Efficacy and mechanisms of andrographolide derivative in acute exacerbations of chronic obstructive pulmonary disease: a meta-analysis, network pharmacology, molecular docking, and in vitro validation study.

BACKGROUND

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) contributes substantially to morbidity and mortality. Andrographolide derivative injections (e.g., Xiyanping, Yanhuning, Chuanhuning, Lianbizhi) are widely used adjunctive treatments in China. Their clinical efficacy remains unclear, and we explored the potential mechanisms of the parent compound andrographolide in this study.

METHODS

A systematic review and meta-analysis of 32 randomized controlled trials (n = 2,668) comparing andrographolide derivatives plus conventional therapy versus conventional therapy alone in patients with AECOPD was conducted. Pulmonary function (FEV1%, FEV1, FVC), arterial oxygen tension (PaO2), inflammatory markers (CRP, WBC, NEUT%, PCT), and overall clinical response were evaluated. Network pharmacology, molecular docking, and in vitro experiments using LPS-stimulated BEAS-2B cells were performed to explore underlying mechanisms.

RESULTS

Adjunctive andrographolide derivatives significantly improved overall clinical response rate [RR = 1.21, 95% CI 1.17-1.26, P < 0.00001], FEV1% [MD = 6.48, 95% CI 3.52-9.45], FEV1 [MD = 0.30 L, 95% CI 0.20-0.40], FVC [MD = 0.28 L, 95% CI 0.10-0.46], and PaO2 [MD = 6.56 mmHg, 95% CI 4.68-8.45]. Inflammatory markers were also reduced: CRP [MD = -4.72 mg/L, 95% CI -6.83 to -2.61], WBC [MD = -1.30 ×109/L, 95% CI -1.79 to -0.80], NEUT% [MD = -4.36 percentage points, 95% CI -6.18 to -2.54], PCT [MD = -0.17 ng/mL, 95% CI -0.23 to -0.10] (all P < 0.0001). Network pharmacology identified 39 overlapping targets, highlighting TNF, IL-1β, NLRP3, and CASP1 as core targets. Molecular docking suggested energetically favorable predicted interactions of andrographolide with NLRP3, caspase-1, IL-1β, and IL-18. In vitro, andrographolide enhanced BEAS-2B cell viability, reduced LDH release, and suppressed NLRP3, caspase-1, IL-1β, and TNF-α expression.

CONCLUSION

Andrographolide derivative injections as adjunctive therapy may improve clinical response, pulmonary function, oxygenation, and inflammatory status in patients with AECOPD. Mechanistic experiments using the parent compound andrographolide suggest that these therapeutic effects are potentially mediated by the NLRP3/caspase-1/IL-1β inflammatory axis. Nevertheless, these findings should be interpreted cautiously given the exclusively Chinese single-center RCTs, substantial heterogeneity in some outcomes, and lack of direct mechanistic data on individual derivatives.