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Molecular mechanisms of alveolar epithelial healing process in acute lung injury

急性肺损伤肺泡上皮愈合过程的分子机制

基本信息

批准号：
16390454
负责人：
SUGAHARA Kazuhiro
金额：
$ 9.15万
依托单位：
University of the Ryukyus
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390454/
关键词：
acute lung injury wound healing cytokines molecular biology in situ hybridization apoptosis growth factor stem cell

项目摘要

1.The inhibition of acute lung injury by growth factors for alveolar type II cells : We have demonstrated that 1)keratinocyte growth factor (KGF) is a potent factor for proliferation and differentiation for alveolar type II cells, 2)intratracheal instillation of KGF induced the alveolar epithelial cell proliferation and increased surfactant protein mRNAs, and 3)intratracheal instillation of KGF prevented acute lung injury by bleomycin and HCI. To clarify the mechanism that KGF prevents lung injury and fibrosis by bleomycin and HCI, we examined expressions of the transcription factors C/EBP, HGF, and TGF on acute lung injury by bleomycin, endotoxin and KGF stimulation. C/EBP family members are differentially expressed in acute lung injury. C/EBPδ is expressed in some alveolar type II cells only, which suggests the existence of the subtypes of alveolar type II cells. C/EBPα and C/EBPδ are reciprocal expressions, which C/EBPα is more expressed in endotoxin lung injury, and C/EBPδ is more … More expressed in bleomycin lung fibrosis.2.The regulation of surfactant protein mRNAs by transcription factor C/EBP : We examined the expression of surfactant protein mRNAs on the lungs from C/EBPα-deficient and C/EBPβ-deficient mice. Mice lacking C/EBPα showed pulmonary abnormality resembling alveolar proteinosis and have died of respiratory failure within several hours after birth. Immunohistochemical and in situ hybridization analyses revealed that positive cells for SP-A and SP-C were abundant, and expression of SP-A, SP-B and SP-C mRNAs were increased in the lungs of newborn C/EBPα-deficient mice, compared to those of control mice. Thus, these results suggest that C/EBPα may play a key role in the proliferation of alveolar type II cells and the gene regulation of surfactant proteins.3.Lung stem cells from bone marrow derived cells of GFP rats. We injected stem cells transvenously into the bleomycin treated rats. We found the alveolar epithelial cells which are green and stained with SP-A & SP-C. These cells may be important for repairing process of lung injury.4.We have examined whether KGF prevents another organ injury, transient brain ischemia-induced delayed neuronal death in hippocampal region in gerbils. We have demonstrated that KGF mRNA is observed in the neuronal cells of hippocampus and amygdala, and KGF has a protective effect against ischemic hippocampal neuronal damage. We also demonstrated the effect of ethyl pyruvate on spinal cord ischemia in rats. Less

1.生长因子对肺泡II型细胞急性肺损伤的抑制作用：我们已经证明1)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，2)气管内灌注KGF诱导肺泡上皮细胞增殖并增加表面活性剂蛋白mrna， 3)气管内灌注KGF可预防博来霉素和HCI引起的急性肺损伤。为了阐明KGF预防博来霉素和HCI对肺损伤和纤维化的作用机制，我们检测了转录因子C/EBP、HGF和TGF在博来霉素、内毒素和KGF刺激下急性肺损伤中的表达。C/EBP家族成员在急性肺损伤中有差异表达。C/EBPδ仅在部分肺泡II型细胞中表达，提示肺泡II型细胞存在亚型。C/EBPα与C/EBPδ呈互负表达，其中C/EBPα在内毒素肺损伤中表达较多，C/EBPδ在博来霉素肺纤维化中表达较多。转录因子C/EBP对表面活性剂蛋白mrna的调控：我们检测了C/EBPα-缺陷和C/EBPβ-缺陷小鼠肺表面活性剂蛋白mrna的表达。缺乏C/EBPα的小鼠表现出类似肺泡蛋白沉积症的肺异常，并在出生后数小时内死于呼吸衰竭。免疫组织化学和原位杂交分析显示，新生C/ ebp α-缺陷小鼠肺中SP-A和SP-C阳性细胞丰富，SP-A、SP-B和SP-C mrna的表达高于对照组。因此，这些结果提示C/EBPα可能在肺泡II型细胞的增殖和表面活性剂蛋白的基因调控中起关键作用。GFP大鼠骨髓来源细胞制备肺干细胞。我们将干细胞注射到博来霉素治疗的大鼠体内。肺泡上皮细胞呈绿色，SP-A和SP-C染色。这些细胞可能在肺损伤的修复过程中起重要作用。我们研究了KGF是否能预防沙鼠海马区另一种器官损伤，即短暂性脑缺血引起的延迟性神经元死亡。我们已经证明在海马和杏仁核神经元细胞中观察到KGF mRNA，并且KGF对缺血性海马神经元损伤具有保护作用。我们还证实了丙酮酸乙酯对大鼠脊髓缺血的影响。少