Yadanzigan, a quassinoid glucoside, attenuates NLRP3 inflammasome
activation to prevent LPS-induced acute lung injury
Abstract
BACKGROUND AND PURPOSE Acute lung injury (ALI) is a challenging clinical
syndrome that manifests as an acute inflammatory response. The NLRP3
inflammasome is involved in the development of ALI. Yadanzigan (YDZG) is
isolated from Brucea javanica (Linn.) Merr (Simaroubaceae) (Yadanzi), an
anti-inflammatory herb widely used in traditional Chinese medicine.
However, the anti-inflammatory effect and mechanism of YDZG on ALI have
not been reported. ¬ EXPERIMENTAL APPROACH The in vitro
anti-inflammatory effect and mechanism of YDZG were investigated through
ELISA, qRT-PCR, Western blotting, and immunoprecipitation assay. ALI
model was established by non-invasive intratracheal instillation of LPS
into lung of mice. The therapeutic effect of YDZG on ALI was assessed by
changes in histopathological and pro-inflammatory markers. The
underlying mechanisms were investigated by Western blotting on lung
tissue. KEY RESULTS YDZG specifically inhibits NLRP3 inflammasome
activation. In cultured macrophages, YDZG attenuated the NF-κB pathway
and mitochondrial reactive oxygen species production and enhanced TRIM31
expression to inhibit NLRP3 inflammasome activation. YDZG also
ameliorated LPS-induced acute lung injury in mice by inhibiting the
expression of NLRP3. CONCLUSIONS AND IMPLICATIONS This study uncovers
the underlying mechanism and the anti-inflammatory activity of YDZG in
ALI, suggesting that NLRP3 inflammasome may be an effective target of
the treatment with ALI.