Codonopsis radix improves bleomycin-induced idiopathic pulmonary fibrosis by regulating TGF-β1/Smad signaling pathway and inhibiting fibroblast differentiation and proliferation.

ETHNOPHARMACOLOGICAL RELEVANCE: Codonopsis radix (CR), an herbal medicine, has been officially named and used since Wu Yiluo's "Bentushu Letter" in the Qing Dynasty. It has the effect of invigorating the spleen and lung, nourishing blood, and benefiting body fluid. However, there are few reports on the impact of CR on idiopathic pulmonary fibrosis (IPF).

AIM OF THE STUDY: This study evaluated the therapeutic effects of CR on IPF through in vivo and in vitro experiments and explored possible mechanisms. Specifically, we aimed to clarify whether the main pharmacodynamic components in CR exert synergistic regulatory effects and to reveal the underlying synergistic mechanism.

MATERIALS AND METHODS: The water extract group (CWE), polysaccharide group (CP), and small molecules group (CS) were successfully extracted from CR, the CS components were purified, and the CWE and CP components were preliminarily characterized. Next, based on the activation of lung fibroblasts by transforming growth factor-β1 (TGF-β1), Compusyn software was used to analyze the combination index (CI) of CS and CP. The effects of CR components on fibroblast differentiation, proliferation, apoptosis, and related signaling pathways were studied. Based on the bleomycin (BLM) induced IPF model in rats, the effects of CR on histopathologic manifestations and fibrotic marker expression levels were observed. Histological analysis, immunofluorescence, and Western blot were used to observe changes in CR effective components after intervention. The synergies of CS and CP components in CR and their effects on related signaling pathways were evaluated to identifypotential anti-IPF mechanisms.

RESULTS: In vitro experiments confirmed a synergistic effect when the CS to CP ratio was 1:8. The effective components of CR reversed TGF-β1-induced proliferation, migration, and extracellular matrix (ECM) deposition in MRC-5 cells while promoting cell apoptosis. CP and CS components exhibited a synergistic effect. Additionally, results showed that CR effective components inhibited fibroblast differentiation into myofibroblasts. In vivo pharmacodynamic evaluation and mechanism demonstrated that CR effective components improved the severity of BLM-induced IPF in rats, as evidenced by histopathological manifestations and fibrosis marker expression levels. The synergistic anti-IPF mechanism of CS and CP components in CR was linked to interference with the TGF-β1/Smad signaling pathway.

CONCLUSIONS: This study for the first time revealed that the main anti-IPF pharmacological active components of CR are derived from CS and CP components, with an optimal CS:CP ratio of 1:8. They inhibit fibroblast proliferation by suppressing TGF-β1/Smad-mediated expression of proliferative proteins (PCNA, Survivin) and promote Bcl-2/Bax-regulated fibroblast apoptosis, thereby reducing ECM deposition proteins (FN, α-SMA, Col-I). By inhibiting the transformation of fibroblasts into myofibroblasts, they exert a synergistic anti-fibrotic effect. These findings suggest that the effective components in CR may represent a new approach for IPF treatment.