Molecular mechanisms of alveolar epithelial healing process in acute lung injury

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)气管内滴注KGF可预防博莱霉素和盐酸所致的急性肺损伤。为了阐明KGF预防博莱霉素和盐酸诱导的肺损伤和纤维化的机制，我们检测了博莱霉素、内毒素和KGF刺激下急性肺损伤时转录因子C/EBP、HGF和转化生长因子的表达。C/EBP家族成员在急性肺损伤中的表达存在差异。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。结论：1.C/eBPα和C/eBPδ是双向表达的，其中C/eBPα在内毒素肺损伤中高表达，C/eBPδ在博莱霉素性肺纤维化中高表达。转录因子C/eBP对表面活性蛋白…的调节作用C/eBPα缺陷小鼠和C/eBPβ缺陷小鼠肺表面活性蛋白mRNAs表达增加。缺乏C/EBPα的小鼠表现出类似肺泡蛋白沉积症的肺异常，并在出生后几个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/eBPα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。绿色荧光蛋白大鼠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。肺泡上皮细胞呈绿色，SP-A、SP-C染色。这些细胞在肺损伤修复过程中可能起重要作用。我们研究了KGF是否能预防另一种器官损伤，即短暂性脑缺血引起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。我们还证实了丙酮酸乙酯对大鼠脊髓缺血的影响。较少

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 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 expressed in bleomycin lung fibrosis.2. The regulation of surfactant protein mRNAs by transcription factor C/EBP: We examined the … More 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