期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 140, 期 12, 页码 2371-2379出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2020.04.006
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资金
- German Research Foundation (DFG) [STE 2312/1-3]
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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