AdipoRon attenuates lipopolysaccharide-induced acute lung injury with reduced early fibroproliferative remodeling.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of intensive care unit admission and are associated with high mortality. Despite advances in supportive care, effective pharmacological therapies remain lacking. Adiponectin exerts anti-inflammatory and antioxidant effects, and AdipoRon, an adiponectin receptor agonist, may represent a potential therapeutic strategy for ALI. Female C57BL/6 J mice were fed either a standard diet (SD) or a high-fat diet (HFD) for 12 weeks to establish distinct metabolic conditions before assignment to control, lipopolysaccharide (LPS), and LPS + AdipoRon treatment groups. ALI was induced by intratracheal administration of LPS (0.5 mg/kg), and AdipoRon (50 mg/kg) was administered orally for three consecutive days after LPS exposure. LPS challenge induced severe lung injury in both SD and HFD mice, characterized by histopathological damage, inflammatory cell infiltration, increased oxidative DNA damage, apoptosis, and early fibroproliferative responses. AdipoRon significantly attenuated these changes, reducing lung injury scores, inflammatory cell counts, oxidative DNA damage, TUNEL-positive apoptotic cells, collagen deposition, and the expression of profibrotic markers, including Fn1, Col1a1, and Col3a1. AdipoRon also broadly modulated inflammatory cytokine responses in both dietary groups and significantly reduced serum leptin levels in HFD mice. In HFL-1 human lung fibroblasts, AdipoRon suppressed apoptosis and profibrotic protein expression. These findings demonstrate that AdipoRon attenuates LPS-induced ALI and early fibroproliferative remodeling while maintaining its protective effects under both standard- and high-fat-diet conditions. Overall, these findings support adiponectin receptor activation as a promising therapeutic strategy for ALI, even in metabolically dysregulated conditions.