FK866, a Visfatin Inhibitor, Protects Against Acute Lung Injury After Intestinal Ischemia-Reperfusion in Mice via NF-.BPathway

Objective: To determine whether administration of FK866, a competitive inhibitor of visfatin, attenuates acute lung injury induced by intestinal ischemia-reperfusion (I/R). Background: Acute lung injury, a frequent complication of intestinal I/R, is an inflammatory disorder of the lung, which is characterized by an overproduction of proinflammatory cytokines and increased permeability of the alveolar-capillary barrier, resulting in multiple organ dysfunction. Therefore, the development of novel and effective therapies for intestinal I/R is critical for the improvement of patient outcome. Visfatin, a 54-kDa secretory protein, is known as a proinflammatory cytokine and plays a deleterious role in inflammatory diseases. Methods: Male C57BL/6J mice were subjected to intestinal I/R induced by occlusion of the superior mesenteric artery for 90 minutes, followed by reperfusion. During reperfusion period, mice were treated with vehicle or FK866 (10 mg/kg of body weight) by an intraperitoneal injection. The levels of visfatin, proinflammatory mediators, and other markers were assessed 4 hours after reperfusion. In addition, survival study was conducted in intestinal I/R mice with or without FK866 treatment. Results: Plasma and lung visfatin protein levels were significantly increased after intestinal I/R. FK866 treatment significantly attenuated intestinal and lung injury by inhibiting proinflammatory cytokine production, cellular apoptosis, and NF-B activation, hence improving survival rate. In vitro studies showed that macrophages treated with lipopolysaccharides upregulated visfatin expression, whereas FK866 inhibited proinflammatory cytokine production via modulation of the NF-B pathway. Conclusions: Collectively, these findings implicate FK866 as a novel therapeutic compound for intestinal I/R-induced attenuates acute lung injury via modulation of innate immune functions.