Bu-Fei Formula Ameliorates Inflammation in a Preclinical COPD-Like Model by Targeting Mitochondrial Hyperactivity to Inhibit the NLRP3 Inflammasome

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airflow limitation and chronic airway inflammation. While the traditional Chinese medicine Bu-Fei Formula (BFF) effectively ameliorates COPD symptoms clinically, however, the precise molecular mechanisms underlying its therapeutic effects remain a knowledge gap. Methods: The therapeutic effects and anti-inflammatory mechanisms of BFF in COPD were investigated using cigarette smoke + LPS-induced COPD-like rats and CSE-stimulated macrophages. BFF treatment was administered in both models for 8 weeks in a dose-dependent manner. Lung injury, collagen deposition, and macrophage ultrastructure were assessed by H&E, Masson’s staining, and TEM. The evaluation of IL-1β, IL-18, NLRP3, ASC, and Caspase-1 p20 expression was performed via ELISA, IHC, IF, and Western blot. Oxidative stress (MDA, SOD) and mitochondrial function (complexes I–V, ATP, ROS) were also evaluated. Results: BFF treatment produced a pronounced improvement in lung pathology of COPD-like rats, characterized by alleviation of tissue damage, suppression of inflammatory and alveolar degeneration, and reduction of collagen accumulation in the interstitium. It also ameliorated inflammatory injury at the cellular level by inhibiting macrophage pyroptosis. Mechanistically, BFF suppressed the overexpression of mitochondrial respiratory chain complexes I–V. It reduced the levels of ROS, ATP, MDA, NLRP3, ASC, Caspase-1 p20, IL-1β, and IL-18, while enhancing SOD activity. These findings suggest that BFF mitigates the inflammatory damage in COPD by suppressing the hyperactivation of mitochondrial energy metabolism, enhancing the efficiency of the oxidative respiratory chain, and reducing ROS production, and suppressing the NLRP3 inflammasome response. Keywords: Bu-Fei formula, inflammation, NLRP3 Inflammasome, mitochondrial respiratory chain complexes, chronic obstructive pulmonary disease