Claudin-7蛋白在早产儿支气管肺发育不良发病机制中的影响作用北大核心CSCD

支气管肺发育不良(bronchopulmonary dysplasia,BPD)是早产儿常见的并发症,与肺泡上皮屏障结构和功能失调有关。Claudin蛋白家族是紧密连接(tight junctions,TJs)的主要结构之一,参与调节细胞间物质交换。尽管关于Claudin-7蛋白在影响肺泡屏障功能及在肺部的调节机制所知甚少,但Claudin-7蛋白的表达可以影响肺上皮通透性和肺泡发育,进而影响BPD发生发展。Claudin-7蛋白的表达受到多种因子的调节,了解其影响可进一步明确BPD的发病机制并为BPD的诊疗提供新方案。     

对支气管肺发育不良从“经典型”向“新型”转变的思考北大核心CSCD

支气管肺发育不良（bronchopulmonary dysplasia,BPD）是新生儿期常见的慢性肺部疾病,肺发育水平不仅影响BPD患儿的生存,也决定了幸存儿成年后的肺功能状况.随着新生儿救治水平的提高,早产儿尤其是极早早产儿和极低出生体重儿存活率明显上升,与高氧及气压伤相关的“经典型”BPD已不常见,代之出现与肺泡发育及肺血管发育受阻相关的“新型”BPD.     

血管内皮生长因子在支气管肺发育不良方面的研究进展

支气管肺发育不良(BPD)是早产儿中常见的慢性呼吸系统疾病,以肺泡发育受损和血管生长异常为特征的"新型BPD"的发生率呈逐年增高趋势。肺血管生长是影响肺发育的关键,血管内皮生长因子(VEGF),作为血管发生的核心因子,与BPD发生存在一定的相关性。研究表明,BPD的早产儿及高氧BPD模型动物,体内血管内皮生长因子表达水平在不同时间点可有不同程度的下降;抑制动物血管发育,可导致肺血管数目减少,辐射状肺泡计数下降,出现BPD样结构改变。通过病毒介导基因干预或肌肉注射等方式,将适量外源性VEGF带入BPD模型动物体内,则可改善肺血管发育,增加辐射状肺泡计数;但VEGF过表达也可导致肺水肿、肺出血等不良反应。文章综述了临床BPD及BPD模型动物VEGF蛋白表达,及VEDF在BPD动物模型治疗方面的研究进展。     

紧密连接相关蛋白Occludin的研究进展

Occludin是紧密连接相关蛋白中最具有代表性的蛋白之一,它封闭细胞旁路,形成紧密连接的基础结构.Occludin的生理功能主要包括栅栏功能和细胞旁屏障功能,其表达低下可导致肺上皮屏障、血脑屏障、肠上皮屏障及血睾屏障的破坏,与多种疾病的发生、发展密切相关.因此,有关Occludin蛋白的调控机制及其临床意义已成为国内外研究的热点.     

早产儿支气管肺发育不良相关肺外并发症研究进展

早产儿支气管肺发育不良(bronchopulmonary dysplasia, BPD)是在肺发育不成熟的基础上, 由多种因素共同作用导致肺泡化障碍而形成的一种慢性肺部疾病, 往往需要长期的氧疗或反复机械通气治疗。BPD患儿受多种因素影响, 除肺部病变外易合并肺外并发症, 如脑白质损伤、胆汁淤积症和代谢性骨病等。因此, 明确早产儿BPD与其相关并发症的关系, 了解导致肺外并发症发生的高危因素, 对改善BPD患儿的远期预后有重要意义。     

产前感染和炎症与新生儿支气管肺发育不良的研究进展

新生儿支气管肺发育不良(BPD)可导致婴幼儿反复住院,严重影响儿童体格增长和神经系统的发育,病死率较高.产前感染与BPD的发生关系密切,主要病原体为B族溶血性链球菌、解脲脲原体等.细胞因子如白细胞介素-6、白细胞介素-8、转化生长因子-β等在肺部炎症反应中起着非常重要的作用.弹性蛋白、转化生长因子-β、肺泡上皮细胞、血管内皮生长因子等参与肺泡发育过程.产前感染和炎症是BPD发生的危险因素,但如何导致BPD发生尚需深入研究.     

维甲酸对新生大鼠高氧肺损伤的保护作用

新生儿支气管肺发育不良 (bronchopumonarydysplasia ,BPD)是与早产、感染及长期吸入高浓氧有关的严重慢性肺疾病。目前临床多采用地塞米松预防和治疗BPD ,该药虽有助于患儿早日脱离气管插管 ,但由于其可引起血压升高、消化道出血、脑及肺发育受阻等副作用 ,而限制了其在临床的应用[1 ] 。近年研究发现 ,极低出生体重儿BPD的病理改变以肺发育受阻为主 ,表现为肺泡隔形成受阻和肺泡化降低[2 ] 。维甲酸 (retinoicacid ,RA)可降低维生素A缺乏的早产儿BPD的发病率 ,显著提高新生大鼠由于使用地塞米松而降低了的肺泡化水平[3] 。本实验通…     

胎儿和新生儿肺发育

一直以来,肺发育都是围生医学研究的热点.肺发育包括3个时期:胚胎期、胎儿期(假腺期、小管期、终末囊泡期)和肺泡期.胚胎期是肺发育的最初阶段,即肺芽出现;假腺期主要是主呼吸道发育和末端支气管形成;小管期特点是腺泡出现、气血屏障形成,以及Ⅰ型和Ⅱ型上皮细胞分化,并逐渐开始分泌表面活性物质;终末囊泡期以第二嵴引起的囊管再分化、肺泡囊在肺泡管呈簇状形成、表面活性物质产生加快为特征;肺泡期主要是肺泡的发育成熟.伴随着肺组织结构的发育成熟,其功能发育亦趋成熟.     

高氧致细胞衰老在支气管肺发育不良中的作用

支气管肺发育不良(bronchopulmonary dysplasia,BPD)是一种可造成早产儿呼吸衰竭及死亡的慢性呼吸系统疾病,高氧暴露是其发生的主要危险因素。细胞衰老描述了一种细胞周期阻滞的状态,近年来有研究证实高氧暴露可以引起细胞衰老。细胞衰老在肺上皮、肺间质、肺血管以及气道发育过程中起着至关重要的作用,且这些组织的异常发育与BPD的发生相关。因此,该文以细胞衰老和BPD为切入点进行综述,探讨高氧致细胞衰老在BPD发生发展中的作用机制以及目前应用于临床的抗衰老药物,以期为BPD的防治提供新方向。     

高迁移率族蛋白B1在高氧致支气管肺发育不良的表达

目的：检测高迁移率族蛋白B1（HMGB1）在高浓度氧（60% O2）暴露新生小鼠肺组织损伤模型中的表达水平,探讨HMGB1在支气管肺发育不良（BPD）发病机制中的作用。方法：新生足月C57BL/6小鼠随机分为BPD组和对照组,制备高氧浓度致新生鼠BPD模型,应用苏木精-伊红染色、Masson染色、放射性肺泡计数（RAC）、免疫荧光和实时荧光定量PCR技术,观察氧暴露后3 d、7 d、14 d肺组织病理改变及HMGB1的蛋白和mRNA表达水平。结果：BPD组在氧暴露后随时间推移,出现肺泡上皮肿胀,肺泡壁增厚,间质水肿,炎症细胞浸润,胶原样物质产生,肺泡结构紊乱,数量减少,较空白对照组明显发育迟滞。在氧暴露后7 d、14 d,HMGB1及其mRNA表达均强于对照组（P＜0.05）。结论：高氧暴露所致BPD中,HMGB1表达增加。BPD的病理过程可能与HMGB1表达增加有关。［中国当代儿科杂志,2010,12（3）：219-223］     

Fibronectin Expression in Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic fibrotic lung disease of neonates. Fibronectin (FN), a component of the extracellular matrix, is increased in the tracheobronchial effluent of neonates destined to develop BPD. Pulmonary FN is derived from plasma and local cellular synthesis. In order to identify which pulmonary cells synthesize FN and to test the hypothesis that FN is more abundant in lungs with BPD, we examined the distribution of pulmonary FN by in situ hybridization (for mRNA) and immunohistochemistry (for protein) in neonatal autopsy lung specimens, comparing lungs with BPD to those without. We used a staging system in which BPD is characterized by disruption of alveolar architecture, severe vascular changes, airway epithelial necrosis, smooth muscle hypertrophy, and peribronchial fibrosis. FN mRNA and protein were found in vascular endothelium, macrophages, fibroblasts, vascular and airway smooth muscle, and chondrocytes as well as in the pulmonary parenchyma in neonates with and without BPD. Hyaline membranes, when present, immunostained intensely for FN protein. FN mRNA was not seen in airway epithelial cells of either group. FN mRNA and protein were first increased in early acute BPD with their levels appearing greatest during the chronic reparative stage of BPD. In long-standing “healed” BPD, lower levels of FN mRNA and protein were seen. These findings are consistent with the association of increased FN with adult fibrotic lung disease and the previously reported increase in FN tracheal effluent levels in infants with BPD. Our results suggest an important role for pulmonary cell-derived FN in the early inflammatory and later proliferative stages of BPD. Received September 29, 1997; accepted January 13, 1998.     

Cyclooxygenase-2 in human perinatal lung

Cyclooxygenases-1 and -2 are the key enzymes in the conversion of arachidonic acid to prostanoids. Cyclooxygenase-2 (COX-2) takes part both in inflammation and in control of cell growth. COX-2 immunohistochemistry was performed on lung tissues from autopsies, with four groups included: fetuses (n = 4, GA = 16.0 to 32.0 wk), preterm infants (n = 10, GA = 23.0 to 29.9 wk), term infants (n = 6, GA = 38.7 to 42.0 wk), and infants with bronchopulmonary dysplasia (BPD) (n = 4, GA = 28.9 to 30.7 wk). COX-2 staining occurred exclusively in the epithelial cells resembling type II pneumocytes in the alveolae, and in ciliated epithelial cells in the bronchi. In fetuses, moderate intensity alveolar staining was seen in 90-100% cells lining the alveolar epithelium. In preterm infants, high intensity alveolar staining was seen in a scattered pattern. In term infants, the alveolar staining was also scattered, but with a lower proportion of positive cells. In BPD no staining appeared in alveolar epithelial cells. The most intense bronchial staining was found in fetuses and the least intense in term infants; staining was also seen in BPD. COX-2 is present in human perinatal lung from the gestational age of 16 wk, in a changing pattern. We suggest that COX-2 may, in addition to participating in inflammation, also play a developmental role in the perinatal lung.     

紧密连接相关蛋白与肺疾病的研究进展

紧密连接是内皮细胞和上皮细胞之间的重要连接方式,能起到栅栏和屏障的作用。紧密连接相关蛋白是维持紧密连接结构和功能的重要组成蛋白,由膜蛋白和闭小环蛋白等外周胞浆蛋白组成,其中膜蛋白包括occludin、claudin和连接黏附分子(junctional adhesion molecules,JAMs),闭小环蛋白由ZO-1、ZO-2和ZO-3组成。尽管各种蛋白功能有所差异,但它们之间相互连接,共同构成了细胞间的紧密连接复合体,维持着生物体内环境的稳态。近年来研究发现,多种肺部疾病,包括感染、肺水肿、纤维化和肿瘤都与紧密连接蛋白的异常表达和紧密连接复合体的结构破坏密切相关。因此,阐明紧密连接蛋白与肺疾病之间的关系,对揭示一些肺疾病的病理基础,以及疾病的诊断和治疗都有重要意义。[临床儿科杂志,2012,30(5):492-495]     

Caco-2建立肠黏膜屏障模型及其在通透性研究中的应用

目的：利用 Caco-2细胞建立体外肠黏膜屏障模型,系统评价并初步探讨其在炎症损伤后黏膜通透性改变中的应用。方法体外培养 Caco-2细胞,接种于 Transwell 板上,每日观察细胞形态;自培养第5天起,隔日测细胞膜的跨上皮电阻(transepithelial electrical resistance,TEER);对于 TEER 值达标准的孔测定荧光黄透过率,进行透射电镜的完整性验证。应用培养21 d 的 Caco-2细胞屏障,加入不同浓度(0、50、100、200 nmol /L)的血小板活化因子(platelet-activating factor,PAF)孵育24 h,光镜、电镜观察形态学改变,检测 TEER 和荧光黄透过率,应用间接免疫荧光和 Western blot 观察 ZO-1蛋白的分布及表达。结果Caco-2细胞单层 TEER 从第5～15天逐渐增加,在第15天已经达到600Ω?cm2,平台期保持至第21天;在此期间,细胞形成紧密单层,电镜下细胞呈高分化,细胞间形成紧密连接,绒毛整齐,极性形成;荧光黄透过量极低,体外肠上皮细胞屏障形成。加入 PAF 后,以100 nmol /L 对黏膜屏障通透性影响最大：电镜下见紧密连接结构破坏、断裂,细胞表面微绒毛脱落、稀疏;免疫荧光可见紧密连接的标志蛋白 ZO-1荧光信号减弱,ZO-1环断裂,胞浆内可见阳性染色,提示其向膜下转移。此时,TEER 值下降,荧光黄透过量明显增加,与对照组比较差异有统计学意义(P ＜0.01),与形态学改变规律一致;ZO-1蛋白表达亦降至最低,与对照组相比差异有统计学意义(P ＜0.01)。结论经形态学及细胞通透性验证,培养2～3周的 Caco-2细胞可形成肠屏障模型,用于体外肠黏膜屏障的研究;PAF 影响紧密连接相关蛋白的表达,破坏紧密连接结构,从而影响肠黏膜屏障通透性。     

Developmental stage is a major determinant of lung injury in a murine model of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a common inflammatory lung disease in premature infants. To study the hypothesis that the sensitivity of the lung to inflammatory injury depends on the developmental stage, we studied postnatal lung development in transgenic mice expressing human IL-1β (hIL-1β) in the lungs during the late canalicular-early saccular, saccular, or late saccular-alveolar stage. Overexpression of hIL-1β in the saccular stage caused arrest in alveolar development, airway remodeling, and goblet cell hyperplasia in the lungs as well as poor growth and survival of infant mice. Overexpression of hIL-1β during the late canalicular-early saccular stage did not adversely affect lung development, growth, or survival of the pups. Mice expressing hIL-1β from the late saccular to alveolar stage had smaller alveolar chord length, thinner septal walls, less airway remodeling and mucus metaplasia, and better survival than mice expressing hIL-1β during the saccular stage. Human IL-1β overexpression in the saccular stage was sufficient to cause a BPD-like illness in infant mice, whereas the lung was more resistant to hIL-1β-induced injury at earlier and later developmental stages.     

Effects of erythropoietin on hyperoxic lung injury in neonatal rats

Pulmonary oxygen toxicity is believed to play a prominent role in the lung injury that leads to the development of bronchopulmonary dysplasia (BPD). To determine whether human recombinant erythropoietin (rhEPO) treatment reduces the risk of developing BPD, we investigated the effect of rhEPO treatment on the histopathologic changes seen in hyperoxia-induced lung injury of BPD. Twenty-five rat pups were divided into four groups: air-exposed control group (n = 5), hyperoxia-exposed placebo group (n = 7), hyperoxia-exposed rhEPO-treated group (n = 6), and air-exposed rhEPO-treated group (n = 7). Measurement of alveolar surface area, quantification of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin immunostaining were performed to assess hyperoxia-induced changes in lung morphology. Treatment of hyperoxia-exposed animals with rhEPO resulted in a significant increase in the mean alveolar area, number of secondary crests formed, and the microvessel count in comparison with hyperoxia-exposed placebo-treated animals. There was significantly less fibrosis in rhEPO-treated animals. However, treatment of hyperoxia-exposed animals with rhEPO did not result in a significant change in smooth muscle content compared with hyperoxia-exposed placebo treated animals. Our results suggest treatment with rhEPO during hyperoxia exposure is associated with improved alveolar structure, enhanced vascularity, and decreased fibrosis. Therefore, we conclude that treatment of preterm infants with EPO might reduce the risk of developing BPD.     

Ureaplasma and bronchopulmonary dysplasia

Advances in neonatal intensive care have greatly improved survival rates for children born in a very early stage of lung development (i.e. less than 26 weeks of gestation). In these premature babies, even low levels of oxygen and methods of minimally invasive ventilation may disrupt the growth of the distal airways, a condition described as “new” bronchopulmonary dysplasia (BPD).Ureaplasma infection can occur in utero or in the perinatal period in premature infants, in some of which the infection with these organisms triggers an important lung pro-inflammatory and pro-fibrotic response, and may increase the risk of developing BPD. The inflammation may be worsened by exposure to oxygen and mechanical ventilation. At present, clinical studies have not clarified the role of Ureaplasma in the pathogenesis of BPD and there is insufficient evidence to determine whether antibiotic treatment of Ureaplasma has influence on the development of BPD and its comorbidities.Future research in the context of well-designed and controlled clinical trials of adequate statistical power should focus on how to determine whether the treatment of Ureaplasma decreases lung inflammation, reduces rates of BPD, and improves long-term neurodevelopment.     

间充质干细胞治疗支气管肺发育不良作用机制的研究进展

支气管肺发育不良（bronchopulmonary dysplasia,BPD）是一种因早产儿肺发育受阻和损伤而导致的慢性肺疾病,是造成早产儿呼吸衰竭的主要病因之一。合并BPD的早产儿其他并发症发生率和病死率显著高于一般早产儿。目前主要通过综合管理对BPD进行干预,包括合理的呼吸循环支持,恰当的肠内、外营养,咖啡因、糖皮质激素及肺表面活性物质等药物的应用和出院后的院外管理。近年来干细胞医学的不断进展为治疗BPD提供了新的思路。多项临床前试验已证实干细胞治疗在有效避免肺损伤的同时促进肺的生长和损伤修复。因此,该文对间充质干细胞治疗BPD的作用机制进行全面分析,以期为临床应用提供依据。     

Alveolar macrophage status in bronchopulmonary dysplasia

The predominant inflammatory cell type within the alveolar structure in bronchopulmonary dysplasia (BPD) is the alveolar macrophage (AM). AM ability to release hydrogen peroxide, a way to evaluate the cell status, was studied in nine infants who developed clinical and radiological evidence of BPD, and was compared to those from infants without lung parenchymal disorders (n = 6). AM were collected by bronchoalveolar lavage which was done after the mechanical ventilation stage in the BPD group. The experiments were performed on unstimulated AM and on AM stimulated by phorbol myristate acetate. Results revealed that the amount of hydrogen peroxide accumulated in the culture medium was significantly enhanced in the BPD group, in both experimental conditions (p less than 0.01 and less than 0.001, respectively). Furthermore, improvement of patients treated with glucocorticoids was closely related to a reduction of the alveolitis with a decrease of AM ability to generate hydrogen peroxide. These data indicate that AM activation is a central component of alveolitis in BPD and that extracellular production of oxidants by stimulated AM may play a critical role in the pathogenesis of the disease.