中文摘要：

目的：观察信号转导子与转录活化子1（STAT1）反义寡核苷酸雾化吸入对博来霉素致肺纤维化大鼠肺组织TGF-β1和Smad4表达的影响。方法：将45只雌性Wistar大鼠按随机数字表法分为对照组、模型组和干预组,每组15只,对照组大鼠气管内灌注生理盐水、模型组和干预组大鼠气管内灌注博来霉素。于气管内灌注药物后0、2、4、6天对照组和模型组大鼠给予雾化吸入生理盐水,而干预组大鼠则雾化吸入STAT1反义寡核苷酸/DOTAP复合物。分别于气管内灌注药物后第7天、第14天和第28天每组各处死5只大鼠。肺组织HE染色和Masson染色观察肺泡炎和肺纤维化改变,收集支气管肺泡灌洗液（BALF）行细胞总分数测定、ELISA测定BALF中TGF-β1的浓度、免疫组织化学SP法测定肺组织中TGF-β1、Smad4表达。结果：（1）干预组大鼠各时间点的肺泡炎和肺纤维化程度均较模型组明显减轻。（2）干预组大鼠各时间点的细胞总数和中性粒细胞比例较模型组减少,巨噬细胞比例增加。（3）模型组大鼠BALF的TGF-1水平在第7d表达明显升高,14d、28d仍持续高于对照组。干预组大鼠各时间点BALF中TGF-β1含量均低于模型组。（4）模型组和干预组大鼠肺组织中TGF-β1、Smad4表达水平均明显高于对照组,模型组和干预组大鼠第7天TGF-β1、Smad4的表达值明显高于对照组,随后下降,第28天时仍高于对照组;干预组大鼠各时间点肺组织TGF-β1、Smad4表达水平均低于模型组。（5）干预组大鼠肺组织中羟脯氨酸含量明显低于模型组。（6）BALF中TGF-β1蛋白浓度、肺组织中TGF-β1蛋白表达、Smad4蛋白表达均与肺组织匀浆中羟脯氨酸含量呈正相关。结论：STAT1反义寡核苷酸雾化吸入能减轻博来霉素致肺纤维化大鼠肺泡炎和肺纤维化,其机制可能与抑制TGFβ-Smads信号转导通路中的TGF-β1和Smad4有关。

英文摘要：

Objective：To investigate the affects of aerosolized signal transdueer and activator of transcription 1 （STAT1） antisense oligonucleotides （ASON） on the expressions of TGF-β1 and Smad4 protein in lung tissue of pulmonary fibrosis rats induced by bleomycin（BLM）.Methods：45 adult female Wistar rats were randomly divided into 3 groups：control group,model group and intervention group.The model group and the intervention group were intratracheally instilled with BLM while the control group was instilled with normal saline （NS）.The control group and the model group were aerosolized with NS while the intervention group was aerosolized with STAT1 ASON after 0,2,4,6days.Then the rats were killed after 7,14,28days.The cells counting and differentiation in the bronchoalveolar lavage fluid （BALF） of right lung was figured out.The level of TGF-β1 in the BALF of right lung was measured by ELISA.TGF-β1 and Smad4 protein in the tissue of left lung were assessed by immunohistochemistry.The content of hydroxyproline in the tissue of left lung was also examined.Results：Compared with the model group,the scores of alveolitis and fibrosis in the intervention group were remarkably ameliorated.Both TGF-β1 and Smad4 protein in lung tissue in the model group and the intervention group were obviously higher as compared with the control group.However,both TGF-β1 and Smad4 protein in lung tissue in the intervention group were obviously lower than those in the model group.The content of hydroxyproline in lung tissue in the intervention group on the 7th,14th and 28th day was respectively lower than that in the model group.Conclusion：Aerosolized STAT1 ASON could abate the alveolitis and fibrosis in BLM-induced pulmonary fibrosis rats,which might result from the inhibition of the TGF-β1 and Smad4 protein in TGF-β-Smads signaling pathway.