A cure for scleroderma?
Managing "cell death" will help defeat a dangerous disease
Researchers from Boston have proposed a way to combat fibrosis by controlling apoptosis – the death of cells in the body. By causing microfibroblasts to self-destruct, they achieved a reduction in fibrosis symptoms in laboratory mice.
Fibrosis is the appearance of scars from connective tissue. It usually occurs in response to inflammation and serves to isolate the affected area of the organ. But sometimes this process begins to develop uncontrollably, as a result of the replacement of healthy tissue with scar tissue, the organ can no longer function normally. The reason for this is the fact that a special type of cells – microfibroblasts – do not self-destruct after performing their functions, but continue to work. Fibrosis affects the skin, lungs, heart, liver and other organs.
Doctors from Massachusetts General Hospital in Boston Andrew Tager and David Lagares and colleagues were looking for a way to combat one of the types of fibrosis – autoimmune scleroderma. They were quite surprised when they found that in active myofibroblasts that cause scleroderma, mitochondria contain the BIM protein responsible for triggering apoptosis. And yet, these cells didn't die. "They should be dying, but for some reason they are not fulfilling this program," Lagares says. Based on their own previous studies and on the results of other scientists, the authors of the work drew attention to the BCL-2 family of proteins, which are also associated with the regulation of apoptosis, and are capable of both stimulating and inhibiting this process. They suspected that the balance between regulatory proteins could be disrupted. The study of the activity of the corresponding genes in mice with scleroderma confirmed this assumption. One of the proteins stopping apoptosis – Bcl-xL – accumulated in microfibroblasts.
Scientists are interested in whether there are drugs aimed specifically at this protein. And it turned out that such a drug called ABT-263, or navitoclax, is undergoing clinical trials as a cancer treatment. This substance was given to experimental mice, and they really started self-destruction of microfibroblasts. ABT-263 acted precisely on these cells, since they contained the largest accumulation of the target protein. As a result, the mice not only stopped the further development of scleroderma, but also the already manifested effects of the disease softened. According to Lagares, the scar tissue seemed to be melting.
Now scientists have to check whether the Bcl-xL protein plays a similar role in the development of fibrosis in humans. If this is confirmed, ABT-263 may become an effective cure for this disease.
The results of the work are published in the journal Science Translational Medicine.
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