Enzyme Inhibitor Reduces Lung Inflammation Caused by Tobacco Smoke

Kent E. Pinkerton, Ph.D. and Bruce D. Hammock, Ph.D.
University of California, Davis
R01ES11634, R37ES02710, P42ES04699, P30ES05707, and P01ES11269

Background: Cigarette smoking causes several pulmonary disorders including bronchitis, airway obstruction and emphysema. These conditions are collectively known as chronic obstructive pulmonary disease (COPD). About 20 million people in the United States suffer from COPD and it is the fourth leading cause of death. COPD is characterized by increased mucus secretion and airway inflammation. The disease is thought to be initiated by an inflammatory process induced by tobacco smoke, leading to cell injury, increased numbers of mucous cells, and sometimes cancer. Continued smoking may intensify and maintain the inflammatory processes. Treatment strategies for COPD generally include oxygen therapy, airway dilators such as ipratropium bromide and albuterol sulfate delivered through metered dose inhalers, and steroid treatment for inflammation control.

Advance: This team of investigators has been studying an enzyme called soluble epoxide hydrolase (sEH). This enzyme is concentrated in the smooth muscle tissue of the veins and arteries that carry blood between the heart and lungs. sEH decreases the anti-inflammatory activity of another group of compounds called the epoxyeicosatrienoic acids (EETs). Hoping to block the anti-inflammatory effects of sEH, the researchers injected rats with an sEH inhibitor. The laboratory rats used are a transgenic strain predisposed to high blood pressure and are an excellent model for examining the inflammatory process. The rats were exposed to tobacco smoke; some were given the sEH inhibitor and others were given the inhibitor along with EET implants. After three days of exposure, the rats that received the inhibitor experienced significantly less inflammation than control rats. Rats that were injected with the inhibitor along with receiving the EET implant had even less inflammation.

Implications: Since the rat and human forms of sHE are 90% the same, the researchers hope the inhibitor, with or without co-administration of EETs, will have similar effects in humans. These results could lead to improved therapies for treating COPD and inflammation in the lungs and potentially improve the lives of people living with COPD.

Citation: Smith KR, Pinkerton KE, Watanabe T, Pedersen TL, Ma SJ, Hammock BD. Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor. Proc Natl Acad Sci USA. 2005 Feb 8;102(6):2186-91.