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

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。

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.