IGFBP-5, a protein that appears to be involved in the early stages of fibrosis, may be a potential therapy for lung fibrosis, new preclinical research done at the Medical University of South Carolina (MUSC) found.
Using human lung fibroblasts and lung organ cultures, researchers showed that IGFBP-5 (standing for insulin-like growth factor-binding protein 5) promotes fibrosis by activating pro-fibrotic genes and genes important to the formation of the extracellular matrix, factors key to scarring (or fibrosis). IGFBP-5 is therefore a potentially attractive target.
The study, “IGFBP-5 Promotes Fibrosis via Increasing Its Own Expression and That of Other Pro-fibrotic Mediators,” was published in the journal Frontiers in Endocrinology.
“IGFBP-5 is upstream of several molecules that are considered key molecules in fibrosis, such as TGF-beta,” Carol Feghali-Bostwick, PhD, Kitty Trask Holt Endowed Chair for Scleroderma Research at MUSC, and senior author of the study, said in a press release. “So targeting it would allow us to possibly reduce the effect of all of the others that are downstream of it.”
Thickening and hardening of the skin is a hallmark of scleroderma, caused by the excessive production of collagen, a major protein of the extracellular matrix, key to the formation of scar tissue. Often, scleroderma can manifest systemically, characterized by the accumulation of scar tissue both in the skin and in other organs, including the lungs.
Lung scarring or fibrosis can be a complication of other diseases, including idiopathic pulmonary fibrosis (IPF) — lung fibrosis of unknown cause.
In prior studies, researchers at MUSC demonstrated that levels of IGFBP-5 were increased in the skin and lung tissues of patients with systemic scleroderma (SSc) and in lung tissues of patients with IPF. Using animal models and human cells grown in the lab, they confirmed that IGFBP-5 was involved in the scarring process.
The findings suggested that IGFBP-5 plays a role in the progression of fibrosis, but it remained unclear exactly how the factor regulated this process. To address this question, the team investigated which fibrosis-related factors and cellular pathways were controlled by IGFBP-5.
They engineered human lung fibroblasts (collagen-producing cells, key to wound healing and formation of scars) to express high levels of IGFBP-5. Results showed that shortly after the levels of IGFBP-5 were increased, there was an induction of fibrosis-related processes, namely the activation of pro-fibrotic genes and genes important to the formation of extracellular matrix, namely collagen.
The extracellular matrix is a network of proteins and sugars surrounding cells that works both as a physical scaffold and a mediator in biological responses. Collagen is a major component of this matrix, and in excessive amounts can cause the tissue to stiffen and become fibrotic.
In addition, the data showed that IGFBP-5 also promoted the expression of its own gene, an effect known as positive feedback loop.
“IGFBP-5 induces its own gene expression and feedback loop,” said Xinh Xinh Nguyen, first author of the study. “This suggests that IGFBP-5 acts together with pro-fibrotic genes to promote fibrosis and tissue remodeling.”
Researchers confirmed these observations in human lung tissues maintained in organ cultures — laboratory cultures of parts of an organ or a whole organ. In this case, lung tissue cores were cultured from pieces of lung tissue collected from SSc and IPF patients undergoing a lung transplant. Organ cultures are thought to better mimic the physiologic conditions and functions of an organ.
“It’s important to understand the effects of IGFBP-5 in human tissue if you are developing therapies,” Feghali-Bostwick said. “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.”
Based on the results, the team believes that an increase in IGFBP-5 seems to be a primary and early event in lung fibrosis, making it a potential therapeutic target.
The team now plans to use human lung fibroblasts and lung tissue to better understand how the increased levels of pro-fibrotic factors caused by IGFBP-5 are able to promote fibrosis. The team will also study these interactions in a mouse model.