Fibrosis of the lungs is often a silent disease until it's too late. By the time patients are diagnosed, the scarring of their lung tissue is already advanced, and current treatments offer little more than a slowing of the inevitable. But what if we could understand the very first steps of this disease before irreversible damage sets in?
That's the question Claudia Loebel , Reliance Industries Term Assistant Professor in Bioengineering, and Donia Ahmed, a doctoral student in Loebel's lab, set out to answer. Their Nature Materials paper , a collaborative study spanning the University of Pennsylvania, the University of Michigan and Drexel University, explores how subtle changes in the mechanical environment of lung tissue might set off the chain reaction that leads to fibrosis.
A Fresh Approach to an Intractable Disease
Lung fibrosis is notoriously difficult to diagnose and treat.
"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," says 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."
Much of the research to date has focused on the later stages of the disease, when tissue has already stiffened and scarred. Loebel and Ahmed decided to flip the script, examining instead what happens right at the onset. Specifically, they looked at how tissue stiffness alone might influence cell behavior in the lungs, offering a new window into fibrosis as it unfolds.
Lighting Up the Problem
Using a technique called photochemical cross-linking, the researchers exposed lung tissue to blue light, which triggered the extracellular matrix — the fibrous scaffolding surrounding cells — to stiffen. Unlike traditional UV light, blue light is gentler on living cells, making it ideal for studying live tissue.
With these flashes of blue light, the team was able to localize the stiffening of tissue in both healthy mouse and human lung tissue.
"Think of the extracellular matrix like loose hair in a ponytail," says Ahmed. "With light-triggered cross-linking, we braid it, stiffening the tissue just enough to mimic the kind of micro-injuries that might trigger fibrosis."
What makes this approach unique is that the team didn't use engineered gels or decellularized tissue. Instead, they worked with intact, living tissue samples. That preservation of natural cellular and matrix interactions makes their technique a powerful tool for understanding real-time responses to mechanical changes in the lung.
Cells That Sense and Get Stuck
As the tissue stiffened under the light, Ahmed observed that cells began to stretch out, changing shape. And, it wasn't just cosmetic. This physical stretching was a sign that the cells were transitioning into a different cell type.
But then they stalled.
"These cells were caught in a sort of identity crisis," says Ahmed. "They were stuck between types, unable to perform either role well. And that's a problem."
These "transitional" cells have been spotted before in fibrotic tissue samples, both in mice and humans. What hasn't been understood, until now, is how they get there.
Loebel and Ahmed's model suggests that changes in tissue stiffness alone can prompt cells to begin transitioning, and when they get stuck, they contribute to the very stiffness that triggered them — setting up a potential feedback loop that accelerates disease.
Imagine a child's play tunnel: when it's soft and flexible, it's easy to crawl through. But once it becomes rigid, movement and communication amongst individuals become difficult. Similarly, in a stiffened extracellular matrix, cells can get trapped, lose their function and change shape. Worse, they may attract other "bad" cells that thrive in rigid environments, compounding the damage.
A Mechanical Problem with Biological Consequences
While the biology of fibrosis has long been studied, this project reframes the disease as a problem of mechanics.
"I love thinking about this from a mechanical engineering perspective," says Ahmed. "It's not just about chemical signals. The physical environment matters deeply."
To measure just how stiff the tissue had become, the team used a nanoindenter, an engineering tool typically reserved for testing materials like plastics or metals. They applied it to biological tissue, providing precise data about how stiffness changes in real time.
"We are uniquely positioned to tackle this problem due to our expertise in both engineering and biology," says Matthew Lee Tan, co-first author and former postdoctoral fellow at the University of Michigan. "This lets us identify opportunities to apply engineering tools to study disease and uncover new biological insights."
This interdisciplinary approach, combining tools from engineering, insights from biology and models built on real human tissue, reflects the collaborative spirit of Penn Engineering's scientific ecosystem.
Where to From Here?
The team's leading hypothesis is that these early-responding cells, once stuck in a transitional state, lay the groundwork for fibrosis to progress. They not only lose their original function but actively stiffen the tissue around them, making the environment more attractive to fibrosis-promoting cells.
And while this study focused on epithelial cells — those at the interface between lung tissue and air — the researchers plan to expand their work to other key players in fibrosis: macrophages, fibroblasts and neutrophils.
"This is just the first step," says Loebel. "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."
A Blueprint for Future Therapies
Ultimately, the hope is that by understanding how stiffness affects cells in the earliest phases of fibrosis, scientists and doctors can better predict who's at risk and when to intervene.
"We're not trying to recreate fibrosis in the lab," Loebel says. "We're identifying its starting point. If we can understand the first responders, we can work toward treatments that prevent the entire cascade from happening."
Funding for this work came from the National Institutes of Health (R00-HL151670, R35GM157063, T32 GM1404, NHLBI T32 HL007749, R35HL160770 and R56ES035710), the American Lung Association (IA-939940), the David and Lucile Packard Foundation, and the National Science Foundation (NSF CMMI-1751898). The authors also thank Steven Huang for his assistance with human tissue sample collection.
