Effective-Component Compatibility of Bufei Yishen Formula Alleviates Alveolar Epithelial Barrier Damage in COPD Through Inhibition of p38 MAPK Phosphorylation

Purpose: Alveolar epithelial barrier (AEB) dysfunction drives the development of chronic obstructive pulmonary disease (COPD). This study aimed to investigate whether the effective-component compatibility of the Bufei Yishen formula (ECC-BYF) protects the AEB in COPD via anti-inflammatory mechanisms, and to elucidate the underlying pathways. Methods: In vivo, a rat model of COPD was established via repeated bacterial infection and cigarette smoke exposure. Following treatment, we analyzed lung function, histopathology, epithelial ultrastructure, inflammatory factors, and AEB-related protein expression. In vitro, MLE-12 cells stimulated with TNF-α were pretreated with ECC-BYF to assess cell viability, inflammatory responses, and barrier protein expression. Additionally, network pharmacology was utilized to predict key therapeutic targets, and the involvement of the p38 MAPK signaling pathway was validated via Western blotting. Results: In vivo, ECC-BYF improved pulmonary function and attenuated histopathological damage in COPD rats. Ultrastructural analysis showed that ECC-BYF improved the morphology of alveolar type 1 (AT1) and type 2 (AT2) cells and preserved intercellular junctions. Furthermore, ECC-BYF upregulated the expression of ZO-1, Occludin, SP-C, and SP-D proteins, increased Interleukin (IL)-10 in bronchoalveolar lavage fluid (BALF), and suppressed BALF levels of IL-6, IL-1β, and TNF-α. Network pharmacology identified TNF/IL-6 and MAPK signaling as key targets. In vitro, ECC-BYF reversed TNF-α-induced elevations in IL-6 and TNF-α mRNA, increased ZO-1, Occludin, and SP-C protein levels, and inhibited p38 MAPK phosphorylation. This reduction in p-p38 MAPK was concordantly observed in rat lung tissues. Critically, asiatic acid abrogated ECC-BYF's suppressive effects, demonstrating that p38 MAPK inhibition is central to its barrier-protective efficacy. Conclusion: ECC-BYF mitigates AEB disruption in COPD by inhibiting the p38 MAPK-mediated inflammatory response, highlighting a crucial mechanism for protecting barrier integrity.