Scientists from the University of California, Davis, have gained new insights into the initial phase of chronic obstructive pulmonary disease (COPD), which kills about 3 million people a year in the U.S.

"Our discovery," corresponding author Ben Davis told BioWorld Today, "helps us better understand how the disease begins, the pattern of the disease and how to design better COPD drugs."

Smoking, which is responsible for 80 percent of COPD cases, causes inflammatory white blood cells called leukocytes to flock to the lung, where they damage the lung by releasing several enzymes that contribute to the development of COPD.

In their study, which appeared in the March 21, 2012, issue of PLoS ONE, Davis and his team looked at how and where, exactly, those leukocytes get into the lung during the early stage of the disease. They found that "during the early stages of COPD development most leukocytes enter the lung from the blood vessels associated with the large airways centrally located within the lung, as opposed to entering the lung from the small vessels associated with the alveoli in the periphery of the lung."

Davis said the leukocytes "actually roll along the inside wall of blood vessels like little marbles rolling through a tube." They leave those vessels and enter the surrounding tissues at sites where the vessels contain adhesion molecules and chemokines.

In their experiments, Davis and his colleagues found that the level of leukocytes in the lung correlated with the level of adhesion molecules and chemokines in the large airways, but not other parts of the lung.

Davis and his team saw the main increase in leukocytes early after smoke exposure. The changes they observed in leukocyte recruitment were stronger at four weeks than 12 weeks. That timecourse, Davis said, is different from the progressive nature of COPD in humans and showed "an important limitation" of the animal model his team used, the so-called spontaneously hypertensive rat model of COPD.

"We can reproduce the damage to the lung seen in COPD patients," he said. "But we do not produce a progressive disease."

In patients, leukocyte recruitment leads to "a positive feedback loop, resulting in more leukocytes being recruited to the lung. That may be one reason COPD continues to progress even after a person quits smoking.

"In our model we do not mimic the increase in lymphocytes seen in COPD patients. There is some evidence that lymphocytes are needed to create the positive feedback loop needed to develop a progressive disease that persists even after quitting smoking. . . . This means our conclusions are most relevant to where the leukocyte-induced damage during the development of COPD begins, but not where the inflammatory positive feedback loops that produce a progressive disease begin."

Still, although the disease induced in his team's model is not progressive, Davis added that "after 12 weeks of smoke the amount of leukocytes and the proportion of neutrophil is more like what is seen in COPD patients." Davis said the work sheds light on potential drug targets that are involved in leukocyte recruitment, "from the initial signaling of IL-1 beta and TNF-alpha, to downstream factors like chemokines and all of the intracellular signaling in between."

The model will allow researchers to gain more insight into which of those potential drug targets will work. "Many current medications and those under investigation already target these areas. However, some failed medicines have targeted these areas. We can now use the spontaneously hypertensive rat model of COPD to better ascertain why some drugs work and some do not to ultimately design better pharmaceuticals."

He added that "because we now know where leukocytes enter the lung, we can easily test whether a drug is acting on the lung tissue and/or the leukocytes directly with this model. Additionally, we can test whether a drug 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 than drugs affecting others."

Cholesterol drug Zocor (simvastatin, Merck & Co. Inc.), appears to protect against COPD to some degree. Davis and his team want to use their model to try to understand the mechanism behind those protective effects.

They also hope to identify additional compounds that might interfere with leukocyte recruitment. For that, Davis said, "we are not currently working with any company to test new drugs, but we are very interested in doing so."