Role of alveolar epithelial cell proliferation and surfactant protein in acute lung injury : effect of KGF and artificial surfactant on lung injury

肺泡上皮细胞增殖和表面活性剂蛋白在急性肺损伤中的作用：KGF和人工表面活性剂对肺损伤的作用

• 批准号: 08457409
• 负责人: SUGAHARA Kazuhiro
• 金额: $ 4.99万
• 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: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457409/
• 关键词: acute lung injury; alveolar epithelial cells; lung fibrosis; growth factor; wound healing; surfactant; cytokines; in situ hybridization

1.Effect of growth factor for alveolar type II cells on lung injury : We have demonstrated that keratinocyte growth factor (KGF) is a potent factr for proliferation and differentiation of alveolar type II cells (Am J Physiol 269,1995). 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 thier 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 HC1) instillation, but not by posttreatme2) nt. 2.Combined posttreatmental effects of KGF and artificial surfactant on lung injury : The combined instillations of KGF and artificial surfactant 48h after bleomycin or acid didn't change lung injury so much because of the strong pulmonary edema. Therefore, we were examining the better time point of instillation for preventing lung injury, with artificial surfactant. 3.To clarify the mechanisms of prevention, we were examining the expression of the transcription factor, C/EBP family members, and the lungs of C/EBP deficient mice. 4.Prevention of lung injury due to intratracheal instillation of cultured alveolar cells : We are under experiments on whether cultured alveolar epithelial cells stimulated by KGF wouldprevent lung injury and fibrosis. 5.Future project : We are going to study gene transfer of KGF using adeno-virus intratracheally for preventing lung injury and fibrosis.

1.肺泡II型细胞生长因子对肺损伤的影响：我们已经证明角化细胞生长因子（KGF）是肺泡II型细胞增殖和分化的有效因子（Am J Physiol 269,1995）。我们研究了KGF是否能预防博莱霉素引起的肺损伤和纤维化。重组人KGF （rhKGF）分别于博莱霉素使用前48小时和使用后24小时气管内注射。KGF治疗可防止博来霉素诱导的大鼠肺部表面活性剂蛋白A （SP-A）、SP-B和SP-C mrna的放射自显影银粒的减少(1)体重减轻，(2)肺活量减少，(3)I型和III型胶原及其mrna的积累。在酸（0.1N HC1）灌注前72h预处理KGF也能预防酸致肺损伤，但处理后不能。KGF和人工表面活性剂联合治疗后对肺损伤的影响：博来霉素或酸治疗后48h，由于肺水肿较强，联合输注KGF和人工表面活性剂对肺损伤的影响不大。因此，我们正在探讨人工表面活性剂预防肺损伤的最佳滴注时间点。3.为了阐明预防机制，我们检测了转录因子、C/EBP家族成员和C/EBP缺陷小鼠肺部的表达。4.气管内灌注培养肺泡细胞对肺损伤的预防作用：我们正在进行KGF刺激培养肺泡上皮细胞是否能预防肺损伤和纤维化的实验。5.未来项目：研究利用腺病毒气管内转移KGF基因，预防肺损伤和纤维化。

项目成果

Sugahara, K., et al: "Differential expression of the transcription factor, C/EBP-a, beta and delta in lung injury and fibrosis." Am J Respir Crit Care Med. 155. A696-A696 (1997)

Sugahara, K. 等人：“转录因子、C/EBP-a、β 和 δ 在肺损伤和纤维化中的差异表达。”

Sugahara, K et al: "Differential expression of the rtranscription factor, C/EBP-and in lung injury and fibrosis in rats." Am. J. Respir. Crit. Care Med.155(in press). (1997)

Sugahara, K 等人：“r 转录因子 C/EBP-and 在大鼠肺损伤和纤维化中的差异表达。”

須加原一博他: "Kerastinocyte growth factor(KGF)による肺胞上皮細胞の増殖、分化と肺サーファクタント・アポ蛋白遺伝子発現動態" 日本界面医学会雑誌. 27. 151-153 (1996)

Kazuhiro Sukahara 等人：“角蛋白细胞生长因子 (KGF) 引起的肺泡上皮细胞的增殖和分化以及肺表面活性物质脱辅基蛋白基因表达的动态”日本表面医学会杂志 27. 151-153 (1996)。

S.Nakano, et al.: "Differential expression of α1(IV),α2(IV),α5(IV),α6(IV) collagen chains in the basement membrane of normal breast,benign and malignant breast diseases." Mol,Biol.Cell. 8. 179a-179a (1997)

S.Nakano 等人：“正常乳腺、良性和恶性乳腺疾病的基底膜中 α1(IV)、α2(IV)、α5(IV)、α6(IV) 胶原链的差异表达”。细胞。8。179a-179a（1997）

Sugahara, K., et al: "Double intratracheal instillation of keratinocyte growth factor prevent bleomycin-induced lung fibrosis in rats demonstrated by immunohistochemistry and in situ hybridization." J Pathol. 184 ; (in press). (1998)

Sugahara, K. 等人：“免疫组织化学和原位杂交证明，气管内两次滴注角质形成细胞生长因子可预防博莱霉素诱导的大鼠肺纤维化。”