Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation
Sepsis remains a major cause of mortality and morbidity in intensive care units. Dexmedetomidine (DEX) has been reported to attenuate cecal ligation perforation (CLP)-stimulated acute lung injury (ALI) by downregulating high-mobility group protein 1 (HMGB1) and receptor for advanced glycation end pr...
Guardado en:
Autores principales: | , , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
Taylor & Francis Group
2021
|
Materias: | |
Acceso en línea: | https://doaj.org/article/6ac67c1f8d094b458a6af15a2e0a6b7e |
Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
id |
oai:doaj.org-article:6ac67c1f8d094b458a6af15a2e0a6b7e |
---|---|
record_format |
dspace |
spelling |
oai:doaj.org-article:6ac67c1f8d094b458a6af15a2e0a6b7e2021-11-11T14:23:43ZProtective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation2165-59792165-598710.1080/21655979.2021.2000723https://doaj.org/article/6ac67c1f8d094b458a6af15a2e0a6b7e2021-11-01T00:00:00Zhttp://dx.doi.org/10.1080/21655979.2021.2000723https://doaj.org/toc/2165-5979https://doaj.org/toc/2165-5987Sepsis remains a major cause of mortality and morbidity in intensive care units. Dexmedetomidine (DEX) has been reported to attenuate cecal ligation perforation (CLP)-stimulated acute lung injury (ALI) by downregulating high-mobility group protein 1 (HMGB1) and receptor for advanced glycation end products (RAGE) expressions. This study aimed to further investigate the specific mechanisms of RAGE and its potential-related mechanisms of DEX on ALI models in vitro and in vivo. The in vitro and in vivo ALI models were established by lipopolysaccharide (LPS) treatment in MLE-12 cells and CLP in mice, respectively. The effect of DEX on pathological alteration was investigated by HE staining. Thereafter, the myeloperoxidase (MPO) activity and inflammatory cytokine levels were respectively detected to assess the lung injury of mice using commercial kits. The expression levels of HMGB1, RAGE, nuclear factor-κB (NF-κB), and pyroptosis-related molecules were detected by quantitative real-time polymerase chain reaction and western blot. HE staining showed that lung injury, increased inflammatory cell infiltration, and lung permeability was found in the ALI mice, and DEX treatment significantly attenuated lung tissue damage induced by CLP. The MPO activity and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1β, and NLR family pyrin domain-containing 3) levels were also significantly reduced after DEX treatment compared with those in the ALI mice. Moreover, DEX activated the HMGB1/RAGE/NF-κB pathway and upregulated the pyroptosis-related proteins. However, the protective DEX effect was impaired by RAGE overexpression in ALI mice and MLE-12 cells. In addition, DEX treatment significantly suppressed HMGB1 translocation from the nucleus region to the cytoplasm, and this effect was reversed by RAGE overexpression. These findings suggested that DEX may be a useful ALI treatment, and the protective effects on ALI mice may be through the inhibition of the HMGB1/RAGE/NF-κB pathway and cell pyroptosis.Huaqin SunHongyi HuXiaoping XuMingsun FangTao TaoZhehao LiangTaylor & Francis Grouparticledexmedetomidineacute lung injuryhmgb1ragenf-κbpyroptosisBiotechnologyTP248.13-248.65ENBioengineered, Vol 0, Iss 0 (2021) |
institution |
DOAJ |
collection |
DOAJ |
language |
EN |
topic |
dexmedetomidine acute lung injury hmgb1 rage nf-κb pyroptosis Biotechnology TP248.13-248.65 |
spellingShingle |
dexmedetomidine acute lung injury hmgb1 rage nf-κb pyroptosis Biotechnology TP248.13-248.65 Huaqin Sun Hongyi Hu Xiaoping Xu Mingsun Fang Tao Tao Zhehao Liang Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation |
description |
Sepsis remains a major cause of mortality and morbidity in intensive care units. Dexmedetomidine (DEX) has been reported to attenuate cecal ligation perforation (CLP)-stimulated acute lung injury (ALI) by downregulating high-mobility group protein 1 (HMGB1) and receptor for advanced glycation end products (RAGE) expressions. This study aimed to further investigate the specific mechanisms of RAGE and its potential-related mechanisms of DEX on ALI models in vitro and in vivo. The in vitro and in vivo ALI models were established by lipopolysaccharide (LPS) treatment in MLE-12 cells and CLP in mice, respectively. The effect of DEX on pathological alteration was investigated by HE staining. Thereafter, the myeloperoxidase (MPO) activity and inflammatory cytokine levels were respectively detected to assess the lung injury of mice using commercial kits. The expression levels of HMGB1, RAGE, nuclear factor-κB (NF-κB), and pyroptosis-related molecules were detected by quantitative real-time polymerase chain reaction and western blot. HE staining showed that lung injury, increased inflammatory cell infiltration, and lung permeability was found in the ALI mice, and DEX treatment significantly attenuated lung tissue damage induced by CLP. The MPO activity and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1β, and NLR family pyrin domain-containing 3) levels were also significantly reduced after DEX treatment compared with those in the ALI mice. Moreover, DEX activated the HMGB1/RAGE/NF-κB pathway and upregulated the pyroptosis-related proteins. However, the protective DEX effect was impaired by RAGE overexpression in ALI mice and MLE-12 cells. In addition, DEX treatment significantly suppressed HMGB1 translocation from the nucleus region to the cytoplasm, and this effect was reversed by RAGE overexpression. These findings suggested that DEX may be a useful ALI treatment, and the protective effects on ALI mice may be through the inhibition of the HMGB1/RAGE/NF-κB pathway and cell pyroptosis. |
format |
article |
author |
Huaqin Sun Hongyi Hu Xiaoping Xu Mingsun Fang Tao Tao Zhehao Liang |
author_facet |
Huaqin Sun Hongyi Hu Xiaoping Xu Mingsun Fang Tao Tao Zhehao Liang |
author_sort |
Huaqin Sun |
title |
Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation |
title_short |
Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation |
title_full |
Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation |
title_fullStr |
Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation |
title_full_unstemmed |
Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation |
title_sort |
protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through hmgb1/rage pathway regulation and pyroptosis activation |
publisher |
Taylor & Francis Group |
publishDate |
2021 |
url |
https://doaj.org/article/6ac67c1f8d094b458a6af15a2e0a6b7e |
work_keys_str_mv |
AT huaqinsun protectiveeffectofdexmedetomidineincecalligationperforationinducedacutelunginjurythroughhmgb1ragepathwayregulationandpyroptosisactivation AT hongyihu protectiveeffectofdexmedetomidineincecalligationperforationinducedacutelunginjurythroughhmgb1ragepathwayregulationandpyroptosisactivation AT xiaopingxu protectiveeffectofdexmedetomidineincecalligationperforationinducedacutelunginjurythroughhmgb1ragepathwayregulationandpyroptosisactivation AT mingsunfang protectiveeffectofdexmedetomidineincecalligationperforationinducedacutelunginjurythroughhmgb1ragepathwayregulationandpyroptosisactivation AT taotao protectiveeffectofdexmedetomidineincecalligationperforationinducedacutelunginjurythroughhmgb1ragepathwayregulationandpyroptosisactivation AT zhehaoliang protectiveeffectofdexmedetomidineincecalligationperforationinducedacutelunginjurythroughhmgb1ragepathwayregulationandpyroptosisactivation |
_version_ |
1718438942873747456 |