Pterostilbene ameliorates pulmonary fibrogenesis and inflammation targeting IL-23/ATP6V0D2 pathway: remodel local microenvironment of alveolar epithelial cells and fibroblasts

Pterostilbene (PTE) is a natural stilbene compound abundantly found in various small berries such as blueberry and grape, and exhibits multiple health promoting potentials and excellent pharmacological activities, especially antioxidant and anti-inflammatory activities. This study explored the protective effects of PTE on pulmonary fibrogenesis and inflammation and its underlying mechanisms. TGF-β-stimulated BEAS-2B or primary lung fibroblasts (LFs) were cultured with PTE or pirfenidone (PFD). Mice were received intratracheal instillation of bleomycin (BLM) and administered PTE or PFD. IL-23/ATP6V 0 D 2 -deficient BEAS-2B were treated with TGF-β or PTE. Primary LFs were stimulated with conditioned medium from TGF-β-primed RLE-6TN (CM) and treated with PTE. In vitro , PTE inhibited TGF-β-induced BEAS-2B cell migration, extracellular matrix (ECM) deposition, epithelial-mesenchymal transition (EMT) and inflammation. In BLM-induced mice, PTE reduced lung index and IL-1β levels in BALF, and improved histopathological changes. PTE inhibited BLM-induced fibrogenesis, EMT, inflammation and immune cell infiltration through blocking IL-23 and activating ATP6V 0 D 2 . In TGF-β-induced BEAS-2B, PTE decreased IL-23, increased ATP6V 0 D 2 and ATP levels, and disrupted the interaction between IL-23 and ATP6V 0 D 2 . In IL-23-deficient BEAS-2B, PTE further elevated ATP6V 0 D 2 and decreased α-SMA, Vimentin and IL-1β expressions. ATP6V 0 D 2 deficiency attenuated the anti-fibrotic and anti-inflammatory effects of PTE in TGF-β-induced BEAS-2B. PTE also inhibited fibrogenesis, EMT, and inflammation in activated-primary LFs and blocked CM-triggered primary LFs activation by regulating IL-23-ATP6V 0 D 2 axis. In conclusion, PTE ameliorated pulmonary fibrosis targeting IL-23/ATP6V 0 D 2 pathway, especially remodeling the local microenvironment of alveolar epithelial cells and fibroblasts, which might be a novel therapeutic strategy against pulmonary fibrosis.