胎粪吸入综合征的临床回顾分析及相关实验研究
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摘要
胎粪吸入综合征(MAS)是新生儿期的常见病，它的病理生理机制复杂，包括炎症细胞因子和介质对肺的损伤、氧自由基的产生增加、肺表面活性物质功能受损等；MAS可导致肺损伤、呼吸衰竭、各种气漏、且易并发持续肺动脉高压，给临床治疗带来一定的困难。近年来，由于围产期诊断治疗技术的提高，MAS的发病趋势呈现下降，但在三级医院内MAS的构成比及并发症变化趋势尚无系统研究资料。因此，收集临床有关MAS的相关资料，并对其并发症及死亡的相关情况进行回顾性分析，对今后防治策略的制定及研究重点的确立是十分必要的。
NO可选择性扩张肺血管，改善氧合，而且还可抑制炎症反应，为临床治疗MAS提供了新的治疗前景。但是NO与超氧阴离子结合形成过氧化亚硝酸盐ONOO~-，后者可通过脂质过氧化和破坏表面活性物质相关蛋白而抑制表面活性物质的功能。为了避免氧自由基造成的肺损伤，抗氧化物对胎粪吸入性肺炎的治疗作用是值得研究的。
抗氧化物重组人超氧化物歧化酶(recombinant human superoxide dismutase，rhSOD)能清除氧自由基，保护肺组织。已有研究表明，rhSOD可减轻内毒素所诱导的肺损伤；且rhSOD气管内给药具有安全、吸收快、半衰期长的特点，还具有抗炎作用。目前已有报道rhSOD可加强一氧化氮吸入(inhaled nitric oxide，iNO)治疗持续肺动脉高压的效果。但rhSOD干预MAS对炎症因子基因表达的影响尚未见报道。
肺表面活性物质(surfactant，surf)是由脂质和蛋白质组成，它的主要功能是降低肺泡表面张力、维持肺泡结构的相对稳定，但是Surf仅含磷脂并不能降低表面张力而需要有表面活性物质相关蛋白(Surfactant protein，SP)才能发挥
浙江大学硕士学位论文
作用，因为SP能促进磷脂分子在肺泡迅速扩散和吸附，且SP一B比SP一C更有效。
研究表明胎粪吸入可损伤肺表面活性物质的功能，已经有应用Sllrf成功治疗
MAS的报道。
因此，本研究第一部分通过收集与锹S相关的临床资料对其并发症和死亡
的相关因素进行分析，了解琳S的现状及其变化趋势，为研究新的治疗方法提供
思路。第二部分通过建立MAS实验动物模型，采用RT一PCR方法观察NO吸入
(inh目ed ni功c oxide，iNo)和rhsoo单独或联合治疗幼鼠胎粪所致肺损伤对巨
噬细胞炎症蛋白(Maerophagei心anunato尽protein一l，MIP一la)、表面活性物质相
关蛋白(s uri油ctant protein一B，SP一B)mRNA表达的影响，为临床治疗提供新的实
验依据。
第一部分
胎粪吸入综合征的临床回顺分析
目的:探讨胎粪吸入综合征的发病趋势、并发症、死亡相关因素，以利进一
步改善治疗措施，降低病死率。
方法:收集199卜2003年浙江大学医学院附属儿童医院MAS病例相关资料，
分成前四年、后四年两组，将两组的发病趋势、并发症及其死亡病例所占的比例
进行比较，并对MCU中MAS的死亡病例的相关因素进行分析。
结果:199卜2003年浙江大学医学院附属儿童医院MAS住院数占同期新生
儿住院人数的比例呈现下降趋势，且前四年与后四年比较有显著性差异
(P 显变化，前后四年比较无显著性差异(P>0.05);死亡组发生PPHN、气胸的比例
明显高于存活组(P<0.01)。
结论:
1 199卜2003年MAS发病总体呈下降趋势，且后四年较前四年下降
明显。
2 MAS有较高的并发症发生率和较高的病死率，易产生PPHN、气
胸、呼吸衰竭等并发症，这些并发症与死亡密切相关。
浙江大学硕士学位论文
第二部分
NO吸入和rhs0D对胎粪诱导幼限急性肺损伤
MIP一la和SP一表达的影响
目的:探讨气管内应用重组人超氧化物歧化酶和一氧化氮吸入干预对幼鼠胎
粪吸入性肺损伤的影响及可能机制。
方法:将40只雄性sD幼年大鼠随机分为5组，每组8只即为:(1)正常对照
组(Normal，N)气管内注入lm掀g生理盐水;(2)胎粪十生理盐水对照组
〔Mee/saline，M组)胎粪吸入+lm掀g生理盐水:(3)NO吸入组(iNO)，暴露
于Zox 10一喻。中;(4)rhsoo干预组(soD):rhsonZomg/kg气管内注入并暴
露于空气中;(5)联合应用Zox 10一。和Zomg/kg:hson组(汹。/500)。N组
气道内生理盐水滴入替代，后四组均先通过气管置管注入20%胎粪lml/Kg建立
幼鼠胎粪性肺损伤模型。24小时后处死动物，取肺组织用10%中性甲醛固定，组
织切片用HE染色行病理检查;并用RT一pCR方法测定MIP一Q和SP一B的mRNA表
达水平。
结果:(1)M组肺泡壁明显水肿、增厚，肺泡腔充满白细胞，肺实质大量炎症
细胞浸润，iNO组、SOD组、iNO/SOD组大鼠肺组织肺部炎症病理改变较M组
明显好转，肺间质中性粒细胞和肺泡腔白细胞渗出减少。(2)M组MIP一10mRNA
表达水平(3.60士0.75)比正常对照组(1.56土0.33)明显升高(只0.01)，iNO
和rhSOD单独或联合治疗组MIP一IQmRNA表达水平较M
Background:Meconium aspiration syndrome(MAS) is a major cause of respiratory morbidity and mortality in neonates. The pathophysiology of MAS is very complicated,including pulmonary inflammation,suifactant inactivation and increased oxygen free radical.MAS can induce acute lung injury,respiratory distress, air leak and persistent pulmonary hypertension of newborn(PPHN).With the improvement in perinatal care, the morbidity of MAS has decreased significantly, but little is known about the number of MAS cases in proportion to the total number of neonatal admission in a tertiary hospital in China. Therefore, collecting and analyzing the clinical data of MAS is of great importance.
Inhaled nitric oxide (iNO) has recently been proved to be a selective pulmonary vasodilator, and it can improve oxygenation and inhibit lung inflammation. But NO is also a free radical,it can rapidly combine with superoxide to form the potent oxidant,the peroxynitrite(ONOO-),which inhibit pulmonary surfactant function by lipid peroxidation and damage surfactant proteins.To protect against lung injury induced by oxygen free radicals, we investigated the effects of antioxidants on the lung injury following meconium aspiration.
Recombinant human superoxide dismutase(rhSOD) can scavenge reactive oxygen species and alleviate lung injury.Previous studies have indicated that intrathacheal administration of rhSOD is well tolerated with significantly increasing in SOD concentrations and activity in serum,tracheal aspirates and urine within 3 days in premature infants with RDS. And rhSOD can also inhibit inflammation. Little is
known of the effects of rhSOD on the expression of cytokine mRNA in acute lung injury following meconium aspiration.
Surfactant consists of phospholipids and proteins. Its function is to reduce surface tension at the air-liquid interface. And surfactant proteins(SP) play an important role in reducing surface tension. Among SPs,SP-B is the most effective substance in promoting rapid spread of surfactant phospholipids.Little is known about rhSOD and iNO on the effect of SP-B mRNA expression following meconium aspiration.In our present studies ,we collected and analyzed the clinical data of MAS to investigate the morbidity trend, complication, the factors relevant to the mortality of MAS.On the other hand ,we estabilished an infant rat model of acute lung injury following meconium aspiration and examined the effects of rhSOD combined with iNO .The aim is to provide possible therapeutic strategies for clinical treatment of this disease.
Part1 The clinical retrospective analyse of MAS
Objective:To investigate the morbidity trend, complication, the factors relevant to the mortality of MAS.
Methods: Clinical data of MAS from 1996 to 2003 in the children's hospital of zhejiang university school of medicine were collected and divided into two groups, the first four-year group and the last four-year group. The morbidity trend , complication, mortality between two groups were compared .The risk factors of death induced by MAS in NICU was analyzed.
Result: The patients of MAS in proportion to total in-patient neonates appeared decline, there was a great difference between two groups(p<0.01), but the proportion of patients with complication or death to the patients of MAS have no difference between the first four-year group and the last four-year group(p>0.05),The differences of the proportion of patients with PPHN or air leak between death and survive groups were significant (p<0.01).
Conclusion: (l)The morbidity of MAS appeared decline,(2)MAS is easy to develop complications including PPHN and air leak,which were related to the high mortality.
Part 2 The effect of iNOand rhSOD on the level of MIP-1 a and SP-B mRNA in acute lung injury of infant
rats following meconium aspiration
Objective: To evaluate the protective effects and possible mechanism of intrathacheal administration of rhSOD combined with inhaled nitric oxide in infant rats acute lung injury following meconium aspiration.
Methods: 40 he
NO可选择性扩张肺血管，改善氧合，而且还可抑制炎症反应，为临床治疗MAS提供了新的治疗前景。但是NO与超氧阴离子结合形成过氧化亚硝酸盐ONOO~-，后者可通过脂质过氧化和破坏表面活性物质相关蛋白而抑制表面活性物质的功能。为了避免氧自由基造成的肺损伤，抗氧化物对胎粪吸入性肺炎的治疗作用是值得研究的。
抗氧化物重组人超氧化物歧化酶(recombinant human superoxide dismutase，rhSOD)能清除氧自由基，保护肺组织。已有研究表明，rhSOD可减轻内毒素所诱导的肺损伤；且rhSOD气管内给药具有安全、吸收快、半衰期长的特点，还具有抗炎作用。目前已有报道rhSOD可加强一氧化氮吸入(inhaled nitric oxide，iNO)治疗持续肺动脉高压的效果。但rhSOD干预MAS对炎症因子基因表达的影响尚未见报道。
肺表面活性物质(surfactant，surf)是由脂质和蛋白质组成，它的主要功能是降低肺泡表面张力、维持肺泡结构的相对稳定，但是Surf仅含磷脂并不能降低表面张力而需要有表面活性物质相关蛋白(Surfactant protein，SP)才能发挥
浙江大学硕士学位论文
作用，因为SP能促进磷脂分子在肺泡迅速扩散和吸附，且SP一B比SP一C更有效。
研究表明胎粪吸入可损伤肺表面活性物质的功能，已经有应用Sllrf成功治疗
MAS的报道。
因此，本研究第一部分通过收集与锹S相关的临床资料对其并发症和死亡
的相关因素进行分析，了解琳S的现状及其变化趋势，为研究新的治疗方法提供
思路。第二部分通过建立MAS实验动物模型，采用RT一PCR方法观察NO吸入
(inh目ed ni功c oxide，iNo)和rhsoo单独或联合治疗幼鼠胎粪所致肺损伤对巨
噬细胞炎症蛋白(Maerophagei心anunato尽protein一l，MIP一la)、表面活性物质相
关蛋白(s uri油ctant protein一B，SP一B)mRNA表达的影响，为临床治疗提供新的实
验依据。
第一部分
胎粪吸入综合征的临床回顺分析
目的:探讨胎粪吸入综合征的发病趋势、并发症、死亡相关因素，以利进一
步改善治疗措施，降低病死率。
方法:收集199卜2003年浙江大学医学院附属儿童医院MAS病例相关资料，
分成前四年、后四年两组，将两组的发病趋势、并发症及其死亡病例所占的比例
进行比较，并对MCU中MAS的死亡病例的相关因素进行分析。
结果:199卜2003年浙江大学医学院附属儿童医院MAS住院数占同期新生
儿住院人数的比例呈现下降趋势，且前四年与后四年比较有显著性差异
(P
明显高于存活组(P<0.01)。
结论:
1 199卜2003年MAS发病总体呈下降趋势，且后四年较前四年下降
明显。
2 MAS有较高的并发症发生率和较高的病死率，易产生PPHN、气
胸、呼吸衰竭等并发症，这些并发症与死亡密切相关。
浙江大学硕士学位论文
第二部分
NO吸入和rhs0D对胎粪诱导幼限急性肺损伤
MIP一la和SP一表达的影响
目的:探讨气管内应用重组人超氧化物歧化酶和一氧化氮吸入干预对幼鼠胎
粪吸入性肺损伤的影响及可能机制。
方法:将40只雄性sD幼年大鼠随机分为5组，每组8只即为:(1)正常对照
组(Normal，N)气管内注入lm掀g生理盐水;(2)胎粪十生理盐水对照组
〔Mee/saline，M组)胎粪吸入+lm掀g生理盐水:(3)NO吸入组(iNO)，暴露
于Zox 10一喻。中;(4)rhsoo干预组(soD):rhsonZomg/kg气管内注入并暴
露于空气中;(5)联合应用Zox 10一。和Zomg/kg:hson组(汹。/500)。N组
气道内生理盐水滴入替代，后四组均先通过气管置管注入20%胎粪lml/Kg建立
幼鼠胎粪性肺损伤模型。24小时后处死动物，取肺组织用10%中性甲醛固定，组
织切片用HE染色行病理检查;并用RT一pCR方法测定MIP一Q和SP一B的mRNA表
达水平。
结果:(1)M组肺泡壁明显水肿、增厚，肺泡腔充满白细胞，肺实质大量炎症
细胞浸润，iNO组、SOD组、iNO/SOD组大鼠肺组织肺部炎症病理改变较M组
明显好转，肺间质中性粒细胞和肺泡腔白细胞渗出减少。(2)M组MIP一10mRNA
表达水平(3.60士0.75)比正常对照组(1.56土0.33)明显升高(只0.01)，iNO
和rhSOD单独或联合治疗组MIP一IQmRNA表达水平较M
Background:Meconium aspiration syndrome(MAS) is a major cause of respiratory morbidity and mortality in neonates. The pathophysiology of MAS is very complicated,including pulmonary inflammation,suifactant inactivation and increased oxygen free radical.MAS can induce acute lung injury,respiratory distress, air leak and persistent pulmonary hypertension of newborn(PPHN).With the improvement in perinatal care, the morbidity of MAS has decreased significantly, but little is known about the number of MAS cases in proportion to the total number of neonatal admission in a tertiary hospital in China. Therefore, collecting and analyzing the clinical data of MAS is of great importance.
Inhaled nitric oxide (iNO) has recently been proved to be a selective pulmonary vasodilator, and it can improve oxygenation and inhibit lung inflammation. But NO is also a free radical,it can rapidly combine with superoxide to form the potent oxidant,the peroxynitrite(ONOO-),which inhibit pulmonary surfactant function by lipid peroxidation and damage surfactant proteins.To protect against lung injury induced by oxygen free radicals, we investigated the effects of antioxidants on the lung injury following meconium aspiration.
Recombinant human superoxide dismutase(rhSOD) can scavenge reactive oxygen species and alleviate lung injury.Previous studies have indicated that intrathacheal administration of rhSOD is well tolerated with significantly increasing in SOD concentrations and activity in serum,tracheal aspirates and urine within 3 days in premature infants with RDS. And rhSOD can also inhibit inflammation. Little is
known of the effects of rhSOD on the expression of cytokine mRNA in acute lung injury following meconium aspiration.
Surfactant consists of phospholipids and proteins. Its function is to reduce surface tension at the air-liquid interface. And surfactant proteins(SP) play an important role in reducing surface tension. Among SPs,SP-B is the most effective substance in promoting rapid spread of surfactant phospholipids.Little is known about rhSOD and iNO on the effect of SP-B mRNA expression following meconium aspiration.In our present studies ,we collected and analyzed the clinical data of MAS to investigate the morbidity trend, complication, the factors relevant to the mortality of MAS.On the other hand ,we estabilished an infant rat model of acute lung injury following meconium aspiration and examined the effects of rhSOD combined with iNO .The aim is to provide possible therapeutic strategies for clinical treatment of this disease.
Part1 The clinical retrospective analyse of MAS
Objective:To investigate the morbidity trend, complication, the factors relevant to the mortality of MAS.
Methods: Clinical data of MAS from 1996 to 2003 in the children's hospital of zhejiang university school of medicine were collected and divided into two groups, the first four-year group and the last four-year group. The morbidity trend , complication, mortality between two groups were compared .The risk factors of death induced by MAS in NICU was analyzed.
Result: The patients of MAS in proportion to total in-patient neonates appeared decline, there was a great difference between two groups(p<0.01), but the proportion of patients with complication or death to the patients of MAS have no difference between the first four-year group and the last four-year group(p>0.05),The differences of the proportion of patients with PPHN or air leak between death and survive groups were significant (p<0.01).
Conclusion: (l)The morbidity of MAS appeared decline,(2)MAS is easy to develop complications including PPHN and air leak,which were related to the high mortality.
Part 2 The effect of iNOand rhSOD on the level of MIP-1 a and SP-B mRNA in acute lung injury of infant
rats following meconium aspiration
Objective: To evaluate the protective effects and possible mechanism of intrathacheal administration of rhSOD combined with inhaled nitric oxide in infant rats acute lung injury following meconium aspiration.
Methods: 40 he
引文
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