Differential effects of Ruxolitinib on airway remodeling in asthma and COPD

Asthma and COPD are characterized by persistent airway inflammation and remodeling driven by dysregulated signaling pathways, including JAK/STAT. Ruxolitinib, a JAK/STAT inhibitor, exhibits promise in modulating inflammation; yet its impact on airway remodeling in unknown. This study investigates the effect of Ruxolitinib on airway remodeling. Primary airway smooth muscle cells (ASMC) from patients with asthma, COPD, and healthy controls were treated with Ruxolitinib (0-100nM) alone or in combination with TGFβ (2ng/ml). Expression levels of MMP-12, MMP-3, VEGF, IL-6, IL-8, aSMA, and fibronectin were evaluated by qPCR and ELISA.TGFβ significantly decreased gene and protein expression of MMP-12 and MMP-3 in ASMC from COPD patients but not from asthmatics or controls, with Ruxolitinib attenuating these effects. While TGFβ elevated gene and protein expression of IL-6, IL-8, VEGF, αSMA, and fibronectin, in ASMC from all groups, Ruxolitinib had an opposite effect and furthermore, mitigated the TGFβ-induced expression of these molecules. The expression of TIMP-1 and TIMP-2 in ASMC from all groups was downregulated by TGFβ, whereas Ruxolitinib had no effect on TIMP-1 levels but decreased TIMP-2 levels. Ruxolitinib attenuated the effect of TGFβ on TIMP-1 expression and had an additive effect on TGFβ-reduced TIMP-2 expression. In conclusion, our findings suggest that Ruxolitinib exhibits broad anti-inflammatory and anti-fibrotic properties, in ASMCs, with varied responses observed between asthma and COPD. These findings underscore the therapeutic potential of Ruxolitinib in targeting airway remodeling processes, highlighting the importance of tailored treatment strategies based on specific disease phenotypes.