Experimental Study On The Effects Of The Novel Endothelin Receptor Antagonist On Bleomycin-induced Pulmonary Fibrosis

Objective:To investigate the effect and the mechanism of a novel endothelin receptor antagonist(ETP-508) on pulmonary fibrosis induced by bleomycin (BLM) in ratsMethods:Rats were divided into four groups:BLM group,ETP-508 group, Dexamethasone group and control group.Pulmonary fibrosis was induced by endotracheal injection of bleomycin(5mg/kg).Then ETP-508 group was treated with intraperitoneal injection of ETP-508(100ug/kg,every other day). Dexamethasone group was treated with intraperitoneal injection of dexamethasone(1mg/kg,every other day).BLM model group and control group were replaced by saline.At the 7^th and the 28^th day,6 rats of control group were executed respectively.And 7 rats of BLM group,Dexamethasone group and ETP-508 group were executed respectively.Hydroxyproline(HYP) levels in lung tissue were determined by alkaline hydrolysis.ET-1,MMP-2,and SP levels in lung tissue were determined by ELISA.Histopathological examination was carried out.Results:Histopathological examination of BLM group's lung tissue showed fibrosis.The degree of Dexamethasone group's and ETP-508 group's pulmonary fibrosis was lower than BLM group's.HYP level of BLM group's lung tissue was significantly higher than other groups at the 28^th day(P＜0.01).HYP levels of ETP-508 group and Dexamethasone group had no significant differences camparing to the control group,at the 7^th and the 28^th day respectively(P＞0.05)ET-1 level in lung tissue of BLM group was significantly higher than those of control group and dexamethasone group at the 28^th day(P＜0.01).ETP-508 group's ET-1 level was higher than other groups,there were significant differences compared to the control group,dexamethasone group(P＜0.01,respectively) and BLM group(P＜0.05).There was no significant difference between the control group and dexamethasone group(P＞0.05).The MMP-2 level of BLM group decreased from the 7^th day to the 28^th day (P＜0.05).It was lower than other groups' at the 28^th day.And it had significant difference compared to the control group's and ETP-508 group's at the 28^th day(P＜0.01).There were no significant differences between the control group and ETP-508 group in MMP-2 level at the 7^th and 28^th day respectively(P＞0.05).SP level in lung tissue of BLM group was significantly higher than those of control group and ETP-508 group at the 7^th and 28^th day respectively(P＜0.01). ETP-508 group's SP level was lower than BLM group's.There were significant differences between the ETP-508 group and BLM group of SP level at the 7^th and 28^th day respectively(P＜0.01).Conclusions:1.A novel endothelin receptor antagonist,ETP-508,has restraining effect on the formation of pulmonary fibrosis induced by bleomycin in rats.2.In the process of pulmonary fibrosis formation,ET-1,MMP-2 and SP take important effects on it.3.ETP-508 restrains the pulmonary fibrosis formation,which may be related to the following pathways:(1) ETP-508 restrains ET-1 from binding to its receptor A,so ET-1 can not take biology effects on fibrosis formation.(2) ETP-508 restrains the decrease of MMP-2 level in the formation of pulmonary fibrosis.(3) ETP-508 prevents the increase of SP level in the formation of pulmonary fibrosis.