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.