Transgelin-2作为哮喘治疗的新靶点
2018/04/04
摘要
有研究显示超过一半的哮喘患者使用现有的治疗，病情无法得到完全控制，因此临床上亟需新的支气管扩张药物。我们发现，肺组织中金属硫蛋白-2蛋白抑制剂的表达的会导致肺阻力增加。在啮齿动物哮喘模型中，与β2-激动剂相比，金属硫蛋白-2蛋白可以更加有效地降低肺阻力并舒缓气道平滑肌细胞（ASMC）。金属硫蛋白-2可以通过Transgelin-2（TG2）和诱导肌球蛋白磷酸酶靶亚基1（MYPT1）的去磷酸化使ASMC松弛。我们证实了TG12是一种无毒且特异性较高的TG2激动剂，可以松弛ASMC并降低肺阻力。体内实验中，TSG12降低了由卵清蛋白和房尘螨诱导的哮喘小鼠的肺阻力。TG12可以诱导RhoA磷酸化，使RhoA-ROCK-MYPT1-MLC途径失活从而引起ASMC松弛。TG12比β2-激动剂在缓解人类ASMC收缩和肺阻力方面更有效，并具有潜在的临床优势。这些结果表明TG12可能是治疗哮喘的新靶点。
Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance.
Yin LM, Xu YD, Peng LL, Duan TT, Liu JY, Xu Z, Wang WQ, Guan N, Han XJ, Li HY, Pang Y, Wang Y, Chen Z, Zhu W, Deng L, Wu YL, Ge GB, Huang S, Ulloa L, Yang YQ.
Abstract
There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than β2-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite-induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than β2-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma.
有研究显示超过一半的哮喘患者使用现有的治疗，病情无法得到完全控制，因此临床上亟需新的支气管扩张药物。我们发现，肺组织中金属硫蛋白-2蛋白抑制剂的表达的会导致肺阻力增加。在啮齿动物哮喘模型中，与β2-激动剂相比，金属硫蛋白-2蛋白可以更加有效地降低肺阻力并舒缓气道平滑肌细胞（ASMC）。金属硫蛋白-2可以通过Transgelin-2（TG2）和诱导肌球蛋白磷酸酶靶亚基1（MYPT1）的去磷酸化使ASMC松弛。我们证实了TG12是一种无毒且特异性较高的TG2激动剂，可以松弛ASMC并降低肺阻力。体内实验中，TSG12降低了由卵清蛋白和房尘螨诱导的哮喘小鼠的肺阻力。TG12可以诱导RhoA磷酸化，使RhoA-ROCK-MYPT1-MLC途径失活从而引起ASMC松弛。TG12比β2-激动剂在缓解人类ASMC收缩和肺阻力方面更有效，并具有潜在的临床优势。这些结果表明TG12可能是治疗哮喘的新靶点。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Sci Transl Med.2018Feb7;10(427).pii:eaam8604.doi:10.1126/scitranslmed.aam8604.)
(Sci Transl Med.2018Feb7;10(427).pii:eaam8604.doi:10.1126/scitranslmed.aam8604.)
Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance.
Yin LM, Xu YD, Peng LL, Duan TT, Liu JY, Xu Z, Wang WQ, Guan N, Han XJ, Li HY, Pang Y, Wang Y, Chen Z, Zhu W, Deng L, Wu YL, Ge GB, Huang S, Ulloa L, Yang YQ.
Abstract
There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than β2-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite-induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than β2-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma.
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过敏性疾病的细胞因子靶向生物学治疗
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哮喘急性加重与重度嗜酸粒细胞性哮喘患者肺功能下降相关
