Myofibroblasts Acquire Steroid Resistance via Bcl-xL in Asthmatic Lung Fibrosis

Severe asthma is characterized by both steroid resistance and fibrotic remodeling. We hypothesized that myofibroblasts in fibrotic lung tissue acquire glucocorticoid resistance through the upregulation of the anti-apoptotic factor B-cell lymphoma-extra large (Bcl-xL). This study aimed to determine whether myofibroblasts become steroid-resistant via Bcl-xL expression in vivo and in vitro. A steroid-resistant asthma model was developed by repeatedly challenging sensitized BALB/c mice intratracheally with a high dose of ovalbumin (OVA). Myofibroblasts were identified by flow cytometry as α-smooth muscle actin (α-SMA)⁺ CD31^- CD45^- CD326^- cells. Lung mesenchymal stem cells (MSCs; platelet-derived growth factor receptor α⁺ CD31^- CD45^- CD326^- cells) were isolated and differentiated into myofibroblasts by culturing them with 15% fetal bovine serum (FBS) for 6 d. In asthmatic lungs, α-SMA⁺ myofibroblasts showed increased Bcl-xL expression, which was unaffected by dexamethasone (DEX) treatment. However, co-treatment with the Bcl-xL inhibitor navitoclax significantly restored steroid sensitivity. In vitro, MSCs were susceptible to DEX-induced early apoptosis, whereas differentiated myofibroblasts were resistant to DEX-induced apoptosis and strongly expressed Bcl-xL. In other words, navitoclax treatment overcame steroid resistance in cultured myofibroblasts. These findings indicate that Bcl-xL-expressing myofibroblasts contribute to the development of glucocorticoid resistance in fibrotic lungs in severe asthma. Targeting Bcl-xL may provide a novel therapeutic strategy to restore steroid responsiveness in severe asthma.