UC Davis probes smoke exposure’s role in development of COPD

Researchers find that COPD may be driven in part by the action of immune cells circulating in the blood entering into the tissues of the lungs, and this finding may identify a potential new target for directed drug therapy to counter the disease

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SACREMENTO, Calif.—Researchers at the University ofCalifornia, Davis are clearing the air about how smoking causes chronicobstructive pulmonary disease (COPD), one of the most common lung diseases andthe third deadliest disease in the United States.
In a study recently published in the Public Library of Science (PLoS), the researchers show that COPDappears to be partly driven by the action of immune cells circulating in theblood entering into the tissues of the lungs. According to their findings, thiskey process begins in the blood vessels around the large airways in the centerof the lung. According to Benjamin Davis, a researcher with the Center forHealth and the Environment and the study's lead author, the research alsoidentifies a potential new target for directed drug therapy to counter thedisease.
"Our findings have important implications for understandingthe etiology of COPD and suggest that pharmaceuticals designed to reduceleukocyte recruitment through the bronchial circulation may be a potentialtherapy to treat COPD," Davis and his colleagues wrote.
According to the UC Davis team, leukocytes recruited to thelung contribute to COPD pathology by releasing reactive oxygen metabolites andproteolytic enzymes. The location of leukocyte emigration into the lung inresponse to tobacco smoke is unknown. However, some evidence from smoke-inducedCOPD suggests that the bronchial blood vessels may play a role in leukocyterecruitment.
The scientists investigated where leukocytes enter the lungin the early stages of COPD in order to better understand their effect as acontributor to the development of the disease. Using a spontaneouslyhypertensive (SH) rat model of COPD to investigate the mechanism and locationof smoke-induced leukocyte recruitment to the lung, they simultaneouslyevaluated the parenchyma and airways for neutrophil accumulation, as well asincreases in the adhesion molecules and chemokines that cause leukocyterecruitment in the early stages of tobacco smoke-induced lung disease. 
"We found neutrophil accumulation and increased expressionof adhesion molecules and chemokines in the bronchial blood vessels thatcorrelated with the accumulation of leukocytes recovered from the lung," Daviswrote. "The expression of adhesion molecules and chemokines in other vascularbeds did not correlate with leukocytes recovered in bronchoalveolar lavagefluid (BALF). These data strongly suggest leukocytes are recruited in largemeasure through the bronchial circulation in response to tobacco smoke."
According to the UC Davis team, the study furtherestablishes the validity of repeated smoke exposure in the SH rat as a viablemodel of chronic obstructive lung disease by demonstrating similarities in themolecular mechanisms of leukocyte recruitment observed in human COPD.
"Repeated, intermittent exposure to tobacco smoke in SH ratscan serve as an excellent animal model of human chronic lung inflammatorydisease due to the fact SH rats possess many of the characteristics found inhuman COPD, including sustained recruitment of leukocytes to the lung withneutrophil infiltration of the bronchial wall, bronchial epithelial cellapoptosis, airway wall thickening, epithelial cell squamous metaplasia, gobletcell hypertrophy and mucous hypersecretion. Increases in inflammatorycytokines, oxidative stress, and protease activity have also been demonstrated,as well as airspace enlargement," they observed.
These inflammatory and histopathological patterns noted inthe SH rat over time further demonstrate the utility of this model forscreening possible pharmaceuticals to treat COPD, the researchers concluded.
"Our laboratory ... found the SH rat, derived from the normotensive Wistar Kyoto(WKY) rat, to be highly sensitive to tobacco smoke exposure," says Davis. "Mostrodents, including mice and many strains of rats, are not susceptible to tobacco smoke-induced lung inflammation. This makes studying theinflammatory component of COPD very difficult. Although there is noperfect animal model of COPD, the SH rat comes closest because whenexposed to tobacco smoke it has an enhanced and sustained inflammatoryresponse, epithelial injury, cellular airway transformation to squamousmetaplasia (due to chronic bronchitis) and hypersecretion of mucin from cells undergoing mucous metaplasia of the airways. These changes aresimilar to what are seen in the airways of human COPD patients." 
Davisand his colleagues are now investigating whether statin drugs may prevent thedevelopment of COPD in their model.
"There are many potential drug targets, such as any factor involved inleukocyte recruitment, from the initial signaling of IL-1 beta and TNFalpha, to downstream factors like chemokines, and all of theintracellular signaling in between," says Davis. "Many current medications and thoseunder investigation already target these areas. However, some failedmedicines have targeted these areas. We can now use the SH rat model ofCOPD to better ascertain why some drugs work and some do not toultimately design better pharmaceuticals. Because we now know whereleukocytes enter the lung, we can target that site or test whether adrug acting on the lung affects the various steps involved in recruiting leukocytes. We may find that drugs affecting one component of leukocyte recruitment are more effective then drugs affecting others."
The team is currently investigating the statin drug Simvastatin, and Davis notes, "We are notcurrently working with any company to test new drugs, but we are veryinterested in doing so." 
COPD often goes by two other names that are the main formsof the disease: chronic bronchitis, which involves a long-term cough withmucus, and emphysema, which involves destruction of the lungs over time.Smoking is the leading cause of COPD, but some people smoke for years and neverdevelop the disease. In rare cases, nonsmokers who lack a protein calledalpha-1 antitrypsin can develop emphysema. Patients diagnosed with COPD are atgreater risk for developing associated health conditions like arrhythmia, heartfailure, pneumonia, malnutrition and osteoporosis. 
According to the National Heart, Lung, and Blood Institute(NHLBI), more than 12 million people are currently diagnosed with COPD, and anadditional 12 million are estimated to have it, but not realize it. The diseaseclaims the lives of about 3 million Americans each year. COPD can causelong-term disability, and the economic burden of COPD in the United States in 2007was estimated at about $42.6 billion in healthcare costs and lost productivity.
Currently, there is no cure for COPD. Depending on diseaseseverity, treatments include the use of inhalers to open the airways, inhaledsteroids to reduce lung inflammation, anti-inflammatory medications or steroidsby mouth or through a vein and oxygen therapy.
The study, "Leukocytes are Recruited Through the BronchialCirculation to the Lung in a Spontaneously Hypertensive Rat Model of COPD," wasfunded by the National Center for Research Resources of the U.S. NationalInstitutes of Health and the Tobacco-Related Disease Research Program. Davis'co-authors include Yi-Hsin Shen, Vanessa Flores and Ryan P. Davis, all in theCenter for Health and the Environment, and Daniel J. Tancredi of the Departmentof Pediatrics in the UC Davis School of Medicine

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