FK866, a visfatin inhibitor, protects against acute lung injury after intestinal ischemia-reperfusion in mice via NF-κB pathway

Akihisa Matsuda, Weng Lang Yang, Asha Jacob, Monowar Aziz, Shingo Matsuo, Takeshi Matsutani, Eiji Uchida, Ping Wang

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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-κB 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-κB 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.

Original languageEnglish (US)
Pages (from-to)1007-1017
Number of pages11
JournalAnnals of surgery
Volume259
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • acute lung injury
  • FK866
  • inflammation
  • intestinal ischemia-reperfusion
  • visfatin

ASJC Scopus subject areas

  • Surgery

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