Japanese scientists have discovered that endothelin-1 (ET-1) signaling through its B-type receptor contributes to the development of skin fibrosis. The finding suggests that ETB can be selectively targeted in new attempts to develop better antifibrotic drugs based on endothelin blockage.
Scientists have long suspected that ET-1 signaling contributes to the development of fibrosis. Patients with scleroderma have higher levels of the factor in their blood and in affected tissues, such as skin and lungs. ET-1 blocking drugs, such as bosentan, have been developed for the treatment of pulmonary arterial hypertension — a common feature in fibrotic patients.
After observations that the drugs decreased fibrotic symptoms in scleroderma patients with pulmonary arterial hypertension, ET-1 blockers were explored as a fibrosis treatment. But so far, the individual contributions to fibrosis development by ET-1 signaling through its two receptors, ETA and ETB, has not been adequately explored.
Since studies have shown that ET-1A is needed for the activation of skin fibroblasts – a key step in the fibrotic process – researchers from Kobe University in Japan used mice lacking the ETB receptor to explore if it also plays a part in fibrosis development.
Exposing the mice to bleomycin, a common way to trigger fibrosis in experimental animals, the study “Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice,” compared the extent of fibrosis between ETB deficient and normal mice, and found that the mutant mice resisted the effects of bleomycin.
Bleomycin normally increases the thickness of the dermis part of the skin between the outer protective layer and the subcutaneous tissue, and it reduces the amount of subcutaneous fat – but mice lacking ETB did not show those characteristics. The animals also did not produce more collagen in the skin, another feature typical of fibrosis development.
Since excessive collagen is produced by myofibroblast cells — a cell type that emerges from normal fibroblasts — the researchers measured the amount of those cells and found that a lack of ETB prevented myofibroblast formation and hindered inflammatory cells from accumulating in the tissue.
The study paper, published in the journal Arthritis Research & Therapy, also described how the prevention of myofibroblast activation was accompanied by a lack of gene expression changes, normally observed in skin fibroblasts exposed to bleomycin.
The data showed that ETB is likely involved in skin fibrosis, although it remains to be proven whether blocking signaling via the receptor can be beneficial for patients.
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