Fndings could lead to a treatment for idiopathic interstitial pneumonia

An incurable, deadly lung disorder, "idiopathic interstitial pneumonia" (IIP), whose causes were mysterious arises from a combination of a genetic predisposition and damage due to inhaled chemicals, notably from cigarette smoking, Duke University Medical Center researchers have found.

They said their findings could lead to a treatment, but more immediately represent a warning to people with the genetic predisposition not to smoke.

The findings suggest that the disease in its many forms may stem from a common genetic defect that prevents the proper repair of lung injury, the researchers report in a forthcoming issue of American Journal of Respiratory and Critical Care Medicine.

IIP is a form of pulmonary fibrosis, a group of diseases characterized by scarring of the lungs. The condition, for which no treatment exists, typically kills its victims within five years. While the prevalence of the disease is unknown according the National Institutes of Health, estimates indicate the numbers are rising with as many as 15,000 new cases of idiopathic pulmonary fibrosis -- a form of the disease having unknown causes -- diagnosed yearly in the U.S.

After examining 111 families including multiple people with IIP, the Duke team found evidence that a single abnormal copy of an as-yet-unidentified gene can spark the disease. However, the condition appears to strike only those prone to the condition who also experience some secondary lung injury. Smokers, in particular, had over three times the risk of developing the condition than members of affected families who had never smoked, found the researchers.

"This is a terrible disease whose causes have remained unclear and for which no treatment exists," said Mark Steele, M.D. "Our findings provide convincing support for a genetic basis. But it's more than that -- development of the disease takes a second hit. One such hit is cigarette smoking."

The findings may lead to the discovery of the genes responsible for IIP and new directions for treating the incurable disease, Steele said. The results also underscore the need for those with a family history of the disease to stop smoking, he added.

Pulmonary fibrosis is an inflammatory disease that results in scarring, or fibrosis, of the lungs. Over time, the fibrosis can progress such that the lungs can no longer deliver oxygen to the body's tissues. Although physicians often prescribe a combination of anti-inflammatory and immunosuppressive therapies, the only clearly effective treatment is lung transplantation.

Last year, a treatment that had shown early promise in alleviating symptoms and preventing the advance of pulmonary fibrosis failed to stall the disorder's progression in 162 patients.

"Therapies that have been tested in clinical trials have not proved effective," Steele said. "We need to identify new directions.

"We've known for some time that idiopathic interstitial pneumonia can run in families," he added. "Currently there is no adequate animal model to study the disease. Therefore, we can use genetics to dissect the causes and mechanism of the disease."

The researchers evaluated 111 families in which at least two relatives had been diagnosed with IIP. The sample included 309 people with the disease and 360 unaffected relatives.

The disease disproportionately affected siblings and also showed a pattern of transmission from parent to child in many families, the team found. Older people, males and those who had smoked cigarettes also showed a greater risk of developing IIP, they reported.

The team found that cigarette smoking had an important independent effect on disease risk. Those with a history of smoking had a 3.6-fold greater chance of getting the disease, they found.

"While the importance of cigarette smoking in the progression of idiopathic pulmonary fibrosis remains controversial, case control studies among patients with the disease support the current findings in the familial form of the disease as well as sporadic forms, and consistently indicate that cigarette smoking is a risk factor for the development of the disease," Steele said.

"This suggests that while certain genetic factors place an individual at risk of developing pulmonary fibrosis, lung injury substantially contributes to the disease. That finding raises the possibility that an intrinsic inability to repair injured lung tissue may be the fundamental biologic defect that ultimately results in fibrosis and lung collapse."

Almost half of the families examined demonstrated symptom variability, with some families including members with different disease subtypes, they reported. That led the researchers to conclude that different subtypes of IIP -- previously considered separate diseases -- may in fact stem from common genetic factors and common mechanisms.