Researchers from the Stanford University School of Medicine have identified a key element that is responsible for fibrosis of many incurable and life-threatening diseases, such as scleroderma. Their finding can help develop new specific and efficient treatments to reverse tissue fibrosis processes.
The finding was reported in a study titled “Unifying mechanism for different fibrotic diseases,” published in the journal Proceedings of the National Academy of Sciences.
Fibrosis is characterized by the uncontrolled expansion of fibroblasts, a class of cells responsible for normal tissue repair, and the production of connective tissue surrounding and supporting organs. This process is the basis of many fibrotic diseases, but until now it was not clear if these diseases shared any specific biological pathway.
In previous studies, the research team found that in a mouse model of myelofibrosis, or fibrosis of the bone marrow, the fibroblasts produced high levels of a protein called c-Jun. This protein controls the expression of several other proteins, working as an essential signaling element.
In the current study, the team evaluated the expression of c-Jun protein in 454 tissue samples collected from patients with different fibrotic diseases. They confirmed that in all samples, the fibroblasts expressed more c-Jun than control non-fibrotic samples.
Additional tests showed that inhibition of c-Jun activity would impair the expansion of fibroblasts collected from patients with fibrosis, but not on those collected from people without fibrosis.
Over-expression of c-Jun protein in genetically modified animals led to the development of fibrosis in nearly all organs, including lung, liver, skin and bone marrow. This confirms the important role this protein has in fibrotic processes, and in the development of several fibrotic diseases.
Interestingly, the authors found that the diseased fibroblasts were surrounded by immune cells called macrophages. This was previously reported in cancer, where cancer cells express a “don’t eat me” signal that makes them evade the macrophages’ anti-cancer activity. This is mediated by a cell surface protein called CD-47.
Inhibition of this signal with an anti-CD47 antibody has shown to restore the ability of the macrophages to detect and destroy the cancer cells. This immunotherapy is currently undergoing a Phase 1 study in humans with advanced solid tumors (NCT02216409).
Because of this resemblance, the researchers administrated anti-CD47 antibody to the fibrosis animal model. Overall, the animals exhibited significantly better lung function, lived longer than untreated animals, and cleared the fibrosis.
“We identified a highly activated pathway that causes fibrosis in many tissues in mice, and we’ve showed that treating the animals with an anti-CD47 antibody reverses the fibrosis,” Wernig said. “We’re hopeful that this could be a potential treatment for people with many types of fibrotic conditions.”
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