Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, PR China.
Respir Physiol Neurobiol. 2010 Mar 31;170(3):253-9. doi: 10.1016/j.resp.2010.02.002. Epub 2010 Feb 10.
The aim of the present study was to evaluate the effects of the CC chemokine receptor (CCR) 2b and CCR1 antagonist RS504393 as well as the roles of CCRs on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In A549 cell line, treatment with RS504393 significantly inhibited the expression of CCR1, CCR2 and interleukin (IL)-8 after either LPS or tumor necrosis factor-alpha stimulation. An ALI model with intranasal LPS administration was used on C57BL/6J, CCR1, CCR2 and CCR3 knockout mice. Treatment with RS504393 had a noteworthy preventative effect on LPS-induced over-expression of IL-1beta, plasminogen activator inhibitor and CCR2. In CCR1 and CCR2-deficient animals, LPS-induced less increase of lung weight, bronchoalveolar lavage (BAL) leukocytes and IL-6 compared to the C57BL/6J and CCR3 knockout mice. This was most prominent in the CCR2 knockout mice where no LPS-induced lung edema and no increase of IL-6 in BAL fluid occurred. Our results indicate that CCR2, and to some extent CCR1, play pivotal roles in the development of ALI.
本研究旨在评估 CC 趋化因子受体（CCR）2b 和 CCR1 拮抗剂 RS504393 的作用以及 CCRs 在脂多糖（LPS）诱导的急性肺损伤（ALI）中的作用。在 A549 细胞系中，RS504393 处理可显著抑制 LPS 或肿瘤坏死因子-α刺激后 CCR1、CCR2 和白细胞介素（IL）-8 的表达。通过鼻内给予 LPS 建立了 C57BL/6J、CCR1、CCR2 和 CCR3 基因敲除小鼠的 ALI 模型。RS504393 治疗对 LPS 诱导的 IL-1β、纤溶酶原激活物抑制剂和 CCR2 的过度表达具有显著的预防作用。与 C57BL/6J 和 CCR3 基因敲除小鼠相比，CCR1 和 CCR2 基因敲除动物的肺重量、支气管肺泡灌洗液（BAL）白细胞和 IL-6 的增加明显减少。在 CCR2 基因敲除小鼠中最为明显，LPS 诱导的肺水肿和 BAL 液中 IL-6 的增加均未发生。我们的结果表明，CCR2，在一定程度上 CCR1，在 ALI 的发展中起关键作用。
