Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, QC H3C3J7, Canada.
Peptides. 2011 Jul;32(7):1447-56. doi: 10.1016/j.peptides.2011.05.005. Epub 2011 May 11.
Pulmonary inflammation is an important pathological feature of tobacco smoke-related lung diseases. Kinin B1 receptor (B1R) is up-regulated in the rat trachea chronically exposed to cigarette-smoke. This study aimed at determining (1) whether exposure to total particulate matter of the cigarette smoke (TPM) can induce B1R in human alveolar epithelial A549 cells, (2) the mechanism of B1R induction, (3) the functionality of de novo synthesized B1R, and (4) the role of B1R in TPM-induced increase of superoxide anion (O₂(●⁻)) level. Results show that A549 cells exposed to 10 μg/ml TPM increased O₂(●⁻) level along with B1R (protein and mRNA) and IL-1β mRNA. In contrast, B2R and TNF-α mRNA were not affected by TPM. The increasing effect of TPM on O₂(●⁻) level was not significantly affected by the B1R antagonist SSR240612. TPM-increased B1R mRNA was prevented by co-treatments with N-acetyl-l-cysteine (potent antioxidant), diphenyleneiodonium (NADPH oxidase inhibitor), IL-1Ra (interleukin-1R antagonist) and SN-50 (specific inhibitor of NF-kB activation) but not by pentoxifylline (TNF-α release inhibitor), indomethacin and niflumic acid (COX-1 and -2 inhibitors). Stimulation of B1R with a selective agonist (des-Arg⁹-BK, 10 μM; 30 min) increased O₂(●⁻)production which was prevented by apocynin and diphenyleneiodonium (NADPH oxidase inhibitors). Data suggest that the increased expression of B1R by TPM in A549 cells is mediated by oxidative stress, IL-1β and NF-kB but not by cyclooxygenases or TNF-α. The amplification of O₂(●⁻) levels via the activation of B1R-NADPH oxidase may exacerbate pulmonary inflammation and contribute to the chronicity of tobacco smoke-related lung diseases.
肺部炎症是与吸烟有关的肺部疾病的重要病理特征。在长期暴露于香烟烟雾的大鼠气管中，激肽 B1 受体（B1R）上调。本研究旨在确定：（1）香烟烟雾总颗粒物（TPM）暴露是否会诱导人肺泡上皮 A549 细胞中的 B1R；（2）B1R 诱导的机制；（3）新合成的 B1R 的功能；（4）B1R 在 TPM 诱导的超氧阴离子（O₂(●⁻)）水平升高中的作用。结果表明，暴露于 10 μg/ml TPM 的 A549 细胞增加了 O₂(●⁻)水平，同时增加了 B1R（蛋白和 mRNA）和 IL-1β mRNA。相反，B2R 和 TNF-α mRNA 不受 TPM 影响。B1R 拮抗剂 SSR240612 对 TPM 增加 O₂(●⁻)水平的影响没有显著影响。用 N-乙酰-L-半胱氨酸（有效抗氧化剂）、二苯乙烯碘（NADPH 氧化酶抑制剂）、IL-1Ra（白细胞介素-1R 拮抗剂）和 SN-50（NF-κB 激活的特异性抑制剂）共同处理可预防 TPM 增加 B1R mRNA，但不能预防五氧嘧啶（TNF-α释放抑制剂）、吲哚美辛和尼氟灭酸（COX-1 和 COX-2 抑制剂）。用选择性激动剂（des-Arg⁹-BK，10 μM；30 分钟）刺激 B1R 会增加 O₂(●⁻)的产生，该作用可被 apocynin 和二苯乙烯碘（NADPH 氧化酶抑制剂）阻止。数据表明，TPM 在 A549 细胞中增加 B1R 的表达是由氧化应激、IL-1β 和 NF-κB 介导的，而不是由环加氧酶或 TNF-α介导的。通过激活 B1R-NADPH 氧化酶放大 O₂(●⁻)水平可能会加剧肺部炎症并导致与吸烟有关的肺部疾病的慢性化。
