Connective tissue holds our body together, but in a condition called fibrosis, an overabundance of material devastates organs such as the liver, heart and lungs . A new study suggests that the fragments of a promising cancer drug may inhibit fibrosis, which is currently incurable.
Fibrosis occurs when cells pump the excess collagen and other connective tissue proteins, which affect the organs. Pulmonary fibrosis, for example, stiff lungs, eventually stifle patients unless they receive a lung transplant. In people with cirrhosis, connective tissue piles up in the liver. Heart and kidney disease can also be caused by fibrosis. So far, no drug to stop or reverse fibrosis won approval in the US.
cell and molecular biologist Carol Feghali-Bostwick of the University of Pittsburgh School of Medicine in Pennsylvania and his colleagues decided to test whether endostatin, a drug in clinical trials as a treatment for various cancers, has also an effect on fibrosis. Endostatin is one of angiogenesis inhibitors supposedly a group of drugs vaunted blocking the formation of new tumor blood vessels in need of growth. Endostatin also occurs naturally in the human body, and patients with pulmonary fibrosis up to 20 times their normal levels in blood or lungs. This finding raised the possibility that the protein is a natural defense against the proliferation of connective tissue, said Feghali-Bostwick.
To test this hypothesis, she and her colleagues studied samples of human skin they fed in the laboratory. They assayed the skin with TGF-β, a cellular signal that promotes fibrosis and causes the skin to thicken the connective tissue accumulates. Adding endostatin prevented patches of skin become thicker, the team found.
Because endostatin counteracts the growth of blood vessels, an undesirable quality for the treatment of fibrosis, the researchers then tested three fragments of the molecule, or peptides. After a few tweaks to improve stability, one of the peptides by itself reverse fibrosis stimulated by TGF-β in the skin patches, the researchers report online today in Science Translational Medicine . In addition, this part of endostatin had little effect on the growth of blood vessels in the culture dish, the team showed.
The peptide also worked in mice, which reduces skin fibrosis caused by TGF-β and the drug bleomycin. After a dose of bleomycin, the peptide also reduced lung fibrosis in animals.
"It makes a lot of sense that the body would try to mount an opposite process to fibrosis," said Feghali-Bostwick. Scientists believe that endostatin produced naturally can not fight against the connective tissue accumulation in fibrosis patients, perhaps because another molecule inhibits. But the peptide may be able to do the job, and it could overcome some of the limitations that have cut down on the use of endostatin in the treatment of cancer, such as the rapid deterioration of the body. The researchers now want to nail down how their fibrosis shorting peptide and to determine if they can make it more powerful, said Feghali-Bostwick.
"I think the peptides are a new approach to target the TGF-β pathway," says immunologist Thomas Wynn of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, which has not was involved in the research. However, he warns that until now, other compounds that block this pathway in mice are not panned in clinical trials, and he would like to see further research with different versions of fibrosis mice. "It is not clear how generally applicable the results will be."
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