Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor.
Changes in the lungs due to smoking include inflammation, epithelial damage, and remodeling of the airways. Airway inflammation is likely to play a critical role in the genesis and progression of tobacco smoke-induced airway disease. Soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in inflammation. Epoxyeicosatrienoic acids (EETs) have demonstrated antiinflammatory properties, and hydrolysis of these epoxides by sEH is known to diminish this activity. To examine whether acute tobacco smoke-induced inflammation could be reduced by a sEH inhibitor, 12-(3-adamantane-1-yl-ureido)-dodecanoic acid n-butyl ester was given by daily s.c. injection to spontaneously hypertensive rats exposed to filtered air or tobacco smoke for a period of 3 days (6 h/day). Acute exposure to tobacco smoke significantly increased by 3.2-fold (P <0.05) the number of cells recovered by bronchoalveolar lavage. The sEH inhibitor significantly decreased total bronchoalveolar lavage cell number by 37% in tobacco smoke-exposed rats with significant reductions noted in neutrophils, alveolar macrophages, and lymphocytes. A combination of sEH inhibitor and EETs was more significant in its ability to further reduce tobacco smoke-induced inflammation compared with the sEH inhibitor alone. The sEH inhibitor led to a shift in some plasma epoxides and diols that are consistent with the hypothetical action of these compounds. We conclude that an sEH inhibitor, in the presence or absence of EETs, can attenuate, in part, inflammation associated with acute exposure to tobacco smoke.
Smith
Kevin R
KR
Center for Health and the Environment, University of California, Davis, CA 95616, USA.
Pinkerton
Kent E
KE
Watanabe
Takaho
T
Pedersen
Theresa L
TL
Ma
Seung Jin
SJ
Hammock
Bruce D
BD
D000818:Animals; D018893:Bronchoalveolar Lavage; D015777:Eicosanoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D019570:Inhalation Exposure; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D014026:Nicotiana
D015777:Eicosanoids; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D004851:Epoxide Hydrolases