The Relationship Between Alpha-1 and COPD: Why Alpha-1 Matters to You Even If You Do Not Have It
In the fall of 2003, a distinguished scientific journal, the American Journal of Respiratory and
Critical Care Medicine, published a special supplement, Standards for the Diagnosis and
Management of Individuals with Alpha-1 Antitrypsin Deficiency. This landmark publication
aimed to do nothing less than change the way health professionals think about Alpha-1.

In probing Alpha-1s effects on the lung, researchers ask questions relevant to all COPD patients. They have difficulty breathing even on short walks. They wheeze or cough during the mildest exertion.
And they may number as many as 32 million in the U.S. They are people with chronic obstructive
pulmonary disease (COPD), a broad term that includes emphysema, chronic bronchitis, and other
obstruction in the lungs. Not all COPD sufferers are Alphas. But in adults, Alpha-1 often manifests itself
first as COPD. The Alpha-1 community is an excellent study group for COPD for a variety of reasons. Alpha-1 is easily diagnosed, sufferers are often younger and have fewer co-morbidities (other health problems
contributing to illness) than other pulmonary diseases, and Alpha-1 has a rapid progression. Thats why
the connection between Alpha-1 research and COPD research seems natural. In learning more precisely
how Alpha-1 Antitrypsin (AAT) deficiency attacks the lungs, scientists also learn more about COPD.







What Are Researchers Looking For?
What role does AAT play in lung inflammation? Inflammation is a hot topic in Alpha-1 research, if
youll pardon that choice of words, says Dr. Bruce Trapnell of the University of Cincinnati School
Medicine, the Foundations scientific director. For decades, scientists have blamed a protease-antiprotease
imbalance for Alpha-1-related lung inflammation. Too little protective antiprotease (AAT) allows the
bodys infection-fighting proteases to attack lung tissue itself. But some researchers wonder, Is it that
simple? Is something else at worksomething that might inactivate AAT? Alpha-1 researchers
investigating the anti-inflammatory role of AAT may also shed light on other forms of COPD.

What role do proteases and antiproteases play in tissue injury? Since agents in cigarette smoke are
capable of rapidly inactivating the antiprotease activity of even normal alpha-1 antitrypsin, some have
suggested that all of COPD may be due to a deficiency of this important protein. The deficiency is
genetic in those with Alpha-1 but in individuals with non-Alpha-1 COPD, the deficiency is a functional
deficiency caused by the action of cigarette smoke, as well as other environmental agents, on the alpha-1
antitrypsin protein. Thus research on Alpha-1 has much broader application to COPD in general. Science is still looking for answers about the exact mechanism of COPD in general and Alpha-1-related lung disease in particular. With its resources and expertise, however, the Alpha-1 Foundation has contributed to taking the first stepsasking the right questions. What role does abnormal AAT play? Maybe this protease-antiprotease imbalance has nothing to do
with inflammation at all. People with the Z gene not only produce low levels of AAT; the AAT that
they do produce is abnormal. According to conventional medical wisdom, expression of this abnormal
AAT primarily causes liver disease; lung disease is a secondary effect. But recent research indicates that
abnormal AAT itself causes inflammation in the lung. Scientists would like to know why and how.

How significant is lung inflammation in the presence of infection? When you get pneumonia, for
example, you get a ton of neutrophils in the lung to kill bacteria, says Trapnell. There so many, the lung
looks like cheese. In non-Alphas with pneumonia, AAT protects the lung tissue from these massive
armies of neutrophils. But in Alphas (who have limited AAT protection at best), the neutrophil armies
may exacerbate (make even worse) a pre-existing, low-level inflammation. In other words, Alphas may
suffer a spectrum of lung damage, from a low-level inflammation in the absence of infection to severe
inflammation during a bout of pneumonia. Research is exploring this spectrum further and gauging its
significance.

Many thanks to these people who are at the forefront of Alpha-1 research: Alan Barker, MD, Clinical Resource Centers Working
Group Chair, Oregon Health & Science University // James C. Hogg, MD, Alpha-1 DNA and Tissue Bank Committee Chair,
University of British Columbia // Robert Sandhaus, Alpha-1 Foundation Clinical Director, University of Colorado Health Sciences
Center // Robert Senior, MD, Alpha-1 Educational Materials Working Group Chair, Washington University School of Medicine //
Edwin K. Silverman, MD, PhD, Epidemiology Working Group Chair, Harvard University // Gordon L. Snider, Alpha-1 Foundation
Board of Directors Member, Boston University School of Medicine and VA Boston Healthcare System James K. Stoller, MD,
MSODA, MASAC Chair, Cleveland Clinic Foundation // Charlie Strange, MD, MASAC Vice-Chair, Medical University of South
Carolina // James M. Stocks, MD, Alpha-1 Research Registry Advisory Committee Chair, University of Texas Health Center, Tyler
// Bruce Trapnell, MD, Grants Advisory Committee Chair, Childrens Hospital & Medical Center, OH // Mark Yarborough, PhD,
Ethical, Legal, and Social Issues Working Group Chair, University of Colorado Health Sciences Ctr.

Summarized and printed by Jane M. Martin with the permission of the Alpha-1 Foundation originally as part of the Breathing
Better, Living Well newsletter, October, 2003. www.breathingbetterlivingwell.com