Lyn Mitigates Mouse Airway Remodeling by Downregulating the TGF-β3 Isoform in House Dust Mite Models

Abstract

Chronic airway remodeling is a serious consequence of asthma, which is caused by complex but largely unknown mechanisms. Despite versatile functions, the role of Lyn in chronic airway remodeling remains undefined. Using Lyn−/− mice, we show that continual exposure (for 8 weeks) of house dust mite (HDM) extracts induced a severe phenotype of chronic airway remodeling including exacerbated mucus production, collagen deposition, dysregulated cytokine secretion, and elevated inflammation. Strikingly, a significant increase in TGF-β3 rather than TGF-β1 was observed in Lyn−/− mouse lungs compared to wild-type mice. Furthermore, TGF-β3 neutralizing antibodies not only inhibited the expression of STAT6 and Smad2/3, but also decreased phosphorylation of Smad2 and NFκB in Lyn−/− mouse lungs. In addition, both recombinant and adenoviral TGF-β3 significantly promoted epithelial to mesenchymal transition (EMT) and intensified collagen I production and MUC5AC expression. Further examining chronic asthma patients showed that a decreased Lyn correlated with the severity of airway inflammation and mucus hypersecretion. Finally, Lyn may critically regulate airway remodeling by directly interacting with TGF-β3. Collectively, these findings revealed that Lyn regulates TGF-β3 isoform and modulates the development of airway remodeling, which may have therapeutic indications for severe chronic asthma.

Type I CRISPR-Cas targets endogenous genes and regulates virulence to evade mammalian host immunity

“…The degree of cellular infiltration was scored using previously described methods [43]. The index was calculated by multiplying severity by extent in 10 random areas, with a maximum passible score of 9 [44].…”

Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

“…The diagnosis of asthma was based on the asthma guidelines according to our previous describes (Li et al, 2013). Human lung tissues were collected according to our previous procedures (Xie et al, 2015).…”

“…From week 3 to week 8 after the initial sensitization, the mice were challenged with an intranasal administration of 10 μg of OVA in 50 μl of normal saline (NS) 2 times per week for duration of 5 weeks, as previously described (Li et al, 2013). Control groups of Lyn-TG mice and WT mice were given NS alone.…”

“…The total cell numbers were counted. Smears of the bronchoalveolar lavage (BAL) cells were fixed and stained as described previously to examine cell differentials (Li et al, 2013). …”

“…Lyn kinase, a member of the Src family of tyrosine kinases, modulates mucus production in asthma. Lyn deficiency resulted in the mucous hypersecretion in a mouse model of asthma (Li et al, 2013). Lyn kinase may be one of the most important targets for the treatment of asthma.…”