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Scientists unlock secret behind cause of chronic lung disease

September 04, 2002

Australian researchers have discovered a vital clue to the causes of the many chronic and incurable lung diseases such as Chronic Obstructive Pulmonary Disorders (COPD), emphysema and asthma.

These diseases are major international healthcare burdens. The World Health Organisation estimates that COPD alone will become the world's third biggest killer by 2010. Until now, nobody knew what caused these diseases and there is still no cure.

Using mice, Dr. Matthias Ernst at the Ludwig Institute for Cancer Research in Melbourne who lead the national research effort, found the clue in an enzyme called Hck that plays a role in activating cells called macrophages that form an important part of the immune system in the lung.

By altering the enzyme slightly, Dr. Ernst and a University of Melbourne team discovered the macrophages went crazy and the mice went on to develop progressive lung disease.

"Now that we understand the mechanism we can start developing effective treatments," says University of Melbourne, Associate Professor Gary Anderson, who worked with Dr. Ernst's team.

The research is published in the latest edition of the prestigious Journal of Experimental Medicine and is a collaborative research effort between the Ludwig Institute for Cancer Research, the University of Melbourne, The Walter and Eliza Hall Institute, the Peter MacCallum Cancer Institute, The Institute for Child Health Research in Perth and the Cooperative Research Centre for Chronic Inflammatory Disease.

Previous research in the USA has dismissed Hck as largely redundant in the control of macrophage activity.

"Because of the USA research, nobody in the world suspected that Hck could be linked to serious lung disease. Our results show otherwise," says Anderson.

Macrophages will devour and destroy foreign bodies entering the lung tissue. In serious lung diseases, however, these macrophages become overactive triggering a cascade of events that destroy the lung and lead to an often slow and distressing death.

The Hck enzyme is normally locked in an inactive state. In the presence of foreign bodies or disease, the Hck enzyme unlocks and becomes active. The active molecule then signals the macrophage to start defending the lung against disease.

The Ludwig team made a change to one amino acid in the Hck enzyme of mice that forced the enzyme into a permanently active state. Anderson and his team at the University of Melbourne then watched to see what happened.

They found the permanently active macrophages triggered the disease process that mimics what is found in humans suffering from the range of COPDs including asthma and emphysema.

"The lining of the airways began to change and accumulate huge amounts of mucus. Elastic fibres built up the around the airways, leading to fibrosis, a condition that restricts the airways, reduces their elasticity and causing scarring of the airways. Over time other enzymes released by the macrophages started to eat away the lung," says Anderson.

"These symptoms eventually lead to respiratory failure and death, the same as what happens in humans," he says.

"The disease process also made a small number of the mice susceptible to lung tumours. Human patients with COPD are also known to be more susceptible to lung cancers.

"Finding Hck's lock and how to control it opens the way to effective drug treatment for COPD.

"We are still unsure if the mechanism seen in mice is the same one working in humans, but all the symptoms are the same and it is highly likely the mechanism is similar. We propose that careful and tight control of the activity of the Hck enzyme will be a critical determinant in preventing the destruction of lung tissue and other organs in those with COPD."

While it is early days and any drug treatment will be eight to ten years away, the precedent for drugs that can target similar molecules like Hck has already been set with successful cancer drugs currently on the market that work to block the activity of similar enzymes in the same way envisaged for the drugs that could treat COPD.

The research is now focusing on doing the biochemistry to ensure that the same mechanism is working in humans.

The team is also analysing the genome of people with COPD to see if there is any genetic variance. The work is part of an international effort to find genes linked to COPD.

"If we can find genetic variations, we can develop screening tests and warn susceptible people to limit their exposure to the lifestyle factors that could exacerbate onset of the disease, for example smoking," says Drs. Ernst and Anderson.
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University of Melbourne

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