Activation of SIRT1 ameliorates LPS-induced lung injury in mice via decreasing endothelial tight junction permeability

Abstract

The integrity of the endothelial barrier is a determinant of the prognosis of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, we investigated whether and how Sirtuin 1 (SIRT1) maintained the vascular integrity during ALI. An experimental model of ALI was established in mice through intratracheal administration of LPS (10 mg/kg). LPS stimulation significantly increased the pulmonary permeability and decreased the expression of SIRT1 and tight junction proteins (TJs), including occludin, claudin-5, tight junction protein 1 and tight junction protein 2. Morphological studies showed that LPS induced obvious lung injury with inflammatory cell infiltration in the interstitial and alveolar space, hemorrhage, edema, and the thickened alveolar wall compared to the control mice. Intratracheal administration of the selective SIRT1 activator SRT1720 (6.25 mg/kg) significantly attenuated LPS-induced lung injury, lung hyper-permeability and increased TJs expression, whereas intratracheal administration of the selective SIRT1 inhibitor EX527 (6.25 mg/kg) aggravated LPS-induced ALI. Similar protective effects of SIRT1 on pulmonary cellular permeability were observed in primary human pulmonary microvascular endothelial cells treated with LPS (2 mg/mL) in vitro. We further demonstrated that the RhoA/ROCK signaling pathway was activated in SIRT1 regulation of tight junction permeability. The RhoA/ROCK inhibitor Y-27632 (10 μM) increased the expression of TJs and reversed LPS- or EX527-induced hyper-permeability. In conclusion, SIRT1 ameliorates LPS-induced lung injury via decreasing endothelial tight junction permeability, possibly via RhoA/ROCK signaling pathway. This finding may contribute to the development of new therapeutic approaches for lung injury.

Sirtuin 1 inhibits lipopolysaccharide-induced inflammation in chronic myelogenous leukemia k562 cells through interacting with the Toll-like receptor 4-nuclear factor κ B-reactive oxygen species signaling axis

“…Data are expressed as mean ± standard deviation. *P < 0.05 relative to the control + pCDNA group; # P < 0.05 relative to the LPS + pCDNA group downregulation in endothelial cells [21][22][23]. Furthermore, one study has demonstrated that LPS treatment decreases SIRT1 stability by inactivating JNK during the inflammatory responses of LPS-activated macrophages [24].…”

Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

“…Several studies have reported a role of SIRT1 in the protection against metabolic damage linked to obesity [ 33 , 34 , 36 ] and its benefit in alleviating LPS-induced metabolic dysfunction in lung [ 68 ], keratinocyte [ 69 ], or endothelial cells [ 70 ]. Our study provides previously unknown evidence of the protection against the decline in IR and AKT phosphorylation in BAT from LPS-injected SIRT1 Tg+ mice in line with the recently reported alleviation of fatty liver by SIRT1 activation [ 71 ].…”

Protectin Conjugates in Tissue Regeneration 1 Restores Lipopolysaccharide-Induced Pulmonary Endothelial Glycocalyx Loss via ALX/SIRT1/NF-kappa B Axis

“…It has been demonstrated that SIRT1 is a negative regulator of in ammation [24] . Previous studies reported that endothelial glycocalyx decreased in vivo and in vitro with a defect in SIRT1 deacetylase activity [25,26] .…”