Inheritance, Smoking Spawn Mysterious And Deadly Lung Disease

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

The findingssuggest that the disease in its many forms may stem from a commongenetic defect that prevents the proper repair of lung injury, theresearchers report in a forthcoming issue of American Journal ofRespiratory and Critical Care Medicine.

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

After examining111 families including multiple people with IIP, the Duke team foundevidence that a single abnormal copy of an as-yet-unidentified gene canspark the disease. However, the condition appears to strike only thoseprone to the condition who also experience some secondary lung injury.Smokers, in particular, had over three times the risk of developing thecondition than members of affected families who had never smoked, foundthe researchers.

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

The findings may lead to thediscovery of the genes responsible for IIP and new directions fortreating the incurable disease, Steele said. The results alsounderscore the need for those with a family history of the disease tostop smoking, he added.

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

Lastyear, a treatment that had shown early promise in alleviating symptomsand preventing the advance of pulmonary fibrosis failed to stall thedisorder's progression in 162 patients.

"Therapies that have beentested in clinical trials have not proved effective," Steele said. "Weneed to identify new directions.

"We've known for some time thatidiopathic 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 ofthe disease."

The researchers evaluated 111 families in which atleast two relatives had been diagnosed with IIP. The sample included309 people with the disease and 360 unaffected relatives.

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

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

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

"This suggests that while certain genetic factorsplace an individual at risk of developing pulmonary fibrosis, lunginjury substantially contributes to the disease. That finding raisesthe possibility that an intrinsic inability to repair injured lungtissue may be the fundamental biologic defect that ultimately resultsin fibrosis and lung collapse."

Almost half of the familiesexamined demonstrated symptom variability, with some families includingmembers with different disease subtypes, they reported. That led theresearchers to conclude that different subtypes of IIP -- previouslyconsidered separate diseases -- may in fact stem from common geneticfactors and common mechanisms.

Collaborators on the studyincluded Marcy Speer, Aretha Herron, Susan Slifer, Lauranell Burch,Momen Wahidi, Thomas Sporn, and Page McAdams and David Schwartz, all ofDuke, and researchers at Vanderbilt University School of Medicine,National Jewish Medical and Research Center and University of ColoradoHealth Sciences Center. The researchers conducted the study using aprogram supported by the National Center for Research Resources.