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Abstract
Asiaticoside (AS) has been reported to have protective effect on pulmonary fibrosis (PF). In this study, we aimed to explore the potential mechanism of the therapeutic role of AS and its relationship with A2AR in PF. Adenosine 2A receptor gene knockout (A2AR−/−) mice and wild‐type (WT) mice were used to establish bleomycin (BLM)‐induced PF models and were then treated with AS (50 mg/kg/d). Pulmonary inflammation and fibrosis were observed in the PF model with much higher severity in A2AR−/−mice than that in WT mice and AS significantly alleviated lung inflammation and fibrosis; however, it was less effective in A2AR−/− mice than in WT mice via histopathological analysis. Using RNA sequencing analysis, we found up‐regulated differentially expressed genes (DEGs) in BLM group were enriched in immune and inflammation‐associated pathways compared with control group. There were 242 common DEGs between down‐regulated in BLM vs control group and up‐regulated in BLM + AS vs BLM group, which were enriched in cAMP and Rap1 signalling pathways. Furthermore, the expression of five key factors of these two pathways including adenylate cyclase (ADCY1, ADCY5, ADCY8, cAMP and Rap1) were confirmed up‐regulated by AS with the presence of A2AR. Therefore, AS might attenuate BLM‐induced PF by activating cAMP and Rap1 signalling pathways which is assisted by A2AR, making it a promising therapeutic optional for PF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by the aberrant proliferation of fibroblasts and excessive extracellular matrix (ECM) with poor prognosis.[1,2]
Studies demonstrated substantial inflammatory infiltration and collagen deposition were significant pulmonary features in BLM-induced pulmonary fibrosis Adenosine 2A receptor (A2AR)−/− mice models, which was used in our study.[44,45]
In accordance with previous research, we found significant inflammatory infiltration and large amounts of collagen fibres deposition in BLM group and even more serious in KOB group, which indicated the PF model was established successfully by BLM and PF were even worsen in A2AR−/− mice
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by the aberrant proliferation of fibroblasts and excessive extracellular matrix (ECM) with poor prognosis.[1,2] It is estimated that over five million people were affected by IPF globally with an average survival time of only 2-3 years.[3]. Asiaticoside (AS) is a triterpenoid saponin purified from the plant Centella asiatica with various biological effects, such as antioxidant, anti-inflammatory and anti-hepatofibric effects.[18,19,20] Centella asiatica is a traditional Chinese medicine, which is widely used to wound healing and alleviating the symptoms of interstitial lung disease.[21,22] Tang et al found AS could inhibit the proliferation of fibroblasts and the expression of type I and type III collagen protein in the process of wound healing.[23] our previous study showed that AS can inhibit the expression of IL-4, TNF-α, and TGF-β1 and increase the expression of A2AR in the lungs preventing the development of BLM-induced pulmonary fibrosis in rats.[24] the exact mechanism for the amelioration of BLM-induced pulmonary fibrosis after treatment with AS remains unclear and requires further investigation. We used BLM-induced PF model in wild-type and A2AR−/− mice and treated them with AS respectively to investigate the effect of AS on PF and to further explore potential mechanism of its the therapeutic role and its relationship with A2AR
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