The Effect Of Glucagon-like Peptide-1Analog On Pulmonary Fibrosis Of Diabetic Rats

Objective:Diabetes mellitus(DM)is a chronic metabolic disorder which is caused by genetic and environmental factors that lead to insulin secretion defection and weakened biological action,it is characterized by chronic high glucose. As most DM patients died of diabetic chronic complications,scholars pay more attention on the changes of kidney,myocardium,vascular in DM patients,but researches have shown that60%DM pantients suffer from pulmonary damages.The characteristic pulmonary damages is fibrosis,which is showed as follow aspects:infiltration of inflammatory cells、hyperplasia of collagenous, alveolar epithelium and vascular endothelial basement membrane were surrounded by protein.Researches show, rennin-angiotensin system called local renin-angiotensin system(RAAS) plays an important role in local tissue. Angiotensin Ⅱ is a key factor of local RAAS,it can be expressed by combing angiotensin Ⅱ type1receptor to lead to pulmonary fibrosis. Transforming growth factor betal is the key medium of fibrosis.Liraglutide is a new synthetic glucagon-like peptide-1analog.GLP-1receptor are widely distributed in tissue and protected these tissue.Recently research shows that GLP-1amide inhibits RAAS in the central nervous system from water intake.Also,lots of recent studies have found that GLP-1protects organs from fibrosis.Is there a possibility that liraglutide may down-regulate local RAAS to alleviate pulmonary fibrosis of diabetic rats?Our study aims at observing the fibrosis of lung in diabetic rats,and establishing a liraglutide intervention group to observe the changes of these indicators, so that to explore whether GLP-1down-regulate local RAAS and protect lung from fibrosis.Methods:36clean grade inbred Wistar rats, were raised separated in specific pathogen-free conditions. Fed adaptively1Week,then selected10of them randomly as normal group(N group),fed with normal animal feedstuff.Others fed with fatty and sugary feedstuff,and8weeks later,STZ was injected into caudal vein to induce type2diabetes mellitus, N group rats was injected with equal buffer solution. After that22of the26got DM.Then,randomly selected11of them as liraglutide intervention group(LR group),subcutaneously injected of liraglutide everyday; N group and DM group were injected with physiological saline of the same way.12weeks later,there were10rats left in each group.At the end of the experiment:①Recorded body weight(BW) of the rats,tested fasting blood-glucose (FBG), kept the blood samples to test glycosylated hemoglobin(HbAlc) and other biochemical indices.②lung samples were obtained for:MASSON staining.to observe the structural changes of lung tissue and collagen aggradation; ELISA:to test Ang Ⅱ level of lung tissue; RT-PCR:to detect the mRNA expression of AT1R、TGF-β1in each group; Western Blotting:to detect the protein expression of AT1R and TGF-β1in each group.Results:①RW、FBG and other biochemical indices:At the end of the experiment,the BW of DM group were less than those in N group(P<0.05),and heavier than LR group(P<0.05).FBG、HbA1c、TG of rats in LR group、DM group were elevated compared to N group(P<0.05), but FBG、HbAlc、TG、TC、HDL-c of LR group were not better than DM group.②MASSON staining:N group had little collgen around pulmonary interstitial and perivascular,in DM group these structure disordered and collgen increased, pulmonary damages were alleviated in LR group,but they didn’t recover to normal level.③ELISA:Compared with N group,AngⅡ in DM group was elevated(P<0.05).It was less in LR group than those in DM group(P<0.05)and more than those in N group.④RT-PCR:DM group expressed more AT1R、TGF-β1than N group(P<0.01),while LR group expressed less AT1R、TGF-β1than DM group(P<0.01).⑤Western Blotting:compared with N group,there were more AT1R、TGF-β1expressed in DM group(P<0.05),while in LR group,there were less AT1R、TGF-β1expressed than DM group(P<0.05).Conclusions:①The expression of Ang Ⅱ、 AT1R、TGF-β1and collgen increased in DM group,which suggest that the pulmonary fibrosis did exist and abnormal expression of local RAAS plays an important role in the progress of fibrosis.②The pathological changes of lungs in LR group were slighter than DM group and the deposition of collagen and the expression of Ang Ⅱ、 AT1R、TGF-β1in pulmonary tissure were declined in LR group,which suggest that liraglutide may relieve pulmonary fibrosis of DM rats by down-regulating local RAAS.