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

Acute
lung injury (ALI) and idiopathic pulmonary fibrosis (IPF)
are both serious public health problems with high incidence and mortality
rate in adults, and with few drugs available for the efficient treatment
in clinic. In this study, we identified that two known histone deacetylase
(HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]­benzamide
(2), are effective inhibitors of Leukotriene A4 hydrolase
(LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4),
across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor
assay, and X-ray crystallographic investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic
inflammation in mouse models of ALI and IPF under a clinical safety
dose. Detailed mechanisms of down-regulation of proinflammatory cytokines
by 1 or 2 were determined in vivo. Collectively, 1 and 2 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.