Researchers at Washington University School of Medicine in St. Louis have defined a new type of immune response that is activated in patients with severe asthma and COPD (chronic obstructive pulmonary disease). Their discovery could dramatically improve diagnosis and treatment of patients with chronic inflammatory lung disease.
"We've cracked the first part of the molecular code that links a viral infection to the later development of chronic inflammatory diseases like asthma and COPD," says senior author Michael Holtzman, M.D., the Selma and Herman Seldin Professor of Medicine, director of the Division of Pulmonary and Critical Care Medicine and a pulmonary specialist at Barnes-Jewish Hospital. "With this information, we can more precisely diagnose and monitor these types of diseases and then better target our treatment to specific abnormalities. That's a big step forward from simply monitoring breathing status."
The findings, published online May 18, 2008, in Nature Medicine, promise a way to determine whether a patient's asthma or COPD is the result of a chronic immune response that can be turned on by a respiratory viral infection. Guided by these new findings, this type of immune response could be detected by monitoring specific types of inflammatory cells or molecules in the lung or potentially in the bloodstream, giving physicians a more precise approach to diagnosis and treatment of lung disease.
This type of testing could eventually tell physicians whether a patient's condition is mild, moderate or severe, as well as track the effectiveness of treatment. It could also lead to the development of new types of drugs that target the underlying cause of inflammatory lung disease.
"With our results, we can now work on developing more rational ways to diagnose and monitor lung conditions such as asthma and COPD," Holtzman says. "As it stands now, the diagnosis of chronic lung disease generally depends on clinical judgment and standardized tests of lung function, but we have little that tells us what's going on in the patient's lungs at the cellular and molecular level."
Asthma and COPD are both serious lung diseases that cause shortness of breath, wheezing, coughing and fatigue. In the United States, about 20 million people have been diagnosed with asthma and about 12 million with COPD, which includes emphysema and chronic bronchitis. Holtzman's research aims to find therapies for these disorders that modify the underlying causes of the disease instead of simply suppressing symptoms as most present-day treatments do.
In this study, Holtzman and colleagues found that a common type of viral infection of the lung can leave behind a persistent trace of the virus. This viral remnant likely becomes an ongoing stimulus for a chronic immune response, which could last for long periods, even a lifetime. This response causes the cells in the lung passages to overproduce mucus and become hyper-reactive to irritants.
The research team uncovered the details of this immune process by studying mice that are infected with a respiratory virus that is very close to the type of viruses that cause similar infections in humans. When the mice got over their infection, they were left with chronic airway disease characterized by mucus production and increased airway reactivity to an inhaled irritant.
A key molecular feature of this chronic disease was the production of a powerful natural inflammatory substance, interleukin-13 (IL-13). Investigating the source of IL-13, the researchers tracked down a previously undescribed type of immune pathway. This pathway is part of the immune system that is supposed to be activated for only short periods of time. However, the investigators found that the pathway can also be persistently activated after viral infection, likely due to the pathway's ability to respond to viral remnants.
Under these conditions, they also found that the pathway is set up to amplify its own activity. This combination of persistent activity and positive feedback leads to the long-term production of IL-13 as well as other substances that then cause continuous inflammation in the lung tissue and the development of chronic lung disease.