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Lipidomics revealed idiopathic pulmonary fibrosis-induced hepatic lipid disorders corrected with treatment of baicalin in a murine model.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. The current standard treatment with glucocorticoids (GCs) leads to many adverse effects, and its effectiveness is questionable. Thus, it is critical and urgent to find new drug(s) for treatment of IPF. Baicalin (BAI) is an attractive candidate for this purpose. Herein, utilizing shotgun lipidomics, we revealed that IPF could lead to a lipid disorder of the liver in an animal model induced by bleomycin and confirmed through histopathological studies of the lung. Lipidomics further demonstrated that this disorder could virtually be corrected after treatment with BAI, but not with dexamethasone (DEX) (a commonly used GC for treatment of IPF). In contrast, the treatment with DEX did not improve IPF but led to tremendous alterations in hepatic lipidomes and accumulation of fat in the liver, which was very different from the lipid disorder induced by IPF. The underpinning mechanisms of the IPF-resultant lipid disorder and DEX-induced lipotoxicity as revealed by shotgun lipidomics were extensively discussed. Taken together, the current study showed that IPF could lead to hepatic lipid disorder, which can be treated with BAI, and demonstrated that lipidomics could be a powerful tool for drug screening.

SUBMITTER: Hu C

PROVIDER: S-EPMC4406959 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Lipidomics revealed idiopathic pulmonary fibrosis-induced hepatic lipid disorders corrected with treatment of baicalin in a murine model.

Hu Changfeng C Wang Yiqi Y Fan Yongsheng Y Li Haichang H Wang Chunyan C Zhang Jida J Zhang Shuijuan S Han Xianlin X Wen Chengping C

The AAPS journal 20150312 3

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. The current standard treatment with glucocorticoids (GCs) leads to many adverse effects, and its effectiveness is questionable. Thus, it is critical and urgent to find new drug(s) for treatment of IPF. Baicalin (BAI) is an attractive candidate for this purpose. Herein, utilizing shotgun lipidomics, we revealed that IPF could lead to a lipid disorder of the liver in an animal model induced by bleomycin and confirmed through histopatholo ...[more]

PMID: 25762447

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease without a cure and new drug strategies are urgently needed. Differences in behavior between diseased and healthy cells are well known and drug response can be different between cells isolated from IPF patients and controls. The macrolide Azithromycin (AZT) has anti-inflammatory and immunomodulatory properties. Recently anti-fibrotic effects have been described. However, the anti-fibrotic effects on primary IPF-fibroblasts (FB) directly compared to control-FB are unknown. We hypothesized that IPF-FB react differently to AZT in terms of anti-fibrotic effects.MethodsPrimary normal human lung and IPF-FB were exposed to TGF-β (5 ng/ml), Azithromycin (50 μM) alone or in combination prior to gene expression analysis. Pro-collagen Iα1 secretion was assessed by ELISA and protein expression by western blot (αSMA, Fibronectin, ATP6V1B2, LC3 AB (II/I), p62, Bcl-xL). Microarray analysis was performed to screen involved genes and pathways after Azithromycin treatment in control-FB. Apoptosis and intraluminal lysosomal pH were analyzed by flow cytometry.ResultsAZT significantly reduced collagen secretion in TGF-β treated IPF-FB compared to TGF-β treatment alone, but not in control-FB. Pro-fibrotic gene expression was similarly reduced after AZT treatment in IPF and control-FB. P62 and LC3II/I western blot revealed impaired autophagic flux after AZT in both control and IPF-FB with significant increase of LC3II/I after AZT in control and IPF-FB, indicating enhanced autophagy inhibition. Early apoptosis was significantly higher in TGF-β treated IPF-FB compared to controls after AZT. Microarray analysis of control-FB treated with AZT revealed impaired lysosomal pathways. The ATPase and lysosomal pH regulator ATP6V0D2 was significantly less increased after additional AZT in IPF-FB compared to controls. Lysosomal function was impaired in both IPF and control FB, but pH was significantly more increased in TGF-β treated IPF-FB.ConclusionWe report different treatment responses after AZT with enhanced anti-fibrotic and pro-apoptotic effects in IPF compared to control-FB. Possibly impaired lysosomal function contributes towards these effects. In summary, different baseline cell phenotype and behavior of IPF and control cells contribute to enhanced anti-fibrotic and pro-apoptotic effects in IPF-FB after AZT treatment and strengthen its role as a new potential anti-fibrotic compound, that should further be evaluated in clinical studies.

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Lipidomics revealed idiopathic pulmonary fibrosis-induced hepatic lipid disorders corrected with treatment of baicalin in a murine model.

Publications

Lipidomics revealed idiopathic pulmonary fibrosis-induced hepatic lipid disorders corrected with treatment of baicalin in a murine model.

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