New study explains how asthma susceptibility gene causes breathing difficulties

The asthma susceptibility gene ADAM33 was discovered in 2002 and is associated both with early life origins of asthma and with impaired lung function. However, its biological role and its contribution to the way asthma develops have not been understood until now.

The Southampton study, led by Professors Donna Davies and Stephen Holgate, describes the biological function of the gene for the first time, providing new insight into the progression and development of asthma.

ADAM33 protein is usually tethered in the cell membrane, but in asthma this tether is broken. Since ADAM33 is an enzyme, Professor Davies and her team reasoned that the untethered or 'rogue' enzyme could attack proteins it should not normally encounter.

They discovered that the cells lining the inner surface of blood vessels become a target for ADAM33, causing the formation of new blood vessels in a process called angiogenesis. These blood vessels can carry more inflammatory cells into the airways, causing swelling of the airways and changes in airway structure (termed 'remodelling'), resulting in breathing difficulties. The research team also identified a potential mechanism that would link environmental exposure to production of the rogue form of ADAM33.

Professor Davies explains: "Human asthma is triggered by both environmental and genetic factors. Our discovery that this rogue form of ADAM33 promotes angiogenesis suggests that it causes airways 'remodelling' to facilitate inflammation and reduced lung function. In both children and adults, the development of new blood vessels is believed to be an important aspect in the development of asthma, with increased levels linked to the severity of the disease. Treatments which specifically target the ADAM33 enzyme may therefore be effective in modifying the natural history of the disease.

"However, the importance of angiogenesis in many physiological and pathological processes broadens the range of the diseases in which the enzyme could be implicated, the most obvious being cancer and atherosclerosis or thickening of the arteries."

According to the charity Asthma UK 5.2m people in the UK are currently receiving treatment for asthma, including 1.1m children, and there is a person with asthma in one in five households in the UK.

The research paper, The soluble form of ADAM33 promotes angiogenesis: implications for airway remodelling in asthma, will be published in the June 2008 issue of the Journal of Allergy and Clinical Immunology and is available online now at www.jacionline.org/inpress

Professor Davies' and Holgate's research was funded by the Medical Research Council and several research charities.