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

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

(1.Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;2.Shanghai Key Laboratory of Regulatory Biology,The Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai 200241,China）

T1-30

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 LU1,2,Jing-yuan WANG1,Xue YAO1,Ping OUYANG1,Ning-ning DONG1,Dang WU1,Jin HUANG1

(1.Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;2.Shanghai Key Laboratory of Regulatory Biology,The Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai 200241,China）

OBJECTIVELeukotriene 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.METHODSIn 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.RESULTSThe 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.CONCLUSIONCollectively,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.

acute lung injury;idiopathic pulmonary fibrosis;histone deacetylase inhibitors;alleviate neutrophilic inflammation;leukotriene A4 hydrolase;leukotriene B4

The project supported by National Natural Science Foundation of China(81402482,91313303)

Jin HUANG,Tel:(021)64253681,E-mail：huangjin@ecust.edu.cn