Gao Rong, Ma Zhongsen, Hu Yuxin, Chen Jiao, Shetty Sreerama, Fu Jian
Center for Research on Environmental Disease, University of Kentucky, Lexington, Kentucky; The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China;
The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China;
Am J Physiol Lung Cell Mol Physiol. 2015 Apr 15;308(8):L847-53. doi: 10.1152/ajplung.00274.2014. Epub 2015 Feb 6.
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.
过度炎症是脓毒症期间器官损伤的主要原因。老年人极易发生脓毒症诱导的器官损伤。衰老过程中Sirt1表达降低。在本研究中，我们调查了组蛋白脱乙酰酶Sirt1在由盲肠结扎和穿刺（CLP）诱导的小鼠脓毒症模型中控制炎症反应的作用。我们检查了CLP后诱导型Sirt1基因敲除（Sirt1(-/-)）小鼠和野生型同窝小鼠（Sirt1(+/+)）的肺炎症信号。我们的结果表明，Sirt1缺乏导致严重的肺炎症损伤。为了进一步研究Sirt1在脓毒症中调节肺炎症反应的分子机制，我们进行了一系列实验来评估CLP后的肺炎症小体激活。我们检测到CLP后Sirt1(-/-)小鼠的肺炎症信号增加，包括NF-κB、信号转导和转录激活因子3以及ERK1/2激活。此外，CLP后Sirt1(-/-)小鼠的炎症小体活性增加，表现为IL-1β和caspase-7裂解及激活增加。Sirt1(-/-)小鼠中炎症小体激活加剧与肺促炎介质的产生增加有关，包括ICAM-1和高迁移率族蛋白B1，以及紧密连接和黏附连接的进一步破坏，表现为肺claudin-1和血管内皮钙黏蛋白表达显著降低，这与基质金属蛋白酶9表达上调有关。总之，我们的结果表明，Sirt1通过控制炎症小体激活途径抑制脓毒症期间的急性肺炎症。
