Department of Health Risk Analysis and Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, PO box 616, 6200 MD, Maastricht, the Netherlands.
Respir Res. 2010 Feb 25;11(1):24. doi: 10.1186/1465-9921-11-24.
Lung cancer often develops in association with chronic pulmonary inflammatory diseases with an influx of neutrophils. More detailed information on inflammatory pathways and the role of neutrophils herein is a prerequisite for understanding the mechanism of inflammation associated cancer.
In the present study, we used microarrays in order to obtain a global view of the transcriptional responses of the lung to LPS in mice, which mimics an acute lung inflammation. To investigate the influence of neutrophils in this process, we depleted mice from circulating neutrophils by treatment with anti-PMN antibodies prior to LPS exposure.
A total of 514 genes was greater than 1.5-fold differentially expressed in the LPS induced lung inflammation model. 394 of the 514 were up regulated genes mostly involved in cell cycle and immune/inflammation related processes, such as cytokine/chemokine activity and signalling. Down regulated genes represented nonimmune processes, such as development, metabolism and transport. Notably, the number of genes and pathways that were differentially expressed, was reduced when animals were depleted from circulating neutrophils, confirming the central role of neutrophils in the inflammatory response. Furthermore, there was a significant correlation between the differentially expressed gene list and the promutagenic DNA lesion M1dG, suggesting that it is the extent of the immune response which drives genetic instability in the inflamed lung. Several genes that were specifically regulated by the presence of activated neutrophils could be identified and these were mostly involved in interferon signalling, oxidative stress response and cell cycle progression. The latter possibly refers to a higher rate of cell turnover in the inflamed lung with neutrophils, suggesting that the neutrophil influx is associated with a higher risk for the accumulation and fixation of mutations.
Gene expression profiling identified specific genes and pathways that are related to neutrophilic inflammation and could be associated to cancer development and indicate an active role of neutrophils in mediating the LPS induced inflammatory response in the mouse lung.
肺癌常与伴有中性粒细胞浸润的慢性肺部炎症性疾病有关。更详细的炎症途径信息和中性粒细胞在此处的作用是理解炎症相关癌症机制的前提。
在本研究中，我们使用微阵列技术来获得 LPS 刺激小鼠肺部转录反应的全景图，这模拟了急性肺部炎症。为了研究中性粒细胞在这个过程中的影响，我们在用抗 PMN 抗体处理小鼠以耗尽循环中的中性粒细胞后，再用 LPS 进行处理。
在 LPS 诱导的肺部炎症模型中，共有 514 个基因的表达差异大于 1.5 倍。在这 514 个基因中，有 394 个上调基因主要涉及细胞周期和免疫/炎症相关过程，如细胞因子/趋化因子活性和信号转导。下调基因代表非免疫过程，如发育、代谢和运输。值得注意的是，当动物被耗尽循环中的中性粒细胞时，差异表达的基因和通路数量减少，这证实了中性粒细胞在炎症反应中的核心作用。此外，差异表达基因列表与促突变 DNA 损伤 M1dG 之间存在显著相关性，表明是免疫反应的程度导致了炎症肺部的遗传不稳定性。可以鉴定出一些受激活中性粒细胞特异性调节的基因，这些基因主要涉及干扰素信号转导、氧化应激反应和细胞周期进展。后者可能指的是炎症肺部中中性粒细胞存在时更高的细胞更新率，这表明中性粒细胞的涌入与突变的积累和固定的风险增加有关。
基因表达谱分析确定了与中性粒细胞炎症相关的特定基因和途径，这些基因和途径可能与癌症的发展有关，并表明中性粒细胞在介导小鼠肺部 LPS 诱导的炎症反应中具有积极作用。
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