期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 14, 期 3, 页码 320-327出版社
ELSEVIER
DOI: 10.1016/j.intimp.2012.07.020
关键词
nAChR; mAChR; Mice; Alveolar macrophage; Inflammation
资金
- National Key Basic Research Program [2010CB529800]
- National Natural Science Foundation of China [81070010, 30873109]
- Science and Technology Commission of Shanghai Municipality [09JC1408800]
- Shanghai Jiao Tong University School of Medicine [BXJ201007]
Objective: We tested the potential role of the mAChR in lipopolysaccharide (LPS)-induced inflammatory response in in vivo and in vitro models and a possible signaling pathway involved in the inflammatory process. Methods: Anesthetized mice were challenged with intratracheal LPS to induce acute lung injury. The cytology and histopathology changes, expression of cytokines and pulmonary vascular permeability were used to evaluate the effects of the cholinergic agent. Alveolar macrophage cell line NR8383 was also used to confirm the role of mAChRs and the molecular mechanisms underlying the LPS-induced events. Results: LPS-induced acute lung injury (ALI) was significantly improved by atropine (a non-selective mAChR antagonist) and 4-DAMP (a M3 mAChR antagonist), as indicated by the diminution of neutrophil infiltration, pulmonary vascular permeability and IL-6 and TNF-alpha production. LPS-induced TNF-alpha production from the alveolar macrophage was significantly inhibited by atropine and 4-DAMP, but not pirenzepine (a M1 mAChR antagonist) and methoctramine (a M2 mAChR antagonist). Interestingly, LPS-induced TNF-alpha production was enhanced by the muscarinic receptor agonist pilocarpine, and treatment with pilocarpine alone was able to trigger TNF-alpha production from the alveolar macrophage, which was effectively attenuated by 4-DAMP. Western blot analysis showed that LPS-induced degradation of I kappa B alpha was strongly blocked by atropine/4-DAMP both in vivo and in vitro, indicating that M3 mAChR was involved in LPS-induced lung inflammation by mediating the NF-kappa B signaling pathway. Conclusion: Our findings bring the evidence that the blockage of mAChR exerts anti-inflammatory properties, in which the M3 mAChR plays an important role in the LPS-induced lung inflammation. (C) 2012 Elsevier B.V. All rights reserved.
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