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.