The anti-inflammatory effects of soluble epoxide hydrolase inhibitors are independent of leukocyte recruitment.

Abstract

Excess leukocyte recruitment to the lung plays a central role in the development or exacerbation of several lung inflammatory diseases including chronic obstructive pulmonary disease. Epoxyeicosatrienoic acids (EETs) are cytochrome P-450 metabolites of arachidonic acid reported to have multiple biological functions, including blocking of leukocyte recruitment to inflamed endothelium in cell culture through reduction of adhesion molecule expression. Inhibition of the EET regulatory enzyme, soluble epoxide hydrolase (sEH) also has been reported to have anti-inflammatory effects in vivo including reduced leukocyte recruitment to the lung. We tested the hypothesis that the in vivo anti-inflammatory effects of sEH inhibitors act through the same mechanisms as the in vitro anti-inflammatory effects of EETs in a rat model of acute inflammation following exposure to tobacco smoke. Contrary to previously published data, we found that sEH inhibition did not reduce tobacco smoke-induced leukocyte recruitment to the lung. Furthermore, sEH inhibition did not reduce tobacco smoke-induced adhesion molecule expression in the lung vasculature. Similarly, concentrations of EETs greater than or equal to their reported effective dose did not reduce TNFα induced expression of the adhesion molecules. These results suggest that the anti-inflammatory effects of sEH inhibitors are independent of leukocyte recruitment and EETs do not reduce the adhesion molecules responsible for leukocyte recruitment in vitro. This demonstrates that the widely held belief that sEH inhibition prevents leukocyte recruitment via EET prevention of adhesion molecule expression is not consistently reproducible.

• Authors: Benjamin B Davis, Jun-Yan Liu, Daniel J Tancredi, Lei Wang, Scott I Simon, Bruce D Hammock, Kent E Pinkerton
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 410 Issue 3 Pg. 494-500 (Jul 08 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21683067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cell Adhesion Molecules
• Enzyme Inhibitors
• Epoxide Hydrolases

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Bronchi (blood supply)
• Cell Adhesion Molecules (antagonists & inhibitors, metabolism)
• Cell Movement (drug effects)
• Enzyme Inhibitors (pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors)
• Leukocytes (drug effects, enzymology, physiology)
• Lung (drug effects, pathology, physiopathology)
• Male
• Pneumonia (chemically induced, pathology, physiopathology)
• Rats
• Rats, Inbred SHR
• Smoking (adverse effects)
• Tobacco (adverse effects)