2.1 Allergic Asthma
The inflammatory airway process in allergic asthma is complex, but Th2-type inflammation and excessive accumulation of eosinophils are important features.12 At the airway inflammation site, Th2 cells secrete large amounts of interleukin (IL)-3, -4, -5, -9 and -13, as well as recruiting/activating eosinophils, mast cells and basophils.13 IL-13 is crucial to the pathogenesis of asthma: overexpression of IL-13 significantly induces the occurrence of allergic asthma in a mouse model;14 additionally, IL-13 not only induces proliferation of goblet cells (the main effector cells for mucus production in the respiratory tract) but also induces subepithelial fibrosis, which leads to airway remodelling.14,15 Activated eosinophils migrate to the bronchial epithelium and release ROS and eosinophil granulocyte protein, resulting in airway hyper responsiveness (AHR) and epithelial damage that exacerbates respiratory symptoms.16 In airway smooth muscle cells, growth and survival signalling induced by ligand/receptor interactions is mediated through ROS.17 In addition, macrophage migration inhibitory factor (MIF; as an important upstream regulator of airway inflammation) promotes eosinophil differentiation, survival, activation and migration by binding CD74 and CXCR4 on the surface of eosinophils.18
The clinical treatment of asthma mainly involves β2-receptor agonists, corticosteroids and aminophylline. β2-agonists are currently the largest class of asthma-treatment agents, but their use is controversial because of poor clinical reactions and possible life-threatening adverse reactions. For moderate and severe asthma, combination therapy with inhaled corticosteroids and long-acting β2-agonists is used; however, this combination cannot prevent, reverse or treat the underlying causes of the disease. Moreover, these treatments require continuous monitoring for side effects and resistance.19 For instance, aminophylline often causes adverse reactions such as palpitations, headaches and vomiting20 (Table 1).
Trx1 is closely associated with asthma. Indeed, serum Trx1 levels in patients with acute exacerbation of asthma are significantly increased, and there is a significant correlation between these levels and eosinophil cationic protein.7,21 Exogenous Trx1 treatment has been shown to significantly improve AHR and airway inflammation in ovalbumin-sensitised mice.22Similarly, in a mouse model of chronic asthma, systemic use of Trx1 significantly inhibits airway remodelling, eosinophil infiltration and AHR, while reducing the expression of eotaxin (an eosinophil chemokine), macrophage inflammatory protein-1 and IL-13 in the lungs; thus, Trx1 improves pathological airway changes to prevent airway remodelling and asthma development.23 Trx1 also inhibits Th2 cytokine production by directly downregulating MIF production and indirectly inhibiting eosinophil chemotaxis. Notably, the realisation of this process does not depend on regulation of systemic Th1/Th2 immunity.24 The proliferation of goblet cells that secrete excessive mucus increases the morbidity and mortality of asthma patients; however, Trx1 prevents the development of goblet cell proliferation or improves established goblet cell proliferation.25 Trx1 also regulates ARH and airway remodelling by directly reducing intracellular ROS production. In addition, the clinical drug ephedrine may produce anti-asthma effectsin vivo through the induction of Trx1 production.26 Overall, Trx1 may be useful for the treatment of asthma and may represent a therapeutic target for asthma control.