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Molecular mechanism of alveolar epithelial healing process in acute lung injury : roles of KGF and transcription factor on lung repair

急性肺损伤肺泡上皮愈合过程的分子机制：KGF和转录因子在肺修复中的作用

基本信息

批准号：
10470320
负责人：
SUGAHARA Kazuhiro
金额：
$ 7.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

1. Effect of growth factor for alveolar type II cells on lung injury: We have demonstrated that keratinocyte growth factor (KGF) is a potent factor for proliferation and differentiation of alveolar type II cells. We have examined whether KGF would prevent bleomycin-induced lung injury and fibrosis. Recombinant human KGF(rhKGF) was injected intratracheally at 48h before and 24h after bleomycin. KGF treatment prevents (1)loss of body weight, (2)reduced total lung capacity, (3)accumulation of collagen type I & III and their mRNAs, and (4)decreased autoradiographic silver grains for surfactant protein A(SP-A), SP-B and SP-C mRNAs in the rat lungs induced by bleomycin. Lung injury due to acid instillation was also prevented by KGF pretreatment at 72h before acid (0.1N HCl) instillation, but not by posttreatment. 2. To clarify the mechanisms of prevention, we were examining the expression of the transcription factor, C/EBP family members, and the surfactant proteins in acute lung injury and in lungs of C/EBP deficient mice. C/EBP family members are differentially expressed in the lung with acute injury. Especially, C/EBPdδ is expressed in some of alveolar type II cells, which suggests the presence of a subtype of the cell. Further C/EBPα-deficient mice had a pulmonary abnormality resembling pulmonary alveolar proteinosis. Molecular study demonstrated overexpression of SP-C mRNA in the lungs of C/EBPα-deficient mice, which suggests C/EBPα may have an inhibitory regulation on SP-C gene. 3. To investigate the mechanism of preventing lung injury by KGF, we have examined whether KGF prevents another organ injury, brain ischemia-induced neuronal death in hippocampal region in gerbils. Histological and TUNEL studies showed its inhibition on neuronal death. 4. Future project: We are going to study gene transfer of KGF using adeno-virus intratracheally for preventing lung injury and fibrosis.

1.肺泡II型细胞生长因子对肺损伤的影响：我们已经证明角化细胞生长因子（KGF）是肺泡II型细胞增殖和分化的有效因子。我们检查了 KGF 是否可以预防博莱霉素引起的肺损伤和纤维化。博来霉素治疗前48小时和治疗后24小时气管内注射重组人KGF(rhKGF)。 KGF 治疗可防止博来霉素诱导的大鼠肺中 (1) 体重减轻，(2) 总肺容量减少，(3) I 型和 III 型胶原蛋白及其 mRNA 的积累，以及 (4) 放射自显影银粒表面活性蛋白 A (SP-A)、SP-B 和 SP-C mRNA 的减少。在酸（0.1N HCl）滴注前72小时KGF预处理也可以预防因酸滴注引起的肺损伤，但不能通过后处理来预防。 2.为了阐明预防机制，我们检测了转录因子、C/EBP家族成员和表面活性蛋白在急性肺损伤和C/EBP缺陷小鼠肺中的表达。 C/EBP 家族成员在急性损伤的肺部有差异表达。特别是，C/EBPdδ 在一些肺泡 II 型细胞中表达，这表明该细胞亚型的存在。此外，C/EBPα 缺陷小鼠出现类似于肺泡蛋白沉积症的肺部异常。分子研究表明，C/EBPα缺陷小鼠的肺中SP-C mRNA过度表达，这表明C/EBPα可能对SP-C基因具有抑制性调节作用。 3.为了研究KGF预防肺损伤的机制，我们检测了KGF是否可以预防沙鼠的另一种器官损伤，即脑缺血引起的海马区神经元死亡。组织学和TUNEL研究显示其对神经元死亡的抑制作用。 4.未来的项目：我们将研究利用腺病毒气管内转移KGF基因来预防肺损伤和纤维化。