New research from the University of Pennsylvania attempts to better understand the early stages of pulmonary fibrosis, including what causes it to initially develop and then worsen over time. The study, “Local Photo-Crosslinking of Native Tissue Matrix Regulates Lung Epithelial Cell Mechanosensing and Function,” was published in Nature Materials.
Claudia Loebel, MD, PhD, lead researcher and assistant professor of bioengineering at Penn Engineering, said most studies of fibrosis are focused on advanced stages — after stiffening and scarring damage have already progressed. Much less is known about the cellular mechanics that initiate fibrosis, she said in a university news release.
“Once it’s diagnosed, patients only have two FDA-approved drugs, and both just slow down the disease. They don’t stop it or reverse it,” said Dr. Loebel. “What’s worse is that we often don’t know what caused it in the first place, so we also don’t have a clear idea of how to prevent it.”
Along with researchers from her lab, the University of Michigan and Drexel University, Dr. Loebel and the collaborative group examined the role of tissue stiffness in influencing lung cell behavior and the formation of fibrosis. The study included analysis of healthy, living mouse and human lung tissue that researchers exposed to blue light. This technique, called photochemical crosslinking, activates the extracellular matrix (the fibrous framework that surrounds cells) and causes it to stiffen. The method allowed scientists to observe real-time responses in the mechanical environment.
“Think of the extracellular matrix like loose hair in a ponytail. With light-triggered crosslinking, we braid it, stiffening the tissue just enough to mimic the kind of microinjuries that might trigger fibrosis,” said Donia Ahmed, a doctoral student in Dr. Loebel’s lab.
According to Ahmed, the stiffened lung tissue changed shape and began changing into a new cell type. The transition never fully finished though, she said.
“These cells were caught in a sort of identity crisis. They were stuck between types, unable to perform either role well. And that’s a problem,” said Ahmed.
Researchers have previously discovered transitional cells in fibrotic tissue samples but did not understand how they reached the in-between state. Based on their new findings, Dr. Loebel and Ahmed said they believe when cells in stiffened lung tissue get stuck and don’t complete the transition, they generate additional stiffness and create a feedback loop that compounds the damage. This also creates an environmental breeding ground for other fibrosis-promoting cells.
The study relied on an interdisciplinary approach that combined biological tissue and laboratory results with engineering tools and models. For example, the group used a nanoindenter, which typically tests metals or plastics, to measure stiffness in real time.
“This [approach] lets us identify opportunities to apply engineering tools to study disease and uncover new biological insights,” said Matthew Lee Tan, co-first author and former postdoctoral fellow at the University of Michigan.
Although this specific study was completed on epithelial cells, Dr. Loebel said the model can translate to other cell types that impact fibrosis, such as macrophages, fibroblasts and neutrophils.
“Now that we’ve built this tool, we can use it to look at cell-specific contributions to fibrosis, not just in the lungs, but potentially in other organs like the liver or skin, where fibrosis also causes major health problems,” she said.
In the future, Dr. Loebel said the groundbreaking work could help doctors predict individual risk of pulmonary fibrosis and develop interventional therapies.
“We’re not trying to recreate fibrosis in the lab. We’re identifying its starting point” she said. “If we can understand the first responders, we can work toward treatments that prevent the entire cascade from happening.”
