Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene a4 hydrolase and blocking LTB4 biosynthesis

Wei-qiang LU; Jing-yuan WANG; Xue YAO; Ping OUYANG; Ning-ning DONG; Dang WU; Jin HUANG

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Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene a4 hydrolase and blocking LTB4 biosynthesis

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OBJECTIVE Leukotriene B4 (LTB4) biosynthesis and subsequently neutrophilic inflam?mation may provide a potential strategy for the treatment of acute lung injury (ALI) or idiopathic pulmonary fibrosis (IPF). To provide a potential strategy for the treatment of ALI or IPF, we identified potent inhibi?tors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of LTB4. METHODS In this study, we identified two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA) and its analogue 4-(dimethylamino)-N-〔7-(hydroxyamino)-7-oxoheptyl〕benzamide (M344), as effective inhibitors of LTA4H using enzymatic assay, thermofluor assay, and X- ray crystallographic investigation. We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay. A murine experimental model of ALI was induced by lipopolysaccharide(LPS) inhalation. Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA. We next examined mRNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using qRT- PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA. We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin (BLM)-induced IPF model. RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H, signif?icantly decrease LTB4 levels in neutrophil, and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. CONCLUSION Collectively, SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.

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《中国药理学与毒理学杂志》 |2017年第10期|972|共1页
作者
Wei-qiang LU; Jing-yuan WANG; Xue YAO; Ping OUYANG; Ning-ning DONG; Dang WU; Jin HUANG;
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作者单位

Shanghai Key Laboratory of New Drug Design;

School of Pharmacy;

East China University of Science and Technology;

Shanghai 200237;

China;

Shanghai Key Laboratory of Regulatory Biology;

The Institute of Biomedical Sciences and School of Life Sciences;

East China Normal University;

Shanghai 200241;

China;

Shanghai Key Laboratory of New Drug Design;

School of Pharmacy;

East China University of Science and Technology;

Shanghai 200237;

China;

Shanghai Key Laboratory of New Drug Design;

School of Pharmacy;

East China University of Science and Technology;

Shanghai 200237;

China;

Shanghai Key Laboratory of New Drug Design;

School of Pharmacy;

East China University of Science and Technology;

Shanghai 200237;

China;

Shanghai Key Laboratory of New Drug Design;

School of Pharmacy;

East China University of Science and Technology;

Shanghai 200237;

China;

Shanghai Key Laboratory of New Drug Design;

School of Pharmacy;

East China University of Science and Technology;

Shanghai 200237;

China;

Shanghai Key Laboratory of New Drug Design;

School of Pharmacy;

East China University of Science and Technology;

Shanghai 200237;

China;

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Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene a4 hydrolase and blocking LTB4 biosynthesis

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