Ginsenoside Rg1 Ameliorates LPS-Induced Sepsis-Associated Lung Injury in Mice via VEGFC/D-VEGFR3 Signaling-Mediated Lymphangiogenesis and Lymphatic Remodeling.

Sepsis-induced acute lung injury (ALI) remains challenging to treat, with conventional anti-inflammatory therapies offering limited efficacy. The lymphatic system is crucial for removing edema and inflammatory mediators, and its impairment can exacerbate lung injury. Ginsenoside Rg1, a bioactive botanical compound, has diverse pharmacological properties, but its ability to modulate lymphangiogenesis in septic ALI is unclear. This study investigated whether Ginsenoside Rg1 can alleviate lipopolysaccharide (LPS)-induced ALI in mice by promoting lymphangiogenesis via the vascular endothelial growth factor C (VEGFC)/D-VEGF receptor 3 (VEGFR3) signaling pathway. ALI was induced in C57BL/6 mice by intraperitoneal injection of LPS (10 mg/kg). Mice were treated with Rg1 at low (30 mg/kg) or high (60 mg/kg) doses. Lung injury was assessed by wet-to-dry weight ratios, vascular permeability, histopathology, and lymphatic vessel density. Levels of inflammatory cytokines, VEGFC/D, VEGFR3, and downstream signaling molecules were measured by enzyme-linked immunosorbent assay, western blotting, and qPCR. Ginsenoside Rg1 treatment dose-dependently reduced pulmonary edema, vascular leakage, and histological damage. It also reversed LPS-induced decreases in VEGFC/D and increased VEGFR3 expression, resulting in enhanced lymphatic vessel density. Rg1 activated VEGFR3 downstream pathways (ERK/Prox-1, AKT) and upregulated lymphatic function genes (CCL21a, ACKR2). Ginsenoside Rg1 can attenuate septic ALI by stimulating the VEGFC/D-VEGFR3 axis to promote functional lymphangiogenesis, thereby facilitating clearance of edema and inflammatory mediators. This mechanism offers a novel therapeutic strategy focused on enhancing clearance rather than only on suppressing inflammation, potentially reducing tissue damage and the side effects associated with conventional treatments.