Therapeutic Effect Of Methylprednisolone Loaded Liposomes Conjugated With SPANb In Treating AE-IPF On Rats Model

ObjectivesTo develop a rat model of acute exacerbation of idiopathic pulmonary fibrosis(AE-IPF)by twice perfusions of bleomycin(BLM).Then prove the therapeutic effect of methylprednisolone loaded liposomes conjugated with SPANb(MPS-NSSLs-SPANb)on rat model of AE-IPF.MethodsPart one: Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis.Ninety male Sprague Dawley(SD)rats were randomized into three groups: an AE-IPF model group(BLM+BLM group),an IPF model group(BLM group),and a normal control group.Rats in the BLM+BLM group underwent a second perfusion with BLM(7 mg/kg)on day 28 after the first perfusion with BLM(5 mg/kg).Rats in the other two groups received saline as the second perfusion.Six rats in each group were sacrificed for investigative experiments on day 31,day 35,and day 42 after the first perfusion,respectively.Additional 18 rats in each group were observed for survival.Part two: The safety and therapeutic effect of MPS-NSSLs-SPANb in treating AE-IPF on rats model.1)The safety of MPS-NSSLs-SPANb was evaluated after analyzing bacteria/fungi in rats,bronchoalveolar lavage fluid(BALF),liver and kidney function test.In addition,MPS distribution in different organsof rats was detected to test the tissue targeting ability of MPS-NSSLs-SPANb.2)The therapeutic effect of MPS-NSSLs-SPANb was evaluated after analyzing histopathologic changes of lung tissue,lung water content,inflammatory factors in the BALF,relative expression of NF-?B mRNA in the lung tissue and survival rates of rats etc.ResultsPart one: Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis.In the AE-IPF model group,pulmonary alveolar inflammation and fibrosis were significantly worse than in the other two groups,and a large amount of hyaline membrane was formed.In addition,there was a large quantity of albumin exudates in the BALF;the lung water content was markedly increased and expression levels of various inflammatory factors were significantly elevated.Furthermore,the survival of the animals was clearly decreased.Part two: The safety and therapeutic effect of MPS-NSSLs-SPANb in treating AE-IPF on rats model.1)Liver and kidney function of group treating with MPS-NSSLs-SPANb showed no significant difference from the normal control group,no significantly bacteria/fungi growing in the BALF.2)MPS-NSSLs-SPANb can suppress the expression of IL-6,IL-17 A,TNF-?,TGF-? in BALF,and mRNA expression of NF-?B in lung tissue.Treating with MPS-NSSLs-SPANb can also reduce pathological damage of lung tissue and increase survival proportions.Half-dosage use of MPS-NSSLs-SPANb was superior to the single use of MPS as well.Conclusions1)A second perfusion with BLM appears to induce acute exacerbation of pulmonary fibrosis and may be used to model AE-IPF in rats.2)MPS-NSSLs-SPANb was safe and stable which can highly specific bind to lung tissue,while it showed terrific therapeutic effect on AE-IPF model of rats,as well as lower the dosage of GCs(MPS)and reduce side effects when systematically use.