Molecular mechanisms of alveolar epithelial healing process in acute lung injury

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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