Basic research on gene therapy by pulmonary epithelial cell growth factor on acute and chronic lung injury

应用渗透泵持续皮下注射博莱霉素可成功建立小鼠肺纤维化模型。利用该模型，我们测试了气管内表达KGF的腺病毒载体（Ad-KGF）对肺纤维化的治疗作用。当给予小鼠Ad-KGF时，与注入盐水或空载体（Ad-1 W1）的小鼠相比，纤维化减轻，肺功能包括肺弹性改善。因此，Ad-KGF的施用降低了死亡率。我们测试了两种不同的剂量，1.0×10^8PFU（低剂量）和1.0×10^9PFU（高剂量）。Ad-1 W1引起剂量依赖性死亡率增加，提示与载体相关的肺损伤。然而，与低剂量的Ad-KGF相比，高剂量的Ad-KGF施用显著降低死亡率，这表明KGF的高表达克服了载体施用的负面影响。其被认为是治疗急性肺损伤或预防纤维化的药物，因此不被认为是“纤维化的药物”。“我们在纤维化发生后给予Ad-KGF，因此本研究的结果对于治疗肺纤维化具有重要意义。进一步的研究，如（1）研究Ad-KGF治疗作用的机制，（2）研究治疗的长期作用和副作用，以及（3）在减轻炎症方面改进病毒载体，将保证该疗法的临床应用步骤。

We could successfully establish a mouse model of pulmonary fibrosis by continuous subcutaneous administration of bleomycin using osmotic pump. Using this model, we tested therapeutic effects of intra-tracheal KGF expressing adenovirus vector (Ad-KGF) on pulmonary fibrosis. When Ad-KGF was administered to the mice, fibrosis was attenuated and lung function including lung elasticity was improved compared with mice instilled either saline or empty vector (Ad-1W1). As a result, administration of Ad-KGF reduced mortality rate. We tested two different doses, 1.0×10^8PFU (low dose) and 1.0×10^9PFU (high dose). Ad-1W1 caused dose dependent mortality increase, suggesting vector related lung injury. However, high dose of Ad-KGF administration significantly reduced mortality rate as compared with low dose of Ad-KGF, suggesting that higher expression of KGF overcame negative effects of vector administration.KGF and other growth factors have been tested on animal models by administering prior to the occurrence of pulmonary fibrosis; which are considered to be a therapy for acute lung injury or a prevention of fibrosis, hence were not concluded as "the therapy for fibrosis." We administered Ad-KGF after the occurrence of fibrosis and thus the result of the present study has significance as a treatment of pulmonary fibrosis.Further investigation such as (1) to study the mechanism of the therapeutic effects of Ad-KGF, (2) to study long term effects and adverse effects of the therapy, and (3) to improve virus vector in terms of reducing inflammation, would warrant the steps to clinical application of this therapy.