Histone Deacetylase 7 Exacerbates the Inflammatory Response by Inhibiting Nur77 Expression to Induce Lesions of Acute Respiratory Distress Syndrome.

Abstract

Acute respiratory distress syndrome (ARDS) is an acute respiratory disease. Nuclear receptor 77 (Nur77) shows anti-ARDS activity. Histone deacetylase 7 (HDAC7) knockdown suppresses inflammatory response in acute lung injury, but its role in ARDS remains unclear. ARDS mouse models were established by cecum ligation and puncture. Assessment of lung function indexes, HE staining, immunohistochemistry, ChIP, and proteomics were performed. In vitro, human non-small cell lung cancer A549 cells were treated with lipopolysaccharide (LPS), and qRT-PCR, CCK8, and flow cytometry were conducted. Silencing of HDAC7 and Nur77, ELISA, and Western blot analysis were performed both in vivo and in vitro. ARDS mice exhibited lower pH, partial pressure of oxygen (PaO), arterial oxygen saturation, PaO/fraction of inspiration oxygen, and higher partial pressure of carbon dioxide (PaCO) and protein levels in bronchoalveolar lavage fluid. In ARDS mice, HDAC7 knockdown inhibited inflammatory infiltration, reduced tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and HDAC7 levels, and enhanced zonula occludens-1, Occludin, Claudin-1, and Nur77 expression, which reversed by Nur77 knockdown. Moreover, the crucial differentially expressed proteins included Igkv14-126, IGLC2, Prss3b, Ccdc50, and Chchd7. HDAC7 bound to Nur77 promoter. Notably, Ccdc50 over-expression enhanced the mitigating effect of Nur77 over-expression on inflammatory response and impaired barrier function aggravated by HDAC7 over-expression in ARDS mice. In LPS-treated cells, HDAC7 knockdown reduced TNF-α, IL-1β, IL-6 levels, and apoptosis, and increased cell viability, which also reversed by Nur77 knockdown. HDAC7 may inhibit Nur77 to exacerbate ARDS by upregulating Igkv14-126, IGLC2, Prss3b, and downregulating Ccdc50 and Chchd7, offering new targets for ARDS treatment.