Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Av. Prof. Lineu Prestes, 1730, ICB IV, 05508-900, São Paulo, SP, Brazil.
Eur J Pharmacol. 2010 May 25;634(1-3):132-7. doi: 10.1016/j.ejphar.2010.02.002. Epub 2010 Feb 11.
Lipopolysaccharides from gram-negative bacteria are amongst the most common causative agents of acute lung injury, which is characterized by an inflammatory response, with cellular infiltration and the release of mediators/cytokines. There is evidence that bradykinin plays a role in lung inflammation in asthma but in other types of lung inflammation its role is less clear. In the present study we evaluated the role of the bradykinin B1 receptor in acute lung injury caused by lipopolysaccharide inhalation and the mechanisms behind bradykinin actions participating in the inflammatory response. We found that in C57Bl/6 mice, the bradykinin B1 receptor expression was up-regulated 24h after lipopolysaccharide inhalation. At this time, the number of cells and protein concentration were significantly increased in the bronchoalveolar lavage fluid and the mice developed airway hyperreactivity to methacholine. In addition, there was an increased expression of tumor necrosis factor-alpha, interleukin-1 beta and interferon-gamma and chemokines (monocytes chemotactic protein-1 and KC) in the bronchoalveolar lavage fluid and in the lung tissue. We then treated the mice with a bradykinin B1 receptor antagonist, R-954 (Ac-Orn-[Oic2, alpha-MePhe5, D-betaNal7, Ile8]desArg9-bradykinin), 30 min after lipopolysaccharide administration. We observed that this treatment prevented the airway hyperreactivity as well as the increased cellular infiltration and protein content in the bronchoalveolar lavage fluid. Moreover, R-954 inhibited the expression of cytokines/chemokines. These results implicate bradykinin, acting through B1 receptor, in the development of acute lung injury caused by lipopolysaccharide inhalation.
革兰氏阴性菌的脂多糖是急性肺损伤最常见的致病因素之一，其特征是炎症反应，伴有细胞浸润和介质/细胞因子的释放。有证据表明缓激肽在哮喘中的肺炎症中起作用，但在其他类型的肺炎症中其作用不太清楚。在本研究中，我们评估了缓激肽 B1 受体在脂多糖吸入引起的急性肺损伤中的作用以及缓激肽参与炎症反应的作用机制。我们发现，在 C57Bl/6 小鼠中，脂多糖吸入后 24 小时缓激肽 B1 受体表达上调。此时，支气管肺泡灌洗液中的细胞数量和蛋白浓度显著增加，并且小鼠对乙酰甲胆碱产生气道高反应性。此外，支气管肺泡灌洗液和肺组织中肿瘤坏死因子-α、白细胞介素-1β和干扰素-γ以及趋化因子（单核细胞趋化蛋白-1 和 KC）的表达增加。然后，我们在脂多糖给药 30 分钟后用缓激肽 B1 受体拮抗剂 R-954（Ac-Orn-[Oic2，alpha-MePhe5，D-betaNal7，Ile8]desArg9-缓激肽）处理小鼠。我们观察到这种治疗可预防气道高反应性以及支气管肺泡灌洗液中细胞浸润和蛋白含量的增加。此外，R-954 抑制了细胞因子/趋化因子的表达。这些结果表明，缓激肽通过 B1 受体参与了脂多糖吸入引起的急性肺损伤的发生。
