Asthma is one of the most common chronic diseases, affecting an estimated 334 million people worldwide (Ntontsi et al., 2021, Enilari and Sinha, 2019). Airway remodeling, also known as airway reconstruction, is a key feature of asthma (Pascual and Peters, 2005). Airway remodeling is primarily characterized by an increased amount of airway smooth muscle in the airway wall, which may be the result of increased muscle hyperplasia (Yap et al., 2019). Therefore, it is of great importance to study the prevention of airway remodeling and the mechanism involved in the proliferation of airway smooth muscle cells (ASMCs) for the treatment of asthma.

Transient receptor potential channels (TRPCs) are considered as one of the first molecular candidates to encode store-operated Ca2+ (SOC) channels and consist of seven members, TRPC1–7 (Gonzalez-Cobos and Trebak, 2010, Qu et al., 2017). TRPCs play an important role in initiating and maintaining intracellular Ca2+ signaling, which is involved in proliferation, migration and contraction of ASMCs (Abramowitz and Birnbaumer, 2009). Our previous study also showed that TRPC1, TRPC3 and TRPC6 were involved in the regulation of cell proliferation in asthmatic ASMCs (Zhang et al., 2018). Moreover, the accumulation of intracellular Ca2+concentration ([Ca2+]i) contributes to the induction of autophagy (Shi, 2018, Li et al., 2015, Lee et al., 2012). Autophagy is a biological option for the cells to survive by recycling degraded compartments under nutrient deficiency or harsh environment (Green and Beth, 2014). Autophagy is closely correlated with the severity of asthma (Liu et al., 2016), and autophagy modulation may be a potential target in severe asthma (Green and Beth, 2014, Cheng et al., 2017). Taken together, these findings suggest an important role for the TRPC1/3/6/Ca2+/autophagy axis in the regulation of ASMC proliferation.

There is increasing evidence that neurotrophins, such as brain-derived neurotrophic factor (BDNF), are expressed in human airway smooth muscle (Abcejo et al., 2012). For instance, Aravamudan et al. (2016). found the increased basal BDNF secretion in asthmatic airway smooth muscle. Furthermore, studies have shown that airway smooth muscle responds to exogenous BDNF with elevated [Ca2+]i and ASMC proliferation (Aravamudan et al., 2012, Prakash et al., 2009). Mizoguchi et al. (2014). claimed that BDNF induced a sustained elevation of [Ca2+]i and activated microglial cell proliferation, migration, and NO release by upregulating the surface expression of TRPC3 channels in rodent microglial cells. Interestingly, studies have also shown that BDNF could induce autophagy to exert neuroprotective effects (Chen, 2013, Zheng, 2018). However, whether BDNF is mediated by autophagy through the TRPC1/3/6/Ca2+ pathway in asthma remains to be elucidated.

Based on these findings, the present study aims to investigate the effects of BDNF on proliferation of ASMCs and airway remodeling and to validate the underlying mechanism. We hypothesize that BDNF mediates the elevation of [Ca2+]i through the upregulation of TRPC1/3/6, thereby inducing autophagy and affecting the ASMC proliferation and airway remodeling in asthma.