Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor

Abstract

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 smokeinduced 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 h͞day). 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 smokeinduced 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. epoxyeicosatrienoic acids ͉ pulmonary ͉ antiinflammatory

Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase

“…In these studies, nbAUDA was effective in attenuating cisplatin-induced renal injury; the protective effect of AUDA was marginal and highly variable (data not shown). Although both AUDA and its butyl ester have been found to be effective in vivo in other systems (Smith et al 2005;Schmelzer et al 2005;Liu et al 2005;Inceoglu et al 2006;Schmelzer et al 2006;Xu et al 2006), it is not surprising that the free acid is less effective under conditions where it needs to be continually available to protect the kidney.…”

“…sEH inhibitors have been shown to normalize blood pressure in spontaneously hypertensive rats (Yu et al 2000) and in rats challenged with angiotensin (Imig et al 2002). Furthermore, the sEH inhibitors have been found to be strongly antiinflammatory in several in vivo bioassays (Smith et al 2005;Schmelzer et al 2005;Liu et al 2005;Inceoglu et al 2006;Schmelzer et al 2006;Xu et al 2006). Arachidonic acid epoxides [epoxyeicosatrienoic acids (EETs)] are endogenous regulators that influence inflammation (Node et al 1999) and blood pressure (Roman 2002) in the kidney; both inflammation and renal blood flow are critical mediators of cisplatin-mediated acute kidney injury (Jo et al 2005;Winston and Safirstein 1985).…”

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

“…Upon evaporation of the organic phase the residue was purified by flash chromatography. The mixture was characterized by LC-MS/MS as described (Smith et al, 2005). LPS was from Sigma-Aldrich (St. Louis, MO) and dissolved in sterile saline for administration.…”

Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

“…In an animal model, elevated plasma DiHOME concentrations are observed upon exposure to tobacco smoke. This effect can be largely blocked by administration of an sEH inhibitor (Smith et al 2005). The DiHOMEs exert a number of effects on mammalian cells including stimulating MCF-7 cell proliferation and acting as an endocrine disrupter (Markaverich et al 2005), modulating the sodium cation current in cardiac cells (Harrell and Stimers 2002), and increasing cellular oxidative stress (Viswanathan et al 2003).…”