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

• 批准号: 14370492
• 负责人: SUGAHARA Kazuhiro
• 金额: $ 9.6万
• 依托单位: University of the Ryukyus Faculty of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370492/
• 关键词: acute lung injury; wound healing; cytokines; molecular biology; in situ hybridization; apoptosis; growth factor; 骨髄幹細胞; 急性肺傷害

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 HCl.To clarify the mechanism that KGF prevents lung injury and fibrosis by bleomycin and HCl, 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/EBPct and C/EBPδ are reciprocal expressions on acute lung injury, which C/EBPα is more expressed in endotoxin lung injury, and … More C/EBPδ is 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/EBPct 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. We injected stem cells transvenously into the bleomycin treated rats. We found the alveolar epithelial cells which are injected stem cells. 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. Less

1.生长因子对肺泡II型细胞急性肺损伤的抑制作用：1)角质形成细胞生长因子(KGF)是促进肺泡II型细胞增殖和分化的有效因子，2)KGF气管内滴注诱导肺泡上皮细胞增殖和表面活性蛋白mRNAs增加，3)KGF气管内滴注预防博莱霉素和HCl所致急性肺损伤。C/EBPδ仅在部分肺泡II型细胞中表达，提示肺泡II型细胞亚型的存在；C/EBPct和C/EBPδ在急性肺损伤中是相互表达的，其中C/EBPα在内毒素肺损伤中表达更多，而…2.转录因子C/eBP对肺表面活性蛋白δ的调节：我们检测了C/eBPα缺陷和C/eBPβ缺陷小鼠肺表面活性蛋白mRNAs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，出生后几小时内死于呼吸衰竭。免疫组织化学和原位杂交分析显示，与对照组相比，新生鼠肺组织中SP-A和SP-C阳性细胞数量较多，SP-A、SP-B和SP-C基因的表达增加。C/EBPα缺陷小鼠肺组织中SP-A、SP-B和SP-C的mRNAs表达增加。这些结果提示，C/EBPct可能在肺泡II型细胞的增殖和表面活性蛋白的基因调控中起关键作用。3.骨髓来源的肺干细胞。我们将干细胞经静脉注入博莱霉素处理的大鼠体内。我们发现了注入干细胞的肺泡上皮细胞。这些细胞可能在肺损伤的修复过程中起重要作用。4.我们研究了KGF是否能预防另一种器官损伤，即短暂性脑缺血诱导的沙土鼠海马区迟发性神经元死亡。我们已经证明KGF mRNA存在于海马神经细胞和杏仁核中，KGF对缺血性海马神经元损伤具有保护作用。较少

项目成果

T Oshiro, K Sugahara et al.: "Effects of antenatal vitamin A on lung maturation and incidence of congenital diaphragmatic hernia in the nitrofen model of rats."J Jpn Med Soc Biol Interface. 34. 54-55 (2003)

T Oshiro、K Sugahara 等人：“产前维生素 A 对除草醚模型大鼠肺成熟和先天性膈疝发病率的影响。”Jpn Med Soc Biol Interface。

T.Oshiro, K.Sugahara, et al.: "Antenatal treatment with vitamin A reduces the incidence of nitrofen-induced congenital diaphragmatic hernia but decreases lung growth"Am J Respir Crit Care Med. 167(in press). (2003)

T.Oshiro、K.Sugahara 等人：“用维生素 A 进行产前治疗可降低除草醚诱发的先天性膈疝的发生率，但会降低肺部生长”Am J Respir Crit Care Med。

T.Ohshiro, K.Sugahara, et al.: "Effects of antenatal vitamin A on lung maturation and incidence of congenital diaphragmatic hernia in the nitrofen of rats"J Jpn Med Soc Biol Interface. 34. 54-55 (2003)

T.Ohshiro、K.Sugahara 等人：“产前维生素 A 对大鼠硝基苯酚肺成熟和先天性膈疝发病率的影响”Jpn Med Soc Biol Interface。

T Sasara, D Cizkova, R Mestril, L Galik, K Sugahara et al.: "Spinal heat shock protein(70)expression : effect of spinal ischemia, hyperthermia(42 C)/hypothermia(27 C), NMDA receptor activation."Neurochemistry Int. 44(1). 53-64 (2004)

T Sasara、D Cizkova、R Mestril、L Galik、K Sugahara 等人：“脊髓热休克蛋白 (70) 表达：脊髓缺血、高温 (42°C)/低温 (27°C)、NMDA 受体激活的影响。”

T.Oshiro, K.Sugahara, et al.: "Effects of vitamin A and growth factors on the lung of drug-induced congenital diaphragmatic hernia (CDH)"J Jpn Med Soc Biol Interface. 33. 67-68 (2002)

T.Oshiro、K.Sugahara 等人：“维生素 A 和生长因子对药物引起的先天性膈疝 (CDH) 肺部的影响”J Jpn Med Soc Biol Interface。