HMN 2025: How Pulmonary fibrosis traced to key signaling pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic disease in which healthy lung tissue is gradually replaced by scar tissue. While the early events that initiate this change are poorly understood, recent research suggests that the disease may stem from failures in the lung’s response to injury.

A new study from Yale researchers, published in Science Translational Medicine, adds clarity to this model by identifying an epithelial-immune signaling pathway crucial to the lung’s injury-repair process. When this signaling is altered, the study shows, it may help push the lung toward fibrosis.

How transitional epithelial cells function

In the tiny air sacs of the lung, epithelial cells form a thin lining that supports the tissue and allows gas exchange across the membrane. These epithelial cells are generally grouped into two categories, type I and type II, based on their structure and function.

According to Maor Sauler, MD, associate professor of medicine in Yale School of Medicine’s Section of Pulmonary, Critical Care and Sleep Medicine (Yale-PCCSM) and senior author of the study, an intermediate epithelial cell state also exists and is critical in both normal and abnormal lung repair.

“In healthy repair, this state is transient, and lasts only a few days, but when repair is disrupted, these cell states accumulate,” says Sauler.

This transitional state has drawn widespread interest because it is highly active and produces numerous signaling molecules that may influence surrounding cells.

“It’s distinct from both type I and type II cells, and it generates a lot of ligands,” Sauler explains. “Rather than trying to eliminate these cells, we wanted to see what would happen if we simply stopped them from signaling.”

The role of MIF in fibrosis

The authors used a variety of in vivo approaches to study these transitional cells more closely. They ultimately found that one molecule secreted by these cells, macrophage migration inhibitory factor (MIF), plays a significant role in driving pulmonary fibrosis.

Sang-Hun Kim, associate research scientist in Sauler’s lab, served as first author of the study and led much of the study’s conceptualization and experimental design, including the establishment of models for studying epithelial cell dysfunction and the comprehensive elucidation of the MIF signaling pathway.

Kim and the other researchers found that when MIF levels rose, it strengthened signals that pushed macrophages—a type of immune cell responsible for clearing debris, responding to injury, and guiding tissue repair—toward a profibrotic state.

“It’s not that MIF alone causes fibrosis,” Sauler explains. “But when the environment is already nudging macrophages in that direction, MIF amplifies the signal. Too much of it can tip the system away from repair and toward scarring.”

Implications for treatment and future research

The findings suggest that during periods of cellular stress, such as when protein buildup overwhelms the epithelial cells’ normal machinery, levels of MIF rise, strengthening signals that drive macrophages into a profibrotic program. In healthy tissue, this transitional state is brief and tightly regulated. But when MIF signaling becomes elevated or prolonged, the balance shifts, allowing transitional cells to accumulate, contributing to the progression of fibrosis.

Such cellular stress becomes more common with aging and smoking, both of which are known to impair proteostasis—the process of maintaining protein homeostasis—and make epithelial cells more vulnerable to mismanaged repair, says Sauler.

This focus on the epithelial cell’s own stress machinery highlights another aspect of the study’s novelty, Kim adds.

“While prior work focused broadly on inflammation or fibrotic response, our insight highlights the epithelial proteostatic collapse as a critical upstream driver,” he says.

Taken together, the findings help clarify the role of transitional epithelial cells in fibrotic lung disease. The study shows that these cells actively communicate with neighboring immune cells in ways that worsen injury, reinforcing a growing view that epithelial-macrophage interactions are central to how fibrosis develops.

Sauler states that the work also opens the door to new therapeutic possibilities. Because elevated MIF levels were associated with more severe fibrosis in both animal models and human samples, the data suggest that targeting this signaling pathway could be clinically meaningful.

“It really raises the possibility that blocking MIF, perhaps alongside other signals, could be a viable therapeutic strategy for patients with IPF,” Sauler says.

The content is provided for information purposes only.