| First Author | Gao R | Year | 2015 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 308 |
| Issue | 8 | Pages | L847-53 |
| PubMed ID | 25659903 | Mgi Jnum | J:232272 |
| Mgi Id | MGI:5776429 | Doi | 10.1152/ajplung.00274.2014 |
| Citation | Gao R, et al. (2015) Sirt1 restrains lung inflammasome activation in a murine model of sepsis. Am J Physiol Lung Cell Mol Physiol 308(8):L847-53 |
| abstractText | 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-kappaB, 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-1beta 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. |
