The Alpha 7 Nicotinic Acetylcholine Receptor: A Promising Target For The Treatment Of Fibrotic Skin Disorders
JOURNAL OF INVESTIGATIVE DERMATOLOGY(2020)
摘要
Targeting neuroendocrine receptors can be considered as another interesting approach to treating fibrotic disorders. Previously, we could demonstrate that tropisetron, a classical serotonin receptor blocker, can modulate collagen synthesis and acts in vitro through the alpha 7 nicotinic acetylcholine receptor (alpha 7nAchR). Here, we used a pharmacologic approach with specific alpha 7nAchR agonists to validate this hypothesis. PHA-543613, an alpha 7nAchR-specific agonist, not only prevented but also reversed established skin fibrosis of mice injected with bleomycin. Interestingly, agonistic stimulation of alpha 7nAchR also attenuated experimental skin fibrosis in the non-inflammation driven adenovirus coding for TGF beta receptor Iact mouse model, indicating fibroblastmediated and not only anti-inflammatory effects of such agents. The fibroblast-mediated effects were confirmed in vitro using human dermal fibroblasts, in which the alpha 7nAchR-specific agonists strongly reduced the impact of TGF beta 1-mediated expression on collagen and myofibroblast marker expression. These actions were linked to modulation of the redox-sensitive transcription factor JunB and impairment of the mitochondrial respiratory system. Our results indicate that pharmacologic stimulation of the alpha 7nAchR could be a promising target for treatment of patients with skin fibrotic diseases. Moreover, our results suggest a mechanistic axis of collagen synthesis regulation through the mitochondrial respiratory system.
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