Ginseng and Platycodon grandiflorum ameliorated pulmonary fibrosis and inflammation targeting TLR4-P2X7r/NLRP3 signaling pathway

Abstract

Ethnopharmacological relevance: Ginseng and Platycodon grandiflorum (Jacq.) A. DC. (PG) are traditional Chinese herb medicine and classified into the lung meridian, which traditionally used to treat respiratory disorders.

Aim of the study: This study investigated the protective mechanisms of ginseng and PG against pulmonary fibrosis.

Materials and methods: Panax ginseng C.A.Mey. (GS), Ginseng Radix et Rhizoma Rubra (RGR), PG and GS + PG extracts were prepared using aqueous or ethanol extraction methods and analyzed by HPLC. Cigarette smoke (CS)-induced pulmonary fibrosis mice were administrated with GS, RGR, PG, GS + PG aqueous extracts or platycodin D (PD, the major active component of PG), respectively. A549 were stimulated with different stimulators TGF-β, LPS + ATP or conditioned medium from LPS-primed THP-1 (CM), then cultured with PG, PD or A438079 (P2X7r antagonist), respectively.

Results: In CS-exposed mice, GS, RGR, PG, or GS + PG extracts significantly reduced lung index elevation without effects on kidney, cardiac or liver indices. These extracts ameliorated CS-induced alveolar wall thickening, extracellular matrix (ECM) accumulation, inflammation, and inhibited P2X7r/NLRP3, TLR4/IRAK4, and NF-κB/IκB-α. PG or PD significantly alleviated lung injury and ECM deposition in CS-exposed mice. PG or PD inhibited CS-induced inflammatory cytokine secretion and immune cell recruitment by TLR4-P2X7r/NLRP3 blockade. In CM-stimulated A549, PG or PD significantly reduced ECM accumulation and inflammatory factors release. PG blocked CM-triggered TLR4-P2X7r/NLRP3 activation in A549, with similar functioning as A438079.

Conclusions: GS and PG ameliorated pulmonary fibrosis via TLR4-P2X7r/NLRP3. PG and PD regulated cell crosstalk in alveolar microenvironment against pulmonary injury, which might be novel therapeutic strategy for pulmonary fibrosis.

Keywords: Ginseng; NLRP3; P2X7r; Platycodon grandiflorum (Jacq.) A. DC.; Pulmonary fibrosis; TLR4.