Genipin attenuates hyperoxia-induced lung injury and pulmonary hypertension via targeting glycogen synthase kinase-3 β in neonatal rats

Abstract

Objectives: Bronchopulmonary dysplasia is the most common chronic lung disease of infancy and is associated with pulmonary hypertension (PH). Inhibition of glycogen synthase kinase (GSK)-3 β has been shown to attenuate lung injury and PH in hyperoxia-exposed newborn rats. Genipin has been widely used for the treatment of inflammatory diseases. The aim of this study was to show that genipin decreased the expression of GSK-3 β in lung tissues of hyperoxia-exposed rat pups.

Methods: We established models of hyperoxia-exposed rat pups, evaluated lung injury and pulmonary hypertension and detected the mRNA and protein expression of key molecules.

Results: Hyperoxia resulted in the reduction of survival rate and histologic injury of lung tissues; an increase of the messenger RNA (mRNA) expression of transforming growth factor-β1, extracellular matrix proteins collagen-I and fibronectin, and α-smooth muscle actin; an increase of right ventricular (RV) systolic pressure and the weight ratio of RV to left ventriclar (LV) plus septum (S) (RV/LV + S) were inhibited by genipin. Genipin also decreased the levels of tumor necrosis factor-α, interleukin-1 β, and interleukin-6 in both bronchoalveolar lavage fluid and lung tissues after hyperoxia exposure. In addition, genipin inhibited p65 nuclear factor-κB nuclear translocation and matrix metalloproteinase-2 and -9 expression. Moreover, hyperoxia resulted in an increase of methane dicarboxylic aldehyde content and a decrease of superoxide dismutase activity, catalytic subunit of glutamate-cysteine ligase, modified subunit of glutamate-cysteine ligase, and nuclear factor erythroid 2-related factor 2 expression were inhibited by genipin. All these effects induced by genipin were blocked by upregulation of GSK-3 β. Genipin downregulated GSK-3 β expression, decreased nuclear factor-κB translocation, increased nuclear factor erythroid 2-related factor 2 expression, attenuated inflammation and oxidative stress, leading to amelioration of lung injury and PH in hyperoxia-exposed rat pups.

Conclusion: Overall, genipin may provide a novel therapeutic option for preventing and treating infants with bronchopulmonary dysplasia.

Keywords: Bronchopulmonary dysplasia; Genipin; Glycogen synthase kinase (GSK)-3 β; Hyperoxia; Pulmonary hypertension.