Dataset Information

The Anti-Fibrotic Effects of CG-745, an HDAC Inhibitor, in Bleomycin and PHMG-Induced Mouse Models.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with poor prognosis and progression to lung fibrosis related to genetic factors as well as environmental factors. In fact, it was discovered that in South Korea many people who used humidifier disinfectants containing polyhexamethylene guanidine (PHMG), died of lung fibrosis. Currently two anti-fibrotic drugs, pirfenidone and nintedanib, have been approved by the FDA, but unfortunately, do not cure the disease. Since the histone deacetylase (HDAC) activity is associated with progression to chronic diseases and with fibrotic phenomena in the kidney, heart and lung tissues, we investigated the anti-fibrotic effects of CG-745, an HDAC inhibitor. After lung fibrosis was induced in two animal models by bleomycin and PHMG instillation, the regulation of fibrosis and epithelial mesenchymal transition (EMT)-related markers was assessed. CG-745 exhibited potent prevention of collagen production, inflammatory cell accumulation, and cytokines release in both models. Additionally, N-cadherin and vimentin expression were lowered significantly by the treatment of CG-745. The anti-fibrotic effects of CG-745 proven by the EMT regulation may suggest a potential therapeutic effect of CG-745 on lung fibrosis.

SUBMITTER: Kim YS

PROVIDER: S-EPMC6696140 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The Anti-Fibrotic Effects of CG-745, an HDAC Inhibitor, in Bleomycin and PHMG-Induced Mouse Models.

Kim Young-Suk YS Cha Hyunju H Kim Hyo-Jin HJ Cho Joong-Myung JM Kim Hak-Ryul HR

Molecules (Basel, Switzerland) 20190731 15

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with poor prognosis and progression to lung fibrosis related to genetic factors as well as environmental factors. In fact, it was discovered that in South Korea many people who used humidifier disinfectants containing polyhexamethylene guanidine (PHMG), died of lung fibrosis. Currently two anti-fibrotic drugs, pirfenidone and nintedanib, have been approved by the FDA, but unfortunately, do not cure the disease. Since the histone deacety ...[more]

PMID: 31370295

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Project description:ObjectiveSecretoglobin (SCGB) 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM)-induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known.MethodsMice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods.ResultsBLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGFβ were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs.ConclusionThe role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2-null mice to BLM-induced pulmonary fibrosis.

Dataset Information

The Anti-Fibrotic Effects of CG-745, an HDAC Inhibitor, in Bleomycin and PHMG-Induced Mouse Models.

Publications

The Anti-Fibrotic Effects of CG-745, an HDAC Inhibitor, in Bleomycin and PHMG-Induced Mouse Models.

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