Research ArticleAsthma

Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance

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Science Translational Medicine  07 Feb 2018:
Vol. 10, Issue 427, eaam8604
DOI: 10.1126/scitranslmed.aam8604

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Tickling transgelin-2 for asthma relief

Asthmatics can be refractive to β2-agonists, creating a need for new pathways to be targeted in this disease. Yin et al. discovered that the protein metallothionein-2 was able to reduce airway resistance in rodent asthma models. This improvement was mediated through transgelin-2, and they further studied a transgelin-2 agonist as a new asthma therapeutic. The agonist improved airway function in multiple preclinical asthma models and relaxed human airway smooth muscle cells. These data indicate that activating transgelin-2 for asthma treatment may be more effective than targeting β2-adrenoceptors.


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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