Abstract

Background The gut–lung axis contributes to the progression of chronic obstructive pulmonary disease (COPD) by impairing intestinal barrier integrity and exacerbating systemic inflammation. Bufei Jianspi Formula (BJF), a traditional Chinese medicine, has been shown to improve lung function and alleviate gastrointestinal symptoms in patients with COPD, thereby enhancing their quality of life. Objective This study aimed to investigate the mechanism by which BJF ameliorates COPD through protection of the intestinal epithelial barrier. Methods We evaluated the effects of BJF on intestinal injury and epithelial barrier integrity in a rat model of COPD. Additionally, an in vitro model of epithelial barrier dysfunction was established by treating Caco-2 cells with lipopolysaccharide (LPS) to elucidate the protective mechanisms of BJF and its active components, particularly their role in inhibiting CAPN2. Results BJF treatment effectively attenuated the decline in lung function and ameliorated pulmonary pathological changes in rats with COPD. It significantly reduced levels of pro-inflammatory cytokines in lung tissue, including IL-1β, IL-6, and TNF-α. Furthermore, BJF alleviated oxidative stress by increasing the activity of glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD), while decreasing malondialdehyde (MDA) levels. The formula also restored the protease–anti-protease balance by suppressing matrix metalloproteinases MMP-9 and MMP-12 and upregulating tissue inhibitor of metalloproteinase-1 (TIMP-1). In the intestine, BJF mitigated tissue injury and inflammation by reducing pro-inflammatory cytokine levels, enhancing the expression of tight junction proteins, and thereby preserving intestinal epithelial barrier integrity and reducing intestinal permeability. In vitro, BJF effectively reversed LPS-induced barrier dysfunction in Caco-2 cells through upregulation of tight junction protein expression. Drug Affinity Responsive Target Stability (DARTS) a