In an article published online by Frontiers in Endocrinology, researchers at the Medical University of South Carolina (MUSC) report that they have identified a potential therapeutic target for lung fibrosis or scarring.

They showed in a preclinical model that the protein promotes fibrosis by turning on profibrotic genes and increasing levels of profibrotic factors, including itself. It is particularly attractive as a target because it exerts its influence early before most other profibrotic factors emerge.

"IGFBP-5 is upstream of several molecules that are considered key molecules in fibrosis, such as TGF-beta," says Carol Feghali-Bostwick, Ph.D., Kitty Trask Holt Endowed Chair for Scleroderma Research at MUSC, and senior author on the article. "So targeting it would allow us to possibly reduce the effect of all of the others that are downstream of it."

Lung Fibrosis

In lung fibrosis, lung tissue thickens, stiffens and scars. It can no longer function normally. That's why people with lung fibrosis have difficulty breathing. Around 100,000 Americans have lung fibrosis without a known cause, known as idiopathic pulmonary fibrosis. Another 50,000 have scleroderma, an autoimmune disease that often leads to lung fibrosis as well as thickening and tightening of the skin.

"There are currently no FDA-approved drugs that can either stop disease progression or reverse it in these patients," says Feghali-Bostwick. "Mortality is high, in some cases higher than cancer, so finding therapies is critical."

For these patients, transplant is often the only option. However, not all patients are eligible for a lung transplant, and it is not without its complications. New therapies that can stop or reverse lung fibrosis are needed.

IGFBP-5

Feghali-Bostwick and her team showed that insulin-like growth factor-binding protein 5 (IGFBP-5) plays an important and early role in promoting fibrosis. It increases profibrotic gene expression, resulting in excessive collagen being deposited to the extracellular matrix (ECM). The ECM is the network that surrounds cells and serves as the scaffold on which they can build tissue. This excess collagen causes the muscle to stiffen and become fibrotic.

These profibrotic genes also help ensure that levels of IGFBP-5 and other profibrotic factors such as matrix crosslinking enzyme lysyl oxidase (LOX) stay high. LOX enables collagen fibrils to cross-link, making tissue stiffer.

"IGFBP-5 induces its gene expression and feedback loop," says Xinh Xinh Nguyen, a graduate student who is working with Feghali-Bostwick and first author on the article. "This suggests that IGFBP5 acts together with profibrotic genes to promote fibrosis and tissue remodeling." The MUSC used collagen-producing cells harvested from patients with IPF or scleroderma to explore the profibrotic effects of IGFBP-5.

But they also went a step further, showing similar increases in human lung tissue cores. These cores more realistically mimic the physiologic conditions of living human tissue. "It's important to understand the effects of IGFBP5 in human tissue if you are developing therapies," explains Feghali-Bostwick. "Many therapies work in mice but fail in humans when you get to the human trials. So we have this system where we take lung tissues and put them in an environment that's a human-based tissue."