone as prophylaxis for BPD, we should use dexamethasone therapy BPD in the late stages, and during the treatment process,we should use dexamethasone as small doses and short treatment as possible.
引文
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