Effective Component Compatibility of Bufei Yishen Formula III Alleviates Pulmonary Vascular Inflammation in COPD: Via VEGF/P38 MAPK Pathway.

[PURPOSE] Chronic inflammation of the lungs can affect pulmonary vascular remodeling in chronic obstructive pulmonary disease (COPD). The Bufei Yishen formula (BYF) and Effective-compound combination of BYF III (ECC-BYF III) ameliorate lung histopathological injury and remodeling, but the mechanism remains unclear. This study aimed to observe the effects of ECC-BYF III on pulmonary vascular inflammation in COPD and to elucidate its detailed mechanism.

[METHODS] In vivo, COPD rat model was established through cigarette smoke exposure (CSE) combined with repeated infections of Klebsiella pneumoniae. Rats were randomly treated with ECC-BYF III (5.5 mg/kg, once a day) or doxofylline (36 mg/kg, once a day) for eight weeks. In vitro, Human umbilical vein endothelial cells (HUVECs) and human monocyte leukemia cells (THP-1) were induced with 10 μg/mL LPS for 24h. The pulmonary function, histopathology, inflammatory factor levels, immunoblotting results were evaluated.

[RESULTS] Compared with the model group, ECC-BYF III significantly improved the lung function, alleviated pulmonary artery inflammation and relieved pulmonary vascular remodeling in COPD rats. At the molecular level, ECC-BYF III down-regulated VEGF/P38 MAPK signaling pathway. In the inflammatory model of HUVEC induced by LPS, 35 and 70μg/mL ECC-BYF III significantly decreased the levels of tumor necrosis factor -α (TNF-α), interleukin-1β (IL-1β) and Endothelin-1 (ET-1) mRNA, and increased the expression of endothelial nitric oxide synthase (eNOS) mRNA. In addition, ECC-BYF III also inhibited VEGF/P38 MAPK pathway in LPS-induced HUVEC and THP-1/HUVEC co-cultured inflammatory models.

[CONCLUSION] Our findings demonstrate that ECC-BYF III can improve pulmonary vascular remodeling in COPD rats, and its key pharmacodynamic mechanism involves the inhibition of the VEGF/P38 MAPK pathway, thereby reducing inflammatory infiltration.