Background: Increasing evidence suggests that Fbxo3 signaling has an important impact on the pathophysiology of the inflammatory process. Fbxo3
protein inhibition has reduced
cytokine-driven
inflammation and improved disease severity in animal model of Pseudomonas-induced
lung injury. However, it remains unclear whether inhibition of Fbxo3
protein provides protection in
acute lung injury induced by
ischemia-reperfusion (I/R). In this study, we investigated the protective effects of
BC-1215 administration, a Fbxo3 inhibitor, on
acute lung injury induced by I/R in rats. Methods: Lung I/R injury was induced by
ischemia (40 min) followed by reperfusion (60 min). The rats were randomly assigned into one of six experimental groups (n = 6 rats/group): the control group, control +
BC-1215 (Fbxo3 inhibitor, 0.5 mg/kg) group, I/R group, or I/R + BC-1215 (0.1, 0.25, 0.5 mg/kg) groups. The effects of
BC-1215 on human alveolar epithelial cells subjected to
hypoxia-reoxygenation (H/R) were also examined. Results:
BC-1215 significantly attenuated I/R-induced lung
edema, indicated by a reduced vascular filtration coefficient, wet/dry weight ratio,
lung injury scores, and
protein levels in bronchoalveolar lavage fluid (BALF). Oxidative stress and the level of inflammatory
cytokines in BALF were also significantly reduced following administration of
BC-1215. Additionally,
BC-1215 mitigated I/R-stimulated apoptosis, NF-κB, and
mitogen-activated protein kinase activation in the injured lung tissue.
BC-1215 increased Fbxl2
protein expression and suppressed Fbxo3 and TNFR associated factor (TRAF)1-6
protein expression.
BC-1215 also inhibited
IL-8 production and NF-κB activation in vitro in experiments with alveolar epithelial cells exposed to H/R. Conclusions: Our findings demonstrated that Fbxo3 inhibition may represent a novel therapeutic approach for I/R-induced
lung injury, with beneficial effects due to destabilizing
TRAF proteins.