Resveratrol attenuates microvascular inflammation in sepsis via SIRT-1-Induced modulation of adhesion molecules in ob/ob mice

Objective: Obesity, a sirtuin-1 (SIRT-1) -deficient state, increases morbidity and resource utilization in critically ill patients. SIRT-1 deficiency increases microvascular inflammation and mortality in early sepsis. The objective of the study was to study the effect of resveratrol (RSV), a SIRT-1 activator, on microvascular inflammation in obese septic mice.

Methods: ob/ob and C57Bl/6 (WT) mice were pretreated with RSV versus dimethyl sulfoxide (DMSO) (vehicle) prior to cecal ligation and puncture (sepsis). We studied (1) leukocyte/platelet adhesion, (2) E-Selectin, ICAM-1, and SIRT-1 expression in small intestine, and (3) 7-day survival. A group of RSV-treated mice received SIRT-1 inhibitor (EX-527) with sepsis induction, and leukocyte/platelet adhesion and E-Selectin/ICAM-1 expression were studied. We treated endothelial (HUVEC) cells with RSV to study E-Selectin/ICAM-1 and p65-acetylation (AC-p65) in response to lipopolysaccharide (LPS).

Results: RSV treatment decreased leukocyte/platelet adhesion and E-Selectin/ICAM-1 expression with increased SIRT-1 expression in septic ob/ob and WT mice, decreased E-Selectin/ICAM-1 expression via increased SIRT-1 expression, and decreased AC-p65 expression in HUVEC. EX-527 abolished RSV-induced attenuation of microvascular inflammation in ob/ob septic mice. Finally, ob/ob mice in the sepsis+RSV group had significantly increased 7-day survival versus the sepsis+vehicle group.

Conclusions: RSV increases SIRT-1 expression in ob/ob septic mice to reduce microvascular inflammation and improves survival.