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。生长因子对肺泡II型细胞对肺损伤的影响：我们已经证明角质形成细胞生长因子（KGF）是肺泡II型细胞增殖和分化的潜在因素。我们已经检查了KGF是否会防止博来霉素诱导的肺损伤和纤维化。重组人KGF（RHKGF）在48h之前的气管内注射，博来霉素后24小时。 KGF治疗可防止（1）体重减轻，（2）降低总肺容量，（3）胶原型I型和III及其mRNA的积累，以及（4）（4）降低了肢体霉素诱导的大鼠肺的生存蛋白A（SP-B和SP-C MRNA）的生存蛋白A（SP-B和SP-C mRNA）的自显影银晶粒。在酸（0.1N HCl）滴注前，KGF预处理以72h的速度预处理，还可以防止酸滴注引起的肺损伤，但治疗后不进行。 2。为了阐明预防的机制，我们正在研究急性肺损伤和C/EBP缺乏小鼠的转录因子，C/EBP家族成员以及基础蛋白的表达。 C/EBP家族成员在肺部因急性损伤而表达不同。特别是，C/EBPDδ在某些肺泡II型细胞中表达，这表明存在细胞的亚型。进一步的C/EBPα缺陷小鼠具有类似于肺肺泡蛋白质的肺绝对。分子研究表明，在C/EBPα缺陷小鼠的肺中，SP-C mRNA过表达，这表明C/EBPα可能对SP-C基因有抑制作用。 3。为了研究防止KGF肺损伤的机制，我们检查了KGF是否防止了另一种器官损伤，脑缺血引起的脑缺血诱导的神经元死亡在沙里比尔人的海马区域。组织学和TUNEL研究表明其对神经元死亡的抑制作用。 4。未来的项目：我们将使用气管内腺病毒病毒来研究KGF的基因转移，以防止肺损伤和纤维化。