title: FK866, a visfatin inhibitor, protects against acute lung injury after intestinal ischemia-reperfusion in mice via NF-κB pathway.
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.
authors.affiliation: *Department of Surgery, Hofstra North Shore-LIJ School of Medicine and Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY †Department of Surgery, Nippon Medical School, Tokyo, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Matsuda
authors.forename: Weng-Lang
authors.initials: WL
authors.lastname: Yang
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Monowar
authors.initials: M
authors.lastname: Aziz
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsuo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsutani
authors.forename: Eiji
authors.initials: E
authors.lastname: Uchida
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000008:administration & dosage*; D064729:Neurokinin-1 Receptor Antagonists; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D016207:Cytokines; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D054409:Nicotinamide Phosphoribosyltransferase; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C581895:FK886