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 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.”
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.
Pulmonary, Critical Care and Sleep Medicine is one of 10 sections in the Yale Department of Internal Medicine. To learn more about Yale-PCCSM, visit PCCSM's website, or follow them on Facebook and X/Twitter.