Institute of Biomedicine and Molecular Immunology A. Monroy (IBIM), Italian National Research Council (CNR), Palermo, Italy.
Immunobiology. 2012 Mar;217(3):345-53. doi: 10.1016/j.imbio.2011.07.013. Epub 2011 Aug 3.
Novel pharmacological strategies are aimed at the resolution of systemic inflammation in COPD potentiating peripheral blood T-cell (PBT-cell) apoptosis. Although muscarinic acetylcholine receptors (mAChRs) M(3) and choline-acetyltransferase (ChAT) participate in the airway inflammation of COPD, their role in PBT-cell apoptosis remains unexplained. We evaluated in PBT-cells from COPD patients, smoker (S) and control (C) subjects: (1) apoptosis (by annexin V binding), (2) mAChR M(3) and ChAT expression, acetylcholine (ACh)-binding; (3) choline levels in serum and PBT-cells extracts. We tested the effects of Tiotropium (Spiriva(®)) and hemicholinium-3 (HCh-3) on apoptosis, NFκB pathway, caspases 3 and 8 activity and choline levels, in PBT-cells from COPD patients. We showed that: (1) apoptosis, mAChR M(3) and ChAT expression and the CD3+ and CD8+ ACh-binding are increased in PBT-cells from COPD patients when compared to C subjects, while CD4+/CD8+ ratio of ACh-binding to PBT cells was reduced in COPD; (2) choline levels are higher in serum and PBT-cells extracts from COPD patients than in S and C; (3) Tiotropium and HCh-3 reduced CD4+ and increased CD8+ apoptosis via caspases 3 and 8 activities and via IκB mediated mechanisms in COPD patients. This study suggests the involvement of non-neuronal components of cholinergic system in the regulation of PBT-cell apoptosis in COPD and demonstrates that Tiotropium regulates CD4+ and CD8+ PBT-cell apoptosis. It provides novel putative pharmacological targets for the resolution of systemic inflammation in COPD.
新型药理学策略旨在解决 COPD 中的全身炎症，促进外周血 T 细胞（PBT 细胞）凋亡。尽管毒蕈碱乙酰胆碱受体（mAChR）M3 和胆碱乙酰转移酶（ChAT）参与 COPD 的气道炎症，但它们在 PBT 细胞凋亡中的作用仍未得到解释。我们在 COPD 患者、吸烟者（S）和对照组（C）的 PBT 细胞中评估了：（1）凋亡（通过 annexin V 结合），（2）mAChR M3 和 ChAT 表达，乙酰胆碱（ACh）结合；（3）血清和 PBT 细胞提取物中的胆碱水平。我们测试了噻托溴铵（Spiriva®）和 hemicholinium-3（HCh-3）对 COPD 患者 PBT 细胞凋亡、NFκB 通路、caspase 3 和 8 活性和胆碱水平的影响。我们发现：（1）与 C 组相比，COPD 患者的 PBT 细胞凋亡、mAChR M3 和 ChAT 表达以及 CD3+和 CD8+ ACh 结合增加，而 COPD 患者 PBT 细胞的 CD4+/CD8+ ACh 结合比例降低；（2）与 S 和 C 相比，COPD 患者的血清和 PBT 细胞提取物中的胆碱水平较高；（3）噻托溴铵和 HCh-3 通过 caspase 3 和 8 活性以及 IκB 介导的机制降低 CD4+和增加 CD8+凋亡，在 COPD 患者中。这项研究表明，胆碱能系统的非神经元成分参与调节 COPD 中的 PBT 细胞凋亡，并表明噻托溴铵调节 CD4+和 CD8+PBT 细胞凋亡。它为 COPD 中的全身炎症提供了新的潜在药理学靶点。
