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Background: Asthma is characterized by chronic inflammation and remodelling of the airways. The airway smooth muscle (ASM) is remodelled in asthma and represents an important source of inflammatory mediators. WNT-5A expression is higher in the ASM of asthmatics compared to health controls but is functional role in asthma has not been studied in detail. Objective: To characterize the functional role of smooth muscle-derived WNT-5A. Methods: We used a tetracyclin-inducible smooth-muscle-specific WNT-5A transgenic mouse model, enabling in vivo characterization of smooth-muscle-derived WNT-5A in response to allergen. In addition, PBMCs of asthma patients and healthy controls were stimulated with WNT-5A and changes in gene transcription were assessed by RNA-seq. Results: Smooth muscle specific WNT-5A overexpression enhanced sm-α-actin expression in the ASM of ovalbumin challenged animals, but had no effect on collagen content. WNT-5A overexpression also enhanced the production of Th2-cytokines IL-4, IL-5 and IL-13 in lung tissue after ovalbumin exposure. Further, WNT-5A increased mucus production in ovalbumin-treated animals, and enhanced eosinophilia and serum IgE production. To validate these findings, we studied the effects of WNT-5A in peripheral blood mononuclear cells (PBMCs) of healthy human subjects and asthma patients, and found the Th2 cytokine IL-31 to be among the top 5 upregulated genes, as identified by RNAseq analysis. IL-31 was also upregulated in response to WNT-5A overexpression in the mouse. Conclusion: Smooth-muscle derived WNT-5A drives Th2 type inflammation and remodelling. These findings imply a pro-inflammatory role for smooth muscle-derived WNT-5A in asthma.

Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and L-proline downstream of the arginase product L-ornithine, and via reduced nitric oxide synthesis.Using the specific arginase inhitibor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbumin-sensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge.Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased L-ornithine/L-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH.These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.