期刊
SHOCK
卷 38, 期 2, 页码 213-219出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0b013e31825d628c
关键词
alpha 7 acetylcholine receptor agonist; alpha 7 acetylcholine receptor antagonists; alpha-bungarotoxin; tumor necrosis factor alpha; upregulation; vecuronium
资金
- National Institutes of Health [RO1-055082, P50-2500]
- Shriners Hospitals for Children
Nicotinic stimulation of the alpha 7 acetylcholine receptors (alpha 7AChRs) mitigates the lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) and other cytokines release in macrophages. This effect is blocked by alpha 7AChR antagonist, alpha-bungarotoxin (BTX). We tested and confirmed the hypotheses that LPS upregulates alpha 7AChRs, and the prototypical alpha 7AChR antagonists, vecuronium and BTX, do not block the effects of GTS-21, a specific alpha 7AChR agonist, on TNF-alpha release. With the knockdown of alpha 7AChR expression by short interference RNA, GTS-21 effects on inhibition of TNF-alpha release were not demonstrable. In addition, GTS-21 mitigated the LPS-induced growth arrest of macrophages in vitro in J774A.1 cells and ex vivo in peritoneal macrophages obtained from mice at 3 days after burn. Moreover, GTS-21 reduced mortality after burn injury in mice. These results indicate that (i) LPS upregulates alpha 7AChRs; (ii) the therapeutic beneficial effects of GTS-21 on cytokine release are specifically mediated via alpha 7AChRs and are preserved even when cotreated with prototypical antagonist, BTX, or clinically used muscle nicotinic antagonist, vecuronium; (iii) activation of alpha 7AChRs by GTS-21 partially reverses the LPS-induced proliferation arrest; and (iv) GTS-21 reduces mortality in mice with burn injury. The in vivo beneficial effects of GTS-21 in burn injury warrant further studies.
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