Li Jing, Zeng Ming, Zhu Chen, Wang Wen-Jun, Zhan Xiao-Qin, Fan Xian-Ming
Department of Respiratory Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou 646000, China.
Zhonghua Yi Xue Za Zhi. 2009 Mar 31;89(12):831-5.
To investigate the curative effects of inhaling signal transducer and activator of transcription 1 (STAT1) antisense oligonucleotide (ASON) on alveolitis and pulmonary fibrosis and the best administration time.
Twenty-five adult female Wistar rats were randomly divided into 5 equal groups: BLM group, undergoing intra-tracheal perfusion of BLM so as to establish animal models of alveolitis and pulmonary fibrosis and then inhaling aerosolized normal saline (NS); NS group undergoing intra-tracheal perfusion of NS and then inhaling aerosolized NS; ASON 0 d group, undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml immediately; ASON 7 d group, undergoing intra-tracheal perfusion of BLM and then inhaling STAT1 ASON 3 ml 7 days later; and ASON 14 d group undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml 14 days later. Aerosolized inhalation was repeated once every other day for 4 times. Twenty-eight days after intra-tracheal perfusion the rats were sacrificed with their lungs taken out to undergo pathological examination. NS was infused into the right lungs to get bronchoalveolar lavage fluid (BALF). ELISA was used to examine the concentrations of transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) in the BALF.
The pathology result of the lung tissues showed that compared with the BLM and ASON 14 d groups, the alveolitis and pulmonary fibrosis of the ASON 0 d group were obviously milder. The scores of alveolitis and pulmonary fibrosis of the ASON 0 d group were (1.80 +/- 0.84) and (2.60 +/- 0.55) respectively, both significantly lower than those of the BLM group [(2.40 +/- 0.55) and (4.40 +/- 0.55) respectively] and those of the ASON 7 d group [(2.20 +/- 0.45) and (3.00 +/- 0.71) respectively] (all P < 0.05). The scores of pulmonary fibrosis of the ASON 7 d group was significantly lower than those of the BLM and ASON 14 d groups (both P < 0.05). The concentrations of TGF-beta and TNF-alpha in BALF of the ASON 0 d group were (48.11 +/- 3.46) pg/ml and (1.93 +/- 0.14) ng/ml respectively, both significantly lower than those of the BLM group [(57.67 +/- 2.46) pg/ml and (2.45 +/- 0.25) ng/ml respectively, both P < 0.05]. The concentration of TGF-beta in BALF of the ASON 0 d group was significantly lower than those of the ASON 7 d and ASON 14 d groups [(51.42 +/- 3.57) pg/ml and (55.8 3 +/- 1.79) pg/ml respectively, both P < 0.05]. The concentration of TGF-beta in BALF of the ASON7 d group was significantly lower than those of the BLM and ASON 14 d groups (both P < 0.05).
STAT1 ASON administered in the early stage helps depress the pulmonary fibrosis procedure, and the earlier the drug is administrated the better effect would be obtained. Aerosolized STAT1 ASON can be used as a therapeutic method for pulmonary fibrosis.
探讨吸入信号转导和转录激活因子1（STAT1）反义寡核苷酸（ASON）对肺泡炎和肺纤维化的治疗作用及最佳给药时间。
将25只成年雌性Wistar大鼠随机分为5组，每组5只：博来霉素（BLM）组，经气管内灌注BLM以建立肺泡炎和肺纤维化动物模型，然后吸入雾化生理盐水（NS）；NS组，经气管内灌注NS，然后吸入雾化NS；ASON 0 d组，经气管内灌注BLM，然后立即吸入3 ml雾化STAT1 ASON；ASON 7 d组，经气管内灌注BLM，7天后吸入3 ml STAT1 ASON；ASON 14 d组，经气管内灌注BLM，14天后吸入3 ml雾化STAT1 ASON。每隔一天重复雾化吸入1次，共4次。气管内灌注28天后处死大鼠，取出肺组织进行病理检查。向右侧肺内注入NS以获取支气管肺泡灌洗液（BALF）。采用酶联免疫吸附测定（ELISA）法检测BALF中转化生长因子-β（TGF-β）和肿瘤坏死因子-α（TNF-α）的浓度。
肺组织病理结果显示，与BLM组和ASON 14 d组相比，ASON 0 d组的肺泡炎和肺纤维化明显较轻。ASON 0 d组肺泡炎和肺纤维化评分分别为（1.80±0.84）和（2.60±0.55），均显著低于BLM组[分别为（2.40±0.55）和（4.40±0.55）]及ASON 7 d组[分别为（2.20±0.45）和（3.00±0.71）]（均P<0.05）。ASON 7 d组肺纤维化评分显著低于BLM组和ASON 14 d组（均P<0.05）。ASON 0 d组BALF中TGF-β和TNF-α浓度分别为（48.11±3.46）pg/ml和（1.93±0.14）ng/ml，均显著低于BLM组[分别为（57.67±2.46）pg/ml和（2.45±0.25）ng/ml，均P<0.05]。ASON 0 d组BALF中TGF-β浓度显著低于ASON 7 d组和ASON 14 d组[分别为（51.42±3.57）pg/ml和（55.83±1.79）pg/ml，均P<0.05]。ASON 7 d组BALF中TGF-β浓度显著低于BLM组和ASON 14 d组（均P<0.05）。
早期给予STAT1 ASON有助于抑制肺纤维化进程，且给药越早效果越好。雾化STAT1 ASON可作为肺纤维化的一种治疗方法。
