Use of a Soluble Epoxide Hydrolase Inhibitor in Smoke-Induced Chronic Obstructive Pulmonary Disease

Use of a Soluble Epoxide Hydrolase Inhibitor in Smoke-Induced Chronic Obstructive Pulmonary Disease Lei Wang1, Jun Yang2, Lei Guo1, Dale Uyeminami1, Hua Dong2, Bruce D. Hammock2, and Kent E. Pinkerton1 1Center for Health and the Environment, and 2Department of Entomology and Cancer Center, University of California at Davis Medical Center, University of California at Davis, Davis, California Tobacco smoke-induced chronic obstructive pulmonary disease (COPD) is a prolonged inflammatory condition of the lungs character- CLINICAL RELEVANCE ized by progressive and largely irreversible airflow limitation attributable to a number of pathologic mechanisms, including bronchitis, Inflammation is provoked by inflammatory leukocytes and bronchiolitis, emphysema, mucus plugging, pulmonary hypertension, mediators thought to play a critical role in the development and small-airway obstruction. Soluble epoxide hydrolase inhibitors of chronic obstructive pulmonary disease (COPD). Soluble (sEHIs) demonstrated anti-inflammatory properties in a rat model epoxide hydrolase inhibitors were shown to possess thera- after acute exposure to tobacco smoke. We compared the efficacy peutic efficacy in the treatment and management of acute of sEHI t-TUCB (trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]- inflammatory disease. It is not known whether soluble ep- cyclohexyloxy}-benzoic acid) and the phosphodiesterase-4 (PDE4) oxide hydrolase inhibitors could ameliorate the pulmonary inhibitor Rolipram (Biomol International, Enzo Life Sciences, Farm- inflammation induced by repeated, subacute exposure to ingdale, NY) to reduce lung injury and inflammation after subacute tobacco smoke. The efficacy of a potent soluble epoxide hy- exposure to tobacco smoke over a period of 4 weeks. Pulmonary drolase inhibitor, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)- physiology, bronchoalveolar lavage, cytokine production, and histo- ureido]-cyclohexyloxy}-benzoic acid, to partly ameliorate the pathology were analyzed to determine the efficacy of sEHI and Roli- impact of injury attributable to repeated exposure to tobacco pram to ameliorate tobacco smoke–induced inflammation and injury smoke suggests that the inhibition of soluble epoxide hydro- in the spontaneously hypertensive rat. Both t-TUCB and Rolipram in- lase could have high therapeutic potential for the treatment of hibited neutrophil elevation in bronchoalveolar lavage. sEHI t-TUCB COPD. suppressed IFN-g, while improving lung function by reducing tobacco smoke–induced total respiratory resistance and tissue damping (small- airway and peripheral tissue resistance). Increases in tobacco smoke– induced alveolar airspace size were attenuated by t-TUCB. Rolipram third leading cause of death by 2020 (1). COPD is characterized inhibited the production of airway mucus. Both t-TUCB and Rolipram by chronic airflow limitation, with progressive deterioration over inhibited vascular remodeling–related growth factor. These findings time and limited reversibility after bronchodilator therapy (2). suggest that sEHI t-TUCB has therapeutic potential for treating COPD The pathology of COPD is complex and heterogeneous, demon- by improving lung function and attenuating the lung inflammation strating inflammation, small-airway remodeling, the hypersecre- and emphysematous changes caused by tobacco smoke. To the best tion of mucus, and emphysema. The primary cause of COPD is of our knowledge, this is the first report to demonstrate that sEHI exerts tobacco smoke, which induces leukocyte activation, cytokine pro- significant protective effects after repeated, subacute tobacco smoke– duction, enhanced proinflammatory gene expression, increased induced lung injury in a rat model of COPD. reactive oxygen and nitrogen species production, and enhanced Keywords: experimental animal models; anti-inflammatory agents; biosynthesis of oxidized lipids (3–6). airway obstruction According to a commonly held belief, anti-inflammatory therapy for COPD may slow disease progression. Current COPD therapy mainly focuses on reducing symptoms and preventing Chronic obstructive pulmonary disease (COPD) is a major cause of exacerbation with short-acting and long-acting bronchodilators morbidity and mortality worldwide, and is expected to become the as monotherapy, or in combination with long-acting b2 agonist bronchodilators and inhaled corticosteroids (7). The failure of inhaled corticosteroid used alone or in combination with b2 agonists to reduce COPD inflammation has intensified the (Received in original form October 11, 2011 and in final form December 12, 2011) search for effective drugs for the disease (2, 8). Because COPD This work was supported by Tobacco-Related Disease Research Program grant is relatively insensitive to currently marketed drugs (9), it is 18XT-0154 and American Asthma Foundation grant 09-0269. B.D.H. is a George and Judy Marce Senior Fellow of the American Asthma Foundation. J.Y. was hoped that novel, anti-inflammatory agents will be found. supported by an Elizabeth Nash Memorial Fellowship from Cystic Fibrosis Re- Phosphodiesterase-4 (PDE4) inhibitors are the most advanced search, Inc. anti-inflammatory therapies currently used for the clinical man- L.W., J.Y., H.D., B.D.H., and K.E.P. designed and planned the research. L.W., J.Y., agement of COPD. The elevation of cellular cyclic adenosine L.G., and D.U. performed the study, data collection, and statistical analysis. L.W. monophosphate can lead to broad anti-inflammatory cellular drafted the manuscript. J.Y., B.D.H., and K.E.P. provided editing and critical re- effects, and PDE4 is the predominant PDE isoenzyme in most visions during the preparation of the manuscript. inflammatory cells thought to play a role in the pathogenesis of Correspondence and requests for reprints should be addressed to Kent E. Pinkerton, COPD (2). Despite reports of PDE4 inhibitor efficacy in Phase Ph.D., Center for Health and the Environment, University of California at Davis, Old III clinical trials and the recent approval of Roflumilast by the Davis Road, Davis, CA 95616. E-mail: [email protected] European Medicines Agency for the treatment of COPD (10), This article has an online supplement, which is accessible from this issue’s table of the class-specific side effects (e.g., nausea and diarrhea) of the contents at www.atsjournals.org high-dose administration of these drugs limit their therapeutic Am J Respir Cell Mol Biol Vol 46, Iss. 5, pp 614–622, May 2012 use (11, 12). Copyright ª 2012 by the American Thoracic Society Originally Published in Press as DOI: 10.1165/rcmb.2011-0359OC on December 22, 2011 Epoxyeicosatrienoic acids (EETs), products of the epoxyge- Internet address: www.atsjournals.org nation of arachidonic acid by cytochrome P450 monoxygenases, Wang, Yang, Guo, et al.: Soluble Epoxide Hydrolase Inhibitor and COPD 615 exert antiinflammatory effects (13). EETs are metabolized by cyclooxygenase (COX) and the b-oxidation pathway, but most EETs are converted to diols by soluble epoxide hydrolase (sEH) (14). The pharmacological inhibition of sEH increases plasma EET concentrations (15). A large number of studies reported the lower- ing of blood pressure in different models of systemic hypertension (16), the prevention of cardiac remodeling after aortic banding (17), and the suppression of inflammation elicited by bacterial LPS (18) with the inhibition of sEH. We previously demonstrated anti-inflammatory effects with the sEH inhibitor 12-(3-adamantane- 1-yl-ureido)-dodecanoic acid n-butyl ester after acute exposure to tobacco smoke in spontaneously hypertensive (SH) rats (19). In the Figure 1. Effects of trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]- present study, we characterize: (1) a model of tobacco smoke– cyclohexyloxy}-benzoic acid (t-TUCB) and Rolipram on tobacco smoke inducedCOPDinSHratstodemonstrate COPD-like lung inflam- (TS) exposure–induced weight loss in spontaneously hypertensive (SH) mation, airway obstruction, the hypersecretion of mucus, and rats. Body weight measurements were taken before and after smoke emphysematous changes; and (2) the efficacy of trans-4-{4-[3-(4- exposure each week. The weekly mean weights measured before trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t- smoke exposure each week are reported. The time course is presented TUCB), a newer generation of sEH inhibitor (sEHI), compared with for body weight changes of age-matched, non–TS-exposed animals as the prototypic PDE4 inhibitor Rolipram on the attenuation of to- controls (open circles), TS-exposed animals treated with vehicle (solid bacco smoke–induced lung injury in SH rats. We found that t-TUCB squares), TS-exposed animals treated with soluble epoxide hydrolase inhibitors (sEHI) t-TUCB (solid triangles), and TS-exposed animals trea- has therapeutic potential for treating COPD by reducing lung inflam- 6 mation and weight loss, improving lung function, and attenuating the ted with Rolipram (open diamonds). Data are expressed as means SEM for 4–8 animals/group. wk, weeks. *P , 0.05, TS-exposed groups emphysematous changes caused by exposure to tobacco smoke. y were significantly different from the control group. P , 0.05, treatment group with sEHI t-TUCB was significantly different from the TS MATERIALS AND METHODS vehicle group. Additional details on measurement methods are provided in the online supplement. compliance, and elastance of the whole respiratory system. Forced oscillation perturbation was consequently applied and resulted in cen- tral airway resistance, tissue damping, and tissue elastance. Animals

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