Integrative Pharmacology, Department of Biosciences, AstraZeneca R&D Lund, Respiratory and Inflammation Research Area, 22187 Lund, Sweden.
Inflamm Res. 2010 Oct;59(10):817-25. doi: 10.1007/s00011-010-0193-5. Epub 2010 Apr 13.
The aim was to create pathological changes in mice relevant to human smoke exposure that can be used to further understand the mechanisms and pathology of smoke-induced inflammatory disease.
Mice were exposed to tobacco smoke or lipopolysaccharide (LPS) to generate an inflammatory infiltrate within the lungs.
Tobacco smoke exposure over a 4 day period led to neutrophilia in the lungs of BALB/c mice. Within the inflammatory exudates, significant changes were also seen in protein levels of IL-1B, IL-6, MIP-2, KC (IL-8) and TIMP-1 as measured by ELISA. Further protein changes, as measured via multiplex analysis revealed increased levels of MMP-9, MDC, LIF and MCP-1, amongst other mediators. Major changes in whole lung tissue gene expression patterns were observed. The neutrophilia seen after smoke exposure was steroid-insensitive, relative to doses of steroid needed to reduce LPS-driven neutrophilia in controls. This exposes pathological switches that are changed upon exposure to tobacco smoke, rendering steroids less effective under these conditions. Challenge of chemokine receptor type 1 (CCR1) KO mice in the tobacco smoke model showed that lack of this gene protected the mice from smoke-induced inflammation.
This suggests the CCR1 receptor has a key role in the pathogenesis of smoke-induced inflammation.
旨在建立与人吸烟暴露相关的小鼠病理学变化模型，以进一步了解吸烟引起的炎症性疾病的机制和病理学。
通过使小鼠暴露于烟草烟雾或脂多糖（LPS），在肺部产生炎症浸润。
在 BALB/c 小鼠中，经过 4 天的烟草烟雾暴露导致肺部嗜中性粒细胞增多。通过 ELISA 测定，在炎症渗出物中，IL-1B、IL-6、MIP-2、KC（IL-8）和 TIMP-1 的蛋白水平也发生了显著变化。通过多重分析进一步测定的蛋白变化表明，MMP-9、MDC、LIF 和 MCP-1 等介质的水平增加。观察到整个肺组织基因表达模式的重大变化。与对照组中减少 LPS 驱动的嗜中性粒细胞所需的类固醇剂量相比，暴露于烟雾后观察到的嗜中性粒细胞增多对类固醇不敏感。这暴露了在接触烟草烟雾时发生变化的病理开关，使类固醇在这些情况下效果降低。在烟草烟雾模型中挑战趋化因子受体 1（CCR1）基因敲除小鼠表明，缺乏该基因可保护小鼠免受烟雾引起的炎症。
这表明 CCR1 受体在吸烟引起的炎症发病机制中具有关键作用。
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