Breakthrough in Understanding of Hereditary Emphysema

Research illuminates cause of lung inflammation in emphysema and how augmentation therapy can improve quality of life in patients with this disease.

Research illuminates cause of lung inflammation in emphysema and how augmentation therapy can improve quality of life in patients with this disease.

Researchers from the Royal College of Surgeons in Ireland (RCSI) claim they have made “a breakthrough in understanding the mechanisms behind the most severe form of hereditary emphysema and how protein treatments can improve the condition.”

A news release from the RCSI says that until now, researchers had only an incomplete understanding of the cause of Alpha-1 Antitrypsin Deficiency (Alpha-1), an inherited condition that is the cause of the most severe form of hereditary emphysema. But with this new research, investigators now more fully understand the mechanisms behind the influx of neutrophils into the lungs that cause inflammation and chronic lung disease in patients with this condition.

The study “α-1 Antitrypsin Regulates Human Neutrophil Chemotaxis Induced by Soluble Immune Complexes and IL-8” was published in the December 2010 issue of the Journal of Clinical Investigation.

Summarizing their results, the authors wrote that their study “has found that [the alpha-1 antitrypsin protein; AAT] modulates the chemotactic response of CXCR1 signaling by binding [IL-8, a ligand for CXCR-1] and inhibiting receptor engagement. Additionally, AAT modulates neutrophil chemotaxis in response to [soluble immune complex; sIC] by inhibiting ADAM-17 activity, thereby decreasing release of FcγRIIIb from the neutrophil membrane. After augmentation therapy in ZZ-AATD individuals, increased serum levels of AAT function to bind IL-8— and FcγRIIIb-expressing neutrophils, thereby inhibiting ADAM-17, and in turn normalizing excessive AATD neutrophil chemotactic responses. Consequently, this study delineates a key anti-inflammatory role for AAT in neutrophil chemotaxis and supports the possibility of additional benefits of AAT augmentation therapy in AATD.

Senior author Gerry McElvaney, professor of medicine at RCSI, said this study is “the first to reveal the mechanisms by which a lack of the Alpha-1 protein causes an increase in white blood cells entering the lungs, leading to the development of lung disease. Our research also reveals how a treatment known as augmentation therapy, where the natural Alpha-1 protein is given intravenously, leads to a decrease in the white blood cells going into the lungs thereby decreasing inflammation. This research gives new hope for a better quality of life for sufferers of this chronic condition.”

McElvaney said that these results may also have important applications for the treatment of emphysema in smokers, due to the fact that the chemicals in cigarette smoke destroys alpha-1, leaving smokers deficient in this important lung-protecting protein.

According to the news release from RCSI, these findings are especially important in Ireland, where Alpha-1 Antitrypsin Deficiency is more common than in most other countries, with 1 in 2,000 people having severe alpha-1 deficiency and 1 in 24 people carrying the gene for the disease. It is reported that Alpha-1 is the second-most common fatal inherited lung condition in Ireland after cystic fibrosis, with more than 2,000 people in the country having the most severe form of the disease and up to 300,000 people having some form of Alpha-1.

John Walsh, president of the Alpha-1 Foundation, a US-based non-profit that is “dedicated to providing the leadership and resources that will result in increased research, improved health, worldwide detection, and a cure for Alpha-1,” said that “Typically Alpha-1 patients present with early onset emphysema somewhere between 35 and 45 years old. The impact on the individual who develops this disease is significant and, according to medical literature, the average lifespan of an Alpha-1 is 54 years. The research being carried out by Prof McElvaney and his team at RCSI Beaumont has really advanced the understanding of Alpha-1.”

Additional Resources

Alpha-1 Association

A patient-focused and patient-driven organization dedicated to identifying individuals affected by Alpha-1 and improving the quality of their lives through support, education, advocacy and to encourage participation in research.

Alpha-1 Antitrypsin Deficiency Genetics Home Reference

This guide to understanding the genetics of Alpha-1 was produced by the US National Library of Medicine and is intended to help patients and caregivers learn more about this disease.

National Organization for Rare Disorders

Alpha-1 Advocacy Alliance

Alpha-1 Research Registry