title: Use of a soluble epoxide hydrolase inhibitor in smoke-induced chronic obstructive pulmonary disease.
abstract: Tobacco smoke-induced chronic obstructive pulmonary disease (COPD) is a prolonged inflammatory condition of the lungs characterized by progressive and largely irreversible airflow limitation attributable to a number of pathologic mechanisms, including bronchitis, bronchiolitis, emphysema, mucus plugging, pulmonary hypertension, and small-airway obstruction. Soluble epoxide hydrolase inhibitors (sEHIs) demonstrated anti-inflammatory properties in a rat model after acute exposure to tobacco smoke. We compared the efficacy of sEHI t-TUCB (trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) and the phosphodiesterase-4 (PDE4) inhibitor Rolipram (Biomol International, Enzo Life Sciences, Farmingdale, NY) to reduce lung injury and inflammation after subacute exposure to tobacco smoke over a period of 4 weeks. Pulmonary physiology, bronchoalveolar lavage, cytokine production, and histopathology were analyzed to determine the efficacy of sEHI and Rolipram to ameliorate tobacco smoke-induced inflammation and injury in the spontaneously hypertensive rat. Both t-TUCB and Rolipram inhibited neutrophil elevation in bronchoalveolar lavage. sEHI t-TUCB suppressed IFN-γ, 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 inhibited the production of airway mucus. Both t-TUCB and Rolipram inhibited vascular remodeling-related growth factor. These findings suggest that sEHI t-TUCB has therapeutic potential for treating COPD by improving lung function and attenuating the lung inflammation and emphysematous changes caused by tobacco smoke. To the best of our knowledge, this is the first report to demonstrate that sEHI exerts significant protective effects after repeated, subacute tobacco smoke-induced lung injury in a rat model of COPD.
authors.affiliation: Center for Health and the Environment, University of California at Davis, Old Davis Road, Davis, CA 95616, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Dale
authors.initials: D
authors.lastname: Uyeminami
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Kent E
authors.initials: KE
authors.lastname: Pinkerton
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D051381:Rats; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use; D012906:Smoke / Q000009:adverse effects*
chemical_list: C572961:4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D016207:Cytokines; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D012906:Smoke; D004851:Epoxide Hydrolases; D020889:Rolipram