Honokiol regulates Acute respiratory distress syndrome (ARDS)‐associated pulmonary fibrosis via the miR‐19a‐3p/POSTN axis

BACKGROUND AND PURPOSE: Acute respiratory distress syndrome (ARDS) and subsequent pulmonary fibrosis are associated with high mortality and limited treatment options. Periostin (POSTN) is a profibrotic mediator predicted to be regulated by microRNA-19a-3p (miR-19a-3p), but the relevance of this axis in ARDS-associated pulmonary fibrosis remains unclear. Honokiol (HKL), a phytochemical derived from Magnolia officinalis, possesses antioxidant and anti-inflammatory properties. This study investigated whether HKL modulates the miR-19a-3p/POSTN axis in ARDS-associated lung injury and fibrosis. EXPERIMENTAL APPROACH: Serum POSTN and miR-19a-3p levels were measured in patients with ARDS and correlated with severity. Mechanistic studies were performed using a lipopolysaccharide (LPS)-induced lung injury mouse model and macrophage-epithelial and macrophage-fibroblast co-culture systems. KEY RESULTS: Patients with ARDS exhibited elevated serum POSTN and reduced miR-19a-3p, which were inversely correlated and associated with indices of disease severity. HKL attenuated LPS-induced lung injury and fibrotic responses, accompanied by reduced POSTN expression and preserved miR-19a-3p levels. Dual-luciferase reporter assays supported a regulatory interaction between miR-19a-3p and POSTN. HKL was associated with alterations in macrophage phenotype and reduced macrophage-associated POSTN expression. In co-culture systems, manipulation of miR-19a-3p in macrophages modulated epithelial apoptotic signalling and fibroblast activation. In vitro loss-of-function experiments suggested that miR-19a-3p contributes, at least in part, to HKL-associated protective effects. CONCLUSION AND IMPLICATIONS: The miR-19a-3p/POSTN axis may represent a regulatory pathway associated with ARDS-related lung injury and fibrosis. HKL attenuated experimental injury and fibrotic responses in association with this axis. These findings support further pharmacological investigation of HKL in ARDS-associated lung injury and fibrosis.