Sirtuin-2 Regulates Sepsis Inflammation in ob-ob MiceReportar como inadecuado




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Objective

Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early-hyper-inflammatory to late-hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins SIRTs modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis.

Methods

Sepsis was induced using cecal ligation and puncture CLP in ob-ob mice. We measured microvascular inflammation in response to lipopolysaccharide-normal saline re-stimulation as a -second-hit- marker of immune function at different time points to track phases of sepsis in ob-ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 RAW cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese DIO mice with sepsis.

Results

We observed that the ob-ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob-ob mice during hypo-inflammation. SIRT-2 inhibition in ob-ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65.

Conclusion

SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis.



Autor: Xianfeng Wang, Nancy L. Buechler, Ayana Martin, Jonathan Wells, Barbara Yoza, Charles E. McCall, Vidula Vachharajani

Fuente: http://plos.srce.hr/



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