title: (Z)-5-(4-Methoxybenzylidene)thiazolidine-2,4-dione, a novel readily available and orally active glitazone, attenuates the bleomycin-induced pulmonary fibrosis in vivo.
abstract: Idiopathic pulmonary fibrosis is regarded as a lethal chronic disease accompanied with excessive collagen disposition. In the early stage, monocyte chemotactic protein-1 (MCP-1) plays a crucial role in the process. Our previously screening with a vitro assay through inhibition of chemotaxis of RAW264.7 cells stimulated by MCP-1 proved that several analogues of thiazolidinediones, especially (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (SKLB010), had potency of protecting acute liver injury in vivo without obvious toxicity. The present study aimed to investigate the preventive effect of SKLB010 in bleomycin-induced pulmonary fibrosis and further explore the underlying mechanisms. Bleomycin (BLM) was injected intratracheally at a single dose of 5 U kg(-1) for pulmonary fibrosis induction. SKLB010 (25, 50 mg/kg/d) was respectively administrated by gavages 1 d prior to BLM administration and continued to the end of the study (for 4 weeks). Our results demonstrated that SKLB010 diminished the increase of macrophage, neutrophil and lymphocyte counts as well as the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in bronchoalveolar lavage fluid on day 14 (p<0.05). Moreover, oral gavages of SKLB010 also ameliorated histological changes and significantly suppressed collagen deposition on day 28. The treatment with SKLB010 exerted approximately 34.6% the hydroxyproline content reduction for 25 mg/kg dose and 56.7% reduction for 50 mg/kg dose in contrast to bleomycin-induced group (p<0.05). Meanwhile, SKLB010 inhibited the overexpression of tumor growth factor (TGF)-β1 and Smad3 in a dose-dependent manner. In conclusion, our results showed that SKLB010 could attenuate the BLM-induced pulmonary fibrosis in vivo and therefore be a promising anti-fibrogenic candidate.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, No. 1 Keyuan Road 4, Chengdu, Sichuan 610041, Chengdu, China.
authors.forename: Guangcheng
authors.initials: G
authors.lastname: Wang
authors.forename: Baowen
authors.initials: B
authors.lastname: Qi
authors.forename: Hao
authors.initials: H
authors.lastname: Zheng
authors.forename: Zhizhi
authors.initials: Z
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Ma
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Youfu
authors.initials: Y
authors.lastname: Luo
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006909:Hydroxyproline / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000517:prevention & control*; D051900:Smad3 Protein / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C546799:5-(4-methoxybenzylidene)thiazolidine-2,4-dione; D016207:Cytokines; D051900:Smad3 Protein; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D003094:Collagen; D006909:Hydroxyproline