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: Akihisa Matsuda, Weng-Lang Yang, Asha Jacob, Monowar Aziz, Shingo Matsuo, Takeshi Matsutani, Eiji Uchida, Ping Wang
• Journal: Annals of surgery (Ann Surg) Vol. 259 Issue 5 Pg. 1007-17 (May 2014) ISSN: 1528-1140 [Electronic] United States
• PMID: 24169192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• FK886
• Morpholines
• Neurokinin-1 Receptor Antagonists
• Piperazines
• Nicotinamide Phosphoribosyltransferase
• Protein Serine-Threonine Kinases
• NF-kappa B kinase

Topics

• Acute Lung Injury (etiology, pathology, prevention & control)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Survival
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Immunohistochemistry
• In Situ Nick-End Labeling
• Injections, Intraperitoneal
• Male
• Mice
• Mice, Inbred C57BL
• Morpholines (administration & dosage)
• Neurokinin-1 Receptor Antagonists
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, metabolism)
• Piperazines (administration & dosage)
• Protein Serine-Threonine Kinases (metabolism)
• Reperfusion Injury (complications, metabolism, pathology)