These images show collagen fibers (left column) and cell-surface proteins that act as markers for macrophages (middle column). The right column shows macrophages aligned with collagen fibers.

These images show collagen fibers (left column) and cell-surface proteins that act as markers for macrophages (middle column). The right column shows macrophages aligned with collagen fibers. Images: University at Buffalo

Probing Macrophages’ Role in Pulmonary Fibrosis Origins

By Cory Nealon

Published April 11, 2024

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Ruogang Zhao.
“Our understanding of how pulmonary fibrosis develops has greatly improved; however, there is still much we do not understand, especially the involvement of immune cells in the formation of the disease. ”
Associate professor of biomedical engineering

Scientists have long known that white blood cells called macrophages accumulate in the lungs of people suffering from pulmonary fibrosis. What role macrophages play in developing the often-fatal lung disease is less clear.

A new University at Buffalo-led study sheds light on this mystery and opens new paths to study pulmonary fibrosis, advancements that could ultimately lead to more effective medicine and therapies for the disease, which affects roughly 100,000 in the U.S.

“Our understanding of how pulmonary fibrosis develops has greatly improved; however, there is still much we do not understand, especially the involvement of immune cells in the formation of the disease,” says the study’s corresponding author Ruogang Zhao, PhD, associate professor of biomedical engineering, a joint program between UB’s School of Engineering and Applied Sciences and the Jacobs School of Medicine and Biomedical Sciences.

Fibrotic Lung Tissue Model Powerful New Tool

In people with pulmonary fibrosis, stiff scar tissue forms in the lungs, making it difficult to breath. This stiff scar tissue cannot be repaired, only slowed down with medicine and therapies.

The study, published March 29 in Science Advances, describes how Zhao and colleagues developed a miniature models of fibrotic lung tissues that act as a proxy for someone with pulmonary fibrosis.

In addition to macrophages, the model included the two main components of stiff scar tissue: fibroblasts and collagen fibers.

During experiments, the team observed macrophages sensing their surroundings and becoming “coaligned” with the fibroblasts and collagen fibers. This activation of the macrophages’ mechanical sensitivity allowed them to secrete additional biochemical factors that promote scar tissue growth.

The team then dosed the diseased tissue with a drug called pirfenidone, which is a Food and Drug Administration-approved treatment that slows down the worsening of pulmonary fibrosis. Pirfenidone blocks certain proteins that can significantly affect how macrophages adhere to and interact with fibroblasts and collagen fibers. As a result, the drug can stop scar tissue from forming.

“The results suggest a potential mechanism, at the tissue level and involving macrophages, of how pulmonary fibrosis originates,” says the study’s first author Ying Xu, a PhD candidate in Zhao’s lab.

The fibrotic lung tissue model, Zhao adds, is a powerful new tool that researchers can use to further study tissue- and cell-level interactions in fibrotic lungs. It could also help test new drugs that further slow down the disease or stop it, he says.

Additional authors include Linxuan Ying, a doctoral student in Zhao’s lab; Jennifer K. Lang, MD, associate professor of medicine in the Jacobs School; and Boris Hinz, professor of dentistry at the University of Toronto.

The work was funded in part by the National Institutes of Health, the American Lung Association, the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Ontario Research Fund.