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目的放射性肺纤维化是放射性肺损伤的晚期改变,发病机制复杂,临床上缺乏有效的治疗方法,患者预后差。对放射性肺纤维化机制及干预的研究是当前的研究热点。ABT-263是抗肿瘤新药,近期发现具有清除衰老细胞、改善造血干细胞辐射损伤的作用。研究在前期研究的基础上建立局部照射诱导的肺纤维化小鼠模型,观察ABT-263对放射性肺纤维化的治疗作用,探讨其作用机制。方法健康雄性C57BL/6J小鼠分为对照组(Control组)、给药组(ABT组)、照射组(IR组)和治疗组(IR+ABT组)。小鼠接受17Gy右侧胸部X射线照射,照射后第16周开始灌胃给予ABT-263 50 mg·kg-1,每疗程给药5 d,停药2周,给药2个疗程后进行观察。两个疗程治疗后CT检查小鼠肺实质的损伤情况。病理观察小鼠肺组织结构的变化、胶原生成(Masson检测)和β-半乳糖苷酶(β-Gal)表达。免疫荧光检测肺组织中肺表面活性前体蛋白C(Pro-SPC)和P16的表达。基因PCR芯片技术检测肺组织纤维化相关基因的表达。结果胸部CT结果显示ABT治疗可以降低放射引起的小鼠肺组织的HU值升高(P<0.05);降低照射引起小鼠肺脏指数显著升高(P<0.05);减轻受照小鼠肺组织病理变化评分(P<0.01),减少胶原沉积面积(P<0.01),降低β-Gal表达细胞比例(P<0.01);可以抑制受照小鼠Ⅱ型肺泡细胞P16表达(P<0.01);纤维化相关基因芯片测定结果显示ABT可以降低受照小鼠肺组织中Bcl-2、Col3a1、Col1a2、Ⅱ1α、Il1βm RNA显著升高(P<0.05或P<0.01)。结论上述研究结果显示ABT263可以减轻小鼠放射性肺纤维化的损伤性改变,降低衰老Ⅱ型肺上皮细胞,抑制Bcl-2及肺组织炎症性因子及纤维化相关因子的表达。研究结果将为放射性肺纤维化防治提供新的思路。
Purpose Radioactive pulmonary fibrosis is a late stage of radiation-induced lung injury with complicated pathogenesis and lack of effective clinical treatment. The prognosis is poor. Research on the mechanism and intervention of radiation-induced pulmonary fibrosis is the current research hotspot. ABT-263 is a new antitumor drug, recently found to have the effect of clearing aged cells and improving the radiation damage of hematopoietic stem cells. Based on the previous studies, we established a mouse model of pulmonary fibrosis induced by local irradiation and observed the therapeutic effect of ABT-263 on radiation-induced pulmonary fibrosis and explored its mechanism. Methods Healthy male C57BL / 6J mice were divided into control group, administration group (ABT group), irradiation group (IR group) and treatment group (IR + ABT group). The mice received 17Gy right chest X-ray irradiation. After the irradiation, the mice were given gavage with ABT-263 50 mg · kg-1 orally for 5 days. After 2 weeks of treatment, they were observed after two courses of treatment . Two courses of CT examination after treatment of lung injury in mice. Pathological changes in mouse lung tissue structure, collagen production (Masson test) and β-galactosidase (β-Gal) expression. Immunofluorescence detection of lung surfactant precursor protein C (Pro-SPC) and P16 expression. Gene PCR chip technique was used to detect the expression of lung fibrosis related genes. Results The results of chest CT showed that the ABT treatment could reduce the HU value of lung tissue in radiation-induced mice (P <0.05), decrease the lung index of mice (P <0.05) (P <0.01), reduce the proportion of β-Gal expressing cells (P <0.01), and inhibit the expression of P16 in type Ⅱ alveolar cells in irradiated mice (P <0.01). Fibrosis-related gene microarray assay showed that ABT could significantly reduce the levels of Bcl-2, Col3a1, Col1a2, Ⅱ1α and Il1βmRNA in the lung tissue of irradiated mice (P <0.05 or P <0.01). Conclusions The above results show that ABT263 can attenuate the damage of radiation-induced pulmonary fibrosis in mice, decrease the expression of Bcl-2, lung inflammatory factors and fibrosis-related factors in senescent type II lung epithelial cells. The results will provide new ideas for the prevention and treatment of radiation-induced pulmonary fibrosis.