The Critical Role of the Histone Modification Enzyme Setdb2 in the Pathogenesis of Acute Respiratory Distress Syndrome

Abstract

Introduction: Acute respiratory distress syndrome (ARDS) is a severe hypoxemic respiratory failure with a high in-hospital mortality. However, the molecular mechanisms underlying ARDS remain unclear. Recent findings have indicated that the onset of severe inflammatory diseases, such as sepsis, is regulated by epigenetic changes. We investigated the role of epigenetic changes in ARDS pathogenesis using mouse models and human samples. Methods: Acute respiratory distress syndrome was induced in a mouse model (C57BL/6 mice, myeloid cell or vascular endothelial cell [VEC]-specific SET domain bifurcated 2 [Setdb2]-deficient mice [Setdb2 ff Lyz2 Cre+ or Setdb2 ff Tie2 Cre+ ], and Cre − littermates) by intratracheal administration of lipopolysaccharide (LPS). Analyses were performed at 6 and 72 h after LPS administration. Sera and lung autopsy specimens from ARDS patients were examined. Results: In the murine ARDS model, we observed high expression of the histone modification enzyme SET domain bifurcated 2 (Setdb2) in the lungs. In situ hybridization examination of the lungs revealed Setdb2 expression in macrophages and VECs. The histological score and albumin level of bronchoalveolar lavage fluid were significantly increased in Setdb2 ff Tie2 Cre+ mice following LPS administration compared with Setdb2 ff Tie2 Cremice, whereas there was no significant difference between the control and Setdb2 ff Lyz2 Cre+ mice. Apoptosis of VECs was enhanced in Setdb2 ff Tie2 Cre+ mice. Among the 84 apoptosis-related genes, the expression of TNF receptor superfamily member 10b (Tnfrsf10b) was significantly higher in Setdb2 ff Tie2 Cre+ mice than in control mice. Acute respiratory distress syndrome patients' serum showed higher SETDB2 levels than those of healthy volunteers. SETDB2 levels were negatively correlated with the partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen concentration ratio. Conclusion: Acute respiratory distress syndrome elevates Setdb2, apoptosis of VECs, and vascular permeability. Elevation of histone methyltransferase Setdb2 suggests the possibility to histone change and epigenetic modification. Thus, Setdb2 may be a novel therapeutic target for controlling the pathogenesis of ARDS.

A Disintegrin and Metalloproteinase with Thrombospondin Motifs 4 Regulates Pulmonary Vascular Hyperpermeability through Destruction of Glycocalyx in Acute Respiratory Distress Syndrome

“…Next, we investigated whether ADAMTS4 is induced in the ARDS mouse model. We previously established an ARDS mouse model by the direct inoculation of LPS intratracheally [10]. In the control group, an equal volume of PBS was inoculated.…”

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca2+ ENTRY REGULATED BY STIM1/ORAI1

“…Recent advancement in the study of endothelial cell damage has shown that further reducing endothelial shear stress caused by large volume resuscitation after hemorrhagic shock leads to persistent tissue hypoxia and increased microvascular endothelial permeability (6). Acute respiratory distress syndrome (ARDS) elevates SET domain bifurcated 2, apoptosis of vascular endothelial cells (VECs), and vascular permeability (7). More recently, some studies have found that endothelial glycocalyx damage occurs in numerous pathological conditions such as heatstroke and results in increased vascular permeability (8).…”