The study team includes, from left, William Lawson, M.D., Timothy Blackwell, M.D., and Dong-Sheng Cheng, M.D. (photo by Joe Howell)
Mutation suggests common lung disease pathway
A rare genetic mutation linked to a chronic lung disease has revealed clues about the disease’s origin.
Vanderbilt University Medical Center researchers have found that the mutation induces a type of cellular “stress” that is a common feature in nearly all cases of idiopathic pulmonary fibrosis (IPF).
The findings, reported recently in the Proceedings of the National Academy of Sciences, suggest that although IPF may have many different causes, the activation of this common stress pathway may provide new therapeutic targets for halting or reversing the condition.
IPF is a rare lung disease characterized by scarring (fibrosis) of the lung tissue, which interferes with the ability of the lungs to exchange oxygen and carbon dioxide.
Most individuals progress to respiratory failure, and the median survival — from time of diagnosis — is about two and a half years.
“In some ways, it’s a disease that’s as bad as aggressive cancers,” said William Lawson, M.D., assistant professor of Medicine and lead author on the study. “The problem is that we don’t know the cause and there are no effective treatments.”
A mutation in the gene encoding surfactant protein C (SFTPC) has been linked to familial forms of the disease (IPF sometimes runs in families) and causes the SFTPC protein to be improperly folded and unable to be processed by the cell. The immature form of the protein gets stuck and accumulates in the endoplasmic reticulum (or “ER,” a cellular compartment involved in protein folding) — a phenomenon called “ER stress.”
SFTPC mutations account for only about 1 percent of familial cases. But, Lawson noted, SFTPC mutations cause the same pattern of disease as seen in other IPF biopsies. “So could there be mechanisms at play in patients with SFTPC mutations that shed light on what happens in IPF patients in general?”
To answer that question, Lawson and colleagues, including Timothy Blackwell, M.D., and Dong-Sheng Cheng, M.D., developed an animal model in which the mutated form of SFTPC is expressed specifically in type 2 alveolar epithelial cells (AECs) — the cells that produce surfactant – in adult mice.
Mice that express the mutant form of SFTPC develop ER stress in type 2 AECs, but no fibrosis. However, the mutation sets up a condition that makes the cells more vulnerable to a second stressor (in this case, the chemotherapy drug bleomycin).
“If we gave them a stimulus that usually causes minimal lung fibrosis (low doses of bleomycin), the mice got exuberant lung fibrosis, and they had excessive epithelial cell death and greater ER stress,” Lawson said.
The results suggest that mutations in SFTPC — or in genes yet to be discovered — create a vulnerability of type 2 AECs to environmental factors, leading to IPF. In humans, the nature of the environmental exposure remains unclear but cigarette smoking and viral infections are potential candidates.
“Our study supports a two-hit model of IPF,” said Blackwell, the Ralph and Lulu Owen Chair in Medicine and senior author on the study. “We think that repetitive exposure of vulnerable type 2 epithelial cells to noxious environmental stimuli ultimately leads to IPF. That probably explains why this disease, which usually occurs in patients greater than 50 years old, takes so long to develop.”
The activation of this cellular pathway (ER stress) broadly among IPF cases suggests that therapies that target this pathway might be beneficial. Lawson and colleagues plan to test some experimental therapies in the mouse model.
Blackwell noted that they will also continue work to identify new disease-causing mutations in familial IPF.
“We plan to make mouse models of these disease-causing mutations, identify the functional changes caused by these mutations, and then try to develop therapies that we can take to the clinic,” he said. “This is a great opportunity to do translational medicine.”
Other Vanderbilt authors included: Amber Degryse M.D., Harikrishna Tanjore, Ph.D., Vasiliy Polosukhin, M.D., Ph.D., Sc.D., Xiaochuan Xu, M.D., Ph.D., Dawn Newcomb, Ph.D., Brittany Jones, Juan Roldan M.D., Kirk Lane, Ph.D., and Fiona Yull, Ph.D.
The work was supported by grants from the National Institutes of Health (National Heart, Lung and Blood Institute, and the National Center for Research Resources), American Lung Association, American Thoracic Society and the Francis Families Foundation.