May 10, 2002

Fibrosis genetic link found

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Fibrosis genetic link found

Investigators in the Center for Lung Research have identified the first genetic mutation associated with idiopathic pulmonary fibrosis (IPF) — a disease of unknown cause that gradually suffocates its victims. The findings, reported May 1 in the American Journal of Respiratory and Critical Care Medicine, suggest new treatment possibilities and research directions.

“We don’t know if this is going to be the mutation that causes IPF; time will tell,” said Dr. Alan Q. Thomas, clinical fellow in the division of Allergy, Pulmonary, and Critical Care Medicine. “It does provide a model for how this disease can occur, and it might open the door for other ideas about the pathophysiology of IPF.”

IPF is the most common of several lung diseases that fall under the broad category of idiopathic interstitial pneumonitis and are characterized by inflammation and damage of the connective tissue framework of the lungs. Scar tissue slowly envelops and strangles the tiny alveoli — the grape-like sacs where gas exchanges happens, leading to shortness of breath, coughing, and eventually death.

There is no effective treatment for IPF, which usually strikes individuals between the ages of 50 and 70 and kills within three to five years, Thomas said. To avert IPF’s death sentence, patients frequently require lung transplantation.

IPF strikes seemingly without rhyme or reason. Various studies have suggested that it results from an abnormal response to an environmental insult, perhaps a virus or other infectious agent, Thomas said. “Even wood dust has been implicated,” he added.

Although the causes of IPF are unknown, a genetic factor contributes to the disease in about two percent of cases, Thomas said. Over the last decade, Dr. James E. Loyd, professor of Medicine, has accumulated clinical data and DNA samples from families with at least two IPF-affected members. He and colleagues have a collection of data and samples from more than 75 families.

The current study probes the genetic basis for pulmonary fibrosis in a Canadian family with 14 affected members. The investigators decided to focus on the gene for surfactant protein-C, based on a recent report that a mutation in that gene was associated with two different forms of interstitial pneumonitis. They found that members of the Canadian family — adults affected with IPF and children affected with cellular nonspecific interstitial pneumonitis — had a mutation in the surfactant protein-C gene. It is the first genetic mutation associated with IPF.

Surfactant protein-C is one of the proteins that combines with phospholipid molecules to make surfactant — a detergent-like coating that prevents the lung’s air sacs from collapsing. A deficiency in another surfactant protein, surfactant protein-B, is the cause of infant respiratory distress syndrome.

The surfactant protein-C mutation identified by Thomas and colleagues hobbles the protein during its manufacture. As proteins are produced inside the cell, they fold into complex structures and are transported to their final destinations inside or outside the cell. The mutant surfactant protein-C molecules in the Canadian family are predicted to fold incorrectly and as a result, they get stuck and accumulate inside the cell.

These mutant molecules also contribute to cell injury and death, Thomas and colleagues demonstrated in cell culture studies.

“We’re very excited about the possibility that drugs that promote proper folding might be useful as a treatment for IPF,” Thomas said. “We are studying whether these drugs work to prevent cell injury in our cell model of this mutation.”

Protein misfolding has been associated with an increasing number of genetic diseases including cystic fibrosis, alpha1-antitrypsin deficiency, congenital nephrogenic diabetes insipidus, and hereditary blindness, Thomas said.

Thomas and colleagues are examining other families with IPF for mutations in the surfactant protein-C gene. And it is possible that defects in surfactant protein-C, perhaps associated with aging, could underlie sporadic IPF as well. “It would be very exciting if surfactant protein-C were implicated in the sporadic disease,” Thomas said.

The current research also casts doubt on a prevailing dogma in the field of pulmonary medicine that the various forms of idiopathic interstitial pneumonitis are distinct entities.

“Our study suggests this might not be true,” Thomas said. “We have one family, one genetic mutation, and two different subclasses of idiopathic interstitial pneumonitis.” Understanding the role of the gene mutation will shed light on the pathophysiology of these diseases, he said.

Thomas was awarded the Elliot V. Newman Prize at this year’s research forum for residents for his presentation on this research. He and Loyd were joined in the studies by Kirk Lane, John Phillips III, Melissa Prince, Cheryl Markin, Marcy Speer, David A. Schwartz, Radhika Gaddipati, Annis Marney, Joyce Johnson, Richard Roberts, Jonathan Haines, and Mildred Stahlman. The research was supported by the National Institutes of Health, the Vanderbilt Discovery Grant Program, and a gift from Jack Holter.