Specific interactions between inflammatory cells and epithelial cells contribute to lung fibrosis, according to a study published last week in JCI Insight fromVanderbilt’s Lisa Young, M.D., associate professor of Pediatrics and Medicine and Cell and Developmental Biology, and colleagues.
For more than a decade, Young has been studying Hermansky-Pudlak syndrome (HPS), an inherited disorder that causes albinism, decreased visual acuity, susceptibility to bleeding due to platelet dysfunction and fatal pulmonary fibrosis.
In the study, which was primarily funded by a grant from the National Institutes of Health, Young used genetic mouse models to understand how interactions between two cell types, alveolar epithelial cells and macrophages, lead to scarring in the lungs.
“Patients with HPS have abnormalities in both of these cell types in their lungs. Through genetic manipulations in mouse models, we were able to dissect how these cell types interact and contribute to lung fibrosis.”
In the JCI study Young and colleagues show that epithelial cells regulate the recruitment and behavior of macrophages, which are the most abundant immune/inflammatory cells in the lungs. Macrophages then directly contribute to fibrosis through the production of a pro-fibrotic mediator called TGF-beta.
But there is more to the story. Macrophages then create a feedback loop where they cause damage to the epithelium as well.
“In genetic diseases we have the great opportunity to study the impact of specific gene products on fundamental processes that form the basis of disease. We can then use this information to design targeted strategies that get to the root of the problem,” Young said. “In HPS, we can identify the genetic syndrome before lung fibrosis develops. There is potential for early disease treatment or even prevention, if we can understand the basic biology of this disease and how the lung fibrosis starts.
“This paper shows us that we might develop treatments to interrupt the signals between the epithelium and macrophages, or to target macrophage functions that result in fibrosis. It really does set the stage for novel therapeutic strategies for patients,” Young said.
Contributing authors include Peter Gulleman, Chelsi Short, Harikrishna Tanjore, Ph.D., Taylor Sherrill, Aidong Qi, M.D., Ph.D., Andrew McBride, Rinat Zaynagetdinov, Ph.D., John Benjamin, M.D., William Lawson, M.D., Sergey Novitskiy, Ph.D., and Timothy Blackwell, M.D., director of Vanderbilt’s Center for Lung Research.
