Glaucocalyxin A improves survival in bleomycin-induced pulmonary fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with unclear etiology and poor prognosis. Despite numerous studies on the pathogenesis of IPF, only scant treatment options are available for the management of IPF. Glaucocalyxin A (GLA), an ent-Kaurane diterpenoid, has been demonstrated to exert anti-inflammatory, anti-neoplastic and anti-platelet activities. In this study, we evaluated the role of GLA as an anti-fibrotic agent in bleomycin-induced pulmonary fibrosis in mice and investigated the underlying mechanisms by which GLA attenuates lung fibrosis. Intraperitoneal administration of GLA (10 mg/kg) significantly reduced collagen deposition and hydroxyproline content in mouse lungs treated with bleomycin. Importantly, GLA significantly improved survival in bleomycin treated mice. In addition, GLA reduced weight loss in mice that reflects cachexia due to pulmonary fibrosis. Mechanistically, GLA alleviated the infiltration of macrophages and neutrophils in lungs, attenuated the increases of proinflammatory cytokines in lung tissue and bronchoalveolar lavage fluid, and inhibited the activation of NF-κB in fibrotic lungs induced by bleomycin. These results provide evidence that GLA can effectively ameliorate pulmonary fibrosis through the antagonism of leukocyte infiltration and proinflammatory cytokine production, suggesting that it may become a potential anti-fibrotic agent in IPF management.