Fibrosis Reversal Through Inhibition of ‘Don’t Eat Me’ Signal

Stanford University School of Medicine researchers have determined it is possible to reverse fibrosis. The researchers found that fibrotic diseases that occur in humans are united with a common signaling pathway. The research team determined that the antibody anti-CD47 reverses fibrosis in mice. Anti-CD47 is currently being tested as an anti-cancer agent.

About Fibrosis 

Fibrosis occurs when the human body's reaction to an injury runs amok. The poor timing or overenthusiastic proliferation of fibroblasts can cause a number of devastating diseases. Fibroblasts form the connective tissue that supports and surrounds the body's organs. The above-referenced study is the first to make it clear that such diseases have a common biological pathway.

About the Pathway

The research team concluded that the mutation of a specific pathway drives fibrosis in an array of body organs. The pathway underlies a number of conditions ranging from idiopathic pulmonary fibrosis to scleroderma, kidney fibrosis, and liver cirrhosis. Many of these diseases are incurable and fatal. Lung fibrosis in mice was reversed by administering the antibody known as anti-CD47. The CD-47 signal guards cancer cells against the immune system and reduces the impact of fibrotic diseases.

Why the Findings are Important

The Stanford research team believes their findings will eventually spur the development of a reliable treatment of several different types of fibrotic diseases. The team will also attempt to determine if the anti-CD47 antibody is an effective treatment for those with fibrosis.

The Inspiration for the Study

The research extrapolated on work previously conducted by Gerlinde Wernig, an assistant professor of pathology. Her previous studies examined fibrosis of the bone marrow known as myelofibrosis. Wernig developed a mouse model and found that fibroblasts generated egregiously high levels of the signaling molecule known as c-Jun.

Study Details

Wernig also served as the lead author of the most recent study. She analyzed c-Jun expression levels in 454 biopsied tissue samples taken from individuals with an array of fibrotic diseases. She determined that in each case the fibroblasts from individuals with fibrosis expressed advanced levels of c-Jun than the control fibroblasts gathered from those with nonfibrotic conditions. Wernig's team found that c-Jun was overexpressed and highly activated. They proceeded to block the expression of c-Jun in lab-grown lung fibroblasts collected from those with idiopathic pulmonary fibrosis. The result was a significant decrease in the proliferation of the cells but not of lung fibroblasts collected from patients without fibrosis.

Wernig's team also determined that c-Jun over-expression and over-activation serves as a unifying mechanism in several different types of fibrosis. It was also determined that immune cells known as macrophages exist around diseased c-Jun-expressing fibroblasts. This is similar to what is commonly observed in human cancers. Researchers have determined that human cancers avoid the immune system with the expression of abnormally high levels of the protein CD47 on their surfaces. Anti-CD47 blocks this protein and restore the macrophages' ability to eat away at the cancer. The research team wondered whether the fibroblasts were proliferating beyond their usual limit as a result of a possible “Don't eat!” surface signal that protects the immune system.

Wernig proceeded to use regular injections of anti-CD47 on mice saddled by lung fibrosis induced with c-Jun. The treatment spurred improved lung function, longer lifespan and fibrosis elimination.  

Summary

In summary, the study:

• Pinpointed a highly activated pathway that induces fibrosis in numerous tissues in mice
• Reversed fibrosis with anti-CD47 
• Tested inhibitors of additional genes activated by c-Jun across abnormal fibroblastic cells. Two pathway inhibitors decreased fibrotic lesions

Wernig's team will now attempt to determine if the technique will reverse fibrosis in humans.