ABSTRACT
OBJECTIVE: This study aimed to investigate the efficacy and molecular mechanisms of ZSP1603 as a novel anti-fibrotic compound. MATERIALS AND METHODS: The unilateral left pulmonary fibrosis model was established in the Sprague Dawley (SD) rats. The bilateral pulmonary fibrosis model was established in the C57BL/6J mice. The therapeutic treatment regimen began after the induction of pulmonary fibrosis. The preventive treatment regimen began on the first day of bleomycin administration. Animals were randomly divided into the sham, model, Nintedanib, and ZSP1603 treatment groups. Haematoxylin and eosin (H&E) and Masson's trichrome staining were performed to evaluate pulmonary injury, inflammation, and fibrosis. Cell Counting Kit-8 (CCK-8) assay and Western blot were used to investigate the effects and mechanisms of ZSP1603 on the proliferation of primary human pulmonary fibroblasts (pHPFs). The messenger ribonucleic acid (mRNA) expression of transforming growth factor (TGF)-ß1, tissue inhibitor of metalloproteinase 1 (TIMP-1), and collagen 1A1 (COL1A1) in pHPFs was detected by quantitative Real Time-Polymerase Chain Reaction (PCR). RESULTS: ZSP1603 inhibited the proliferation of pHPFs in vitro by blocking the platelet-derived growth factor receptor-ß (PDGF-Rß) and extracellular signal-regulated kinase (ERK) signalling pathway. ZSP1603 also inhibited the differentiation of pHPFs by reducing the expression of TGF-ß1, TIMP-1, and COL1A1. ZSP1603 significantly attenuated pulmonary injury, inflammation, and fibrosis in vivo in four independent animal studies of pulmonary fibrosis. CONCLUSIONS: ZSP1603 is an effective anti-fibrotic compound with clear mechanisms.
Subject(s)
Antifibrinolytic Agents/therapeutic use , Disease Models, Animal , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pulmonary Fibrosis/drug therapy , Animals , Antifibrinolytic Agents/chemistry , Antifibrinolytic Agents/pharmacology , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pulmonary Fibrosis/enzymology , Pulmonary Fibrosis/pathology , Rats , Rats, Sprague-DawleyABSTRACT
The pharmacokinetics of diazepam (3 mg.kg-1, i.v.) in rabbits was studied after pretreatment with rifampin (RFP, 100 mg.kg-1.d-1 x 4), isoniazid (INH, 50 mg.kg-1.d-1 x 4) and RFP + INH. The results showed that RFP significantly increased cytochrome P-450 content, but the T 1/2 and AUC of diazepam were significantly decreased. The plasma clearance (CL) was increased in the RFP group. In the INH group the T 1/2 and AUC of diazepam were significantly increased and the CL was significantly decreased. However, cytochrome P-450 content and the pharmacokinetic parameters of diazepam were not changed in the RFP + INH group. Our results indicate that RFP induces the activity of hepatic microsomal enzymes and increases the metabolism of diazepam, INH inhibits the activity of hepatic microsomal enzymes and decreases the metabolism of diazepam in rabbits.
