title: Protective effects of anisodamine on cigarette smoke extract-induced airway smooth muscle cell proliferation and tracheal contractility.
abstract: Anisodamine, an antagonist of muscarinic acetylcholine receptors (mAChRs), has been used therapeutically to improve smooth muscle function, including microvascular, intestinal and airway spasms. Our previous studies have revealed that airway hyper-reactivity could be prevented by anisodamine. However, whether anisodamine prevents smoking-induced airway smooth muscle (ASM) cell proliferation remained unclear. In this study, a primary culture of rat ASM cells was used to evaluate an ASM phenotype through the ability of the cells to proliferate and express contractile proteins in response to cigarette smoke extract (CSE) and intervention of anisodamine. Our results showed that CSE resulted in an increase in cyclin D1 expression concomitant with the G0/G1-to-S phase transition, and high expression of M2 and M3. Functional studies showed that tracheal hyper-contractility accompanied contractile marker α-SMA high-expression. These changes, which occur only after CSE stimulation, were prevented and reversed by anisodamine, and CSE-induced cyclin D1 expression was significantly inhibited by anisodamine and the specific inhibitor U0126, BAY11-7082 and LY294002. Thus, we concluded that the protective and reversal effects and mechanism of anisodamine on CSE-induced events might involve, at least partially, the ERK, Akt and NF-κB signaling pathways associated with cyclin D1 via mAChRs. Our study validated that anisodamine intervention on ASM cells may contribute to anti-remodeling properties other than bronchodilation.
authors.affiliation: Department of Pharmacology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Guang-Ni
authors.initials: GN
authors.lastname: Xu
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Zu-Peng
authors.initials: ZP
authors.lastname: Xu
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Hou
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.forename: Yong-Yao
authors.initials: YY
authors.lastname: Cui
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D012991:Solanaceous Alkaloids / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
chemical_list: D018727:Muscarinic Antagonists; D016328:NF-kappa B; D011976:Receptors, Muscarinic; D012906:Smoke; D012991:Solanaceous Alkaloids; C003922:anisodamine; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt