title: Sirt1 restrains lung inflammasome activation in a murine model of sepsis.
abstract: Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. In the present study, we investigated the role of Sirt1, a histone deacetylase, in controlling inflammatory responses in a murine sepsis model induced by cecal ligation and puncture (CLP). We examined lung inflammatory signaling in inducible Sirt1 knockout (Sirt1(-/-)) mice and wild-type littermates (Sirt1(+/+)) after CLP. Our results demonstrated that Sirt1 deficiency led to severe lung inflammatory injury. To further investigate molecular mechanisms of Sirt1 regulation of lung inflammatory responses in sepsis, we conducted a series of experiments to assess lung inflammasome activation after CLP. We detected increased lung inflammatory signaling including NF-κB, signal transducer and activator of transcription 3, and ERK1/2 activation in Sirt1(-/-) mice after CLP. Furthermore, inflammasome activity was increased in Sirt1(-/-) mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1(-/-) mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway.
authors: Center for Research on Environmental Disease, University of Kentucky, Lexington, Kentucky; The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China;
authors: Rong
authors: R
authors: Gao
authors: The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China;
authors: Zhongsen
authors: Z
authors: Ma
authors: Center for Research on Environmental Disease, University of Kentucky, Lexington, Kentucky; The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China;
authors: Yuxin
authors: Y
authors: Hu
authors: Center for Research on Environmental Disease, University of Kentucky, Lexington, Kentucky;
authors: Jiao
authors: J
authors: Chen
authors: Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors: Sreerama
authors: S
authors: Shetty
authors: Center for Research on Environmental Disease, University of Kentucky, Lexington, Kentucky; Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky; jian.fu@uky.edu.
authors: Jian
authors: J
authors: Fu
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008168:Lung / Q000201:enzymology* / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018345:Mice, Knockout; D018805:Sepsis / Q000201:enzymology / Q000276:immunology*; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C090509:Icam1 protein, mouse; D058847:Inflammasomes; D018799:Intercellular Adhesion Molecule-1; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: caspase; inflammation; interleukin-1; lung; transcription factor