全尚琨, 贺笑笑, 江天, 黄翌, 高雪慧, 张敏, 崔洁, 马景景, 赵晓坤, 郝小惠, 刘和亮, 郭灵丽. 帕比司他对小鼠矽肺纤维化的干预作用[J]. 环境与职业医学, 2019, 36(7): 616-620. DOI: 10.13213/j.cnki.jeom.2019.19022
引用本文: 全尚琨, 贺笑笑, 江天, 黄翌, 高雪慧, 张敏, 崔洁, 马景景, 赵晓坤, 郝小惠, 刘和亮, 郭灵丽. 帕比司他对小鼠矽肺纤维化的干预作用[J]. 环境与职业医学, 2019, 36(7): 616-620. DOI: 10.13213/j.cnki.jeom.2019.19022
QUAN Shang-kun, HE Xiaoxiao, JIANG Tian, HUANG Yi, GAO Xue-hui, ZHANG Min, CUI Jie, MA Jing-jing, ZHAO Xiao-kun, HAO Xiao-hui, LIU He-liang, GUO Ling-li. Interventive effect of panobinostat on silicosis fibrosis in mice[J]. Journal of Environmental and Occupational Medicine, 2019, 36(7): 616-620. DOI: 10.13213/j.cnki.jeom.2019.19022
Citation: QUAN Shang-kun, HE Xiaoxiao, JIANG Tian, HUANG Yi, GAO Xue-hui, ZHANG Min, CUI Jie, MA Jing-jing, ZHAO Xiao-kun, HAO Xiao-hui, LIU He-liang, GUO Ling-li. Interventive effect of panobinostat on silicosis fibrosis in mice[J]. Journal of Environmental and Occupational Medicine, 2019, 36(7): 616-620. DOI: 10.13213/j.cnki.jeom.2019.19022

帕比司他对小鼠矽肺纤维化的干预作用

Interventive effect of panobinostat on silicosis fibrosis in mice

  • 摘要: 背景 矽肺的病理改变主要是大量纤维增生和矽结节的形成。部分矽肺患者肺功能严重受损。目前临床上还没有有效的治疗矽肺的方法。组蛋白去乙酰化酶抑制剂与许多疾病有关,但其在小鼠矽肺纤维化中的作用尚不明确。

    目的 探究组蛋白去乙酰化酶抑制剂帕比司他对二氧化硅诱导小鼠矽肺纤维化的作用。

    方法 将28只C57BL/6雄性小鼠,随机均分为对照组、模型组、帕比司他治疗组及帕比司他药物对照组。模型组每天鼻腔滴注100 mg/mL SiO2悬浊液50 μL,连续7 d;帕比司他治疗组给予与模型组同样处理外,第8天开始每周给予3次帕比司他腹腔注射(5 mg/kg·d),连续3周;帕比司他药物对照组只给予药物,不作其他处理。对照组给予生理盐水。第48天检测小鼠肺功能,并处死所有小鼠。试剂盒检测小鼠肺组织中的羟脯胺酸含量;HE染色观察小鼠肺组织的病理改变;天狼猩红染色观察小鼠肺组织中Ⅰ型胶原、Ⅲ型胶原的表达;ELISA试剂盒检测小鼠血清和肺泡灌洗液中转化生长因子β1(TGF-β1)的含量。

    结果 与对照组相比,模型组肺组织中炎症细胞浸润和矽结节明显增加,Ⅰ、Ⅲ型胶原的分布明显增多;羟脯胺酸含量(1008.43±182.07)mg/g也较对照组(566.83±120.22)mg/g升高;肺泡灌洗液和血清中TGF-β1的含量分别为(109.97±2.14)、(934.65±68.13)mg/L相比对照组(52.62±3.57)、(540.36±1.06)mg/L增加,差异均具有统计学意义(P < 0.05)。与模型组相比,帕比司他治疗组肺组织中矽结节明显减少,羟脯胺酸含量降低至(824.08±94.88)mg/g,Ⅰ、Ⅲ型胶原分布减少;此外,帕比司他还可明显改善矽肺小鼠肺功能,模型组呼吸频率与气道狭窄系数分别为(318.14±9.77)次/min和(2.22±0.41),帕比司他治疗组的分别为(378.95±36.47)次/min和(1.59±0.12);并下调肺泡灌洗液和血清中TGF-β1的蛋白表达水平分别为(72.15±8.81)、(765.46±86.99)mg/L。

    结论 帕比司他可以干预小鼠矽肺纤维化的发展,改善矽肺小鼠肺功能。

     

    Abstract: Background The pathological changes of silicosis are mainly the formation of massive fibrosis and sputum nodules. Some patients with silicosis show severely impaired lung function. Currently, there is no effective clinical therapy for the disease. Histone deacetylase inhibitors are involved in many diseases, but their role in pulmonary fibrosis in mice is not known.

    Objective This experiment is designed to explore the effect of histone deacetylase inhibitor, panobinostat, on the silicosis fibrosis in silica-treated mice.

    Methods Twenty-eight C57BL/6 male mice were randomly divided into four groups:control group, model group, panobinostat treatment group, and panobinostat drug control group. The model group was intranasally instilled with 100 mg/mL SiO2 suspension at 50 μL for seven consecutive days; the panobinostat treatment group was additionally given intraperitoneal injection of panobinostat at 5 mg/kg per day, three times per week, from day 8 for three consecutive weeks; the panobinostat drug control group was given only the drug; and the control group was given normal saline. The lung function of the mice was detected on day 48, and then the mice were sacrificed. The content of hydroxyproline in the lung tissues was detected by corresponding kit. The pathological changes of lung tissue samples were observed with HE staining. The expressions of type Ⅰ collagen and type Ⅲ collagen in mouse lung tissue samples were observed with sirius red staining. The secretion of transforming growth factor β1 (TGF-β1) in serum and bronchoalveolar lavage fluid (BALF) of the mice were determined by ELISA.

    Results Compared with the control group, the model group showed obviously increased infiltration of inflammatory cells, silicotic nodules, and type Ⅰ and type Ⅲ collagens; increased hydroxyproline content(1 008.43±182.07) mg/g versus the control group(566.83±120.22) mg/g; increased contents of TGF-β1 in BALF and serum(109.97±2.14) and (934.65±68.13)mg/L versus the control group(52.62±3.57) and (540.36±1.06)mg/L, which were all statistically significant (P < 0.05). Compared with the model group, the panobinostat treatment group showed effectively reduced silicotic nodules, hydroxyproline(824.08±94.88) mg/g, and type Ⅰ and type Ⅲ collagens. Furthermore, panobinostat significantly improved the lung function of mice as the respiratory rate and of airway stenosis coefficient were (318.14±9.77) breaths/min and (2.22±0.41) in the model group, and (378.95±36.47) breaths/min and (1.59±0.12) in the panobinostat treatment group; panobinostat also down-regulated TGF-β1 in BALF and serum(72.15±8.81) and (765.46±86.99)mg/L respectively.

    Conclusion Panobinostat can obviously alleviate silicosis fibrosis and improve the lung function of silicotic mice.

     

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