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首页> 外文期刊>Archives of Toxicology >Dectin-1 and inflammation-associated gene transcription and expression in mouse lungs by a toxic (1,3)-beta-d glucan
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Dectin-1 and inflammation-associated gene transcription and expression in mouse lungs by a toxic (1,3)-beta-d glucan

机译：毒性（1,3）-β-d葡聚糖在小鼠肺中的Dectin-1和与炎症相关的基因转录和表达

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The form of (1-3)-beta-d glucan found in the cell walls of the anamorphic Trichocomaceae that grow on damp building materials is considered to have potent toxic and inflammatory effects on cells of the respiratory system. It is also considered to have a potential role in the development of non-allergenic respiratory health effects. While human studies involving experimental exposures all point to the inflammatory potential of pure curdlan, a linear (1-3)-beta-d glucan in a triple helix configuration, animal experiments result in conflicting conclusions concerning the inflammatory potency of this glucan. However, because mice appear to be a better model than guinea pigs for exploring the respiratory effects of curdlan and because molecular mechanisms associated with this glucan remain largely unknown, we conducted further work to clarify the role of curdlan on the inflammatory response using our mouse model of lung disease. This study used in situ hybridization (ISH) to probe dectin-1 mRNA transcription with a digoxigenin-labeled cDNA probe, with reverse transcription (RT)-PCR based arrays used to measure inflammation gene and receptor transcriptional responses. Also, immunohistochemistry (IHC) was used to probe dectin-1 as well as anti-mouse Ccl3, Il1-alpha, and TNF-alpha expression to evaluate dose and time-course (4 and 12 h) postex-posure (PE) response patterns in the lungs of intratracheally instilled mice exposed to a single 50 ul dose of curdlan at 10~(-7), 10~(-8), 10~(-9), and 10~(-10) M/animal (=4 mug to 4 ng curd-lan/kg lung wt). Dectin-1 mRNA transcription and expression was observed in bronchiolar epithelium, alveolar macrophages (AMs), and alveolar type II cells (ATIIs) of lungs exposed to 4 ug to 40 ng curdlan/kg lung wt, at both time points. Compared to controls, array analysis revealed that 54 of 83 genes assayed were significantly modulated by curdlan. mRNA transcription patterns showed both dose and time dependency, with highest transcription levels in 10~(-7) and 10~(-8) M treatment animals, especially at 4-h PE. Nine gene mRNA transcripts (Ccl3, Ccll1, Cell 7, Ifng, Il1alpha, Il-20, TNF-alpha, Tnfrsflb, and CD40lg) were significantly expressed at all doses suggesting they may have a central role in immunomodulating curdlan exposures. IHC revealed Ccl3, Il1-alpha, and TNF-alpha expression in bronchiolar epithelium, AMs and ATIIs illustrate the important immunomodulatory role that these cells have in the recognition of, and response to glucan. Collectively, these results confirm the inflammatory nature of curdlan and demonstrate the complex of inflammation-associated gene responses induced by (1-3)-beta-d glucan in triple helical forms. These observations also provide a biological basis for the irritant and inflammatory response to curdlan observed in humans and animals in experimental studies.
机译：在变形的滴虫科的细胞壁上发现的（1-3）-β-d葡聚糖的形式在潮湿的建筑材料上生长被认为对呼吸系统的细胞具有强力的毒性和炎症作用。它也被认为在非过敏性呼吸健康影响的发展中具有潜在作用。虽然涉及实验性暴露的人体研究都指出纯的凝胶多糖（一种三螺旋结构的线性（1-3）-β-d葡聚糖）的炎性潜能，但动物实验得出的关于这种葡聚糖炎性的结论相互矛盾。但是，由于小鼠似乎是比豚鼠更好的模型，可用于研究柯德兰的呼吸作用，并且由于与这种葡聚糖有关的分子机制仍然未知，因此我们使用小鼠模型进行了进一步的工作，以阐明柯德兰在炎症反应中的作用肺部疾病。这项研究使用原位杂交（ISH）来用洋地黄毒苷标记的cDNA探针探测dectin-1 mRNA的转录，并使用基于逆转录（RT）-PCR的阵列来测量炎症基因和受体的转录反应。同样，免疫组化（IHC）被用来探测dectin-1以及抗小鼠Ccl3，Il1-alpha和TNF-alpha的表达，以评估暴露后（PE）反应的剂量和时间（4和12小时）气管内滴注的小鼠在10〜（-7），10〜（-8），10〜（-9）和10〜（-10）M /动物（ = 4杯至4 ng curd-lan / kg肺重量）。在两个时间点，暴露于4 ug至40 ng curdlan / kg肺重量的肺细支气管上皮，肺泡巨噬细胞（AM）和肺泡II型细胞（ATIIs）中均观察到Dectin-1 mRNA的转录和表达。与对照相比，阵列分析显示，测定的83种基因中有54种受到了柯德兰的显着调节。在10〜（-7）和10〜（-8）M处理动物中，尤其是在4 h PE时，mRNA转录模式表现出剂量和时间依赖性，转录水平最高。九种基因mRNA转录本（Ccl3，Ccll1，Cell 7，Ifng，Il1alpha，Il-20，TNF-alpha，Tnfrsflb和CD40lg）在所有剂量下均得到显着表达，表明它们可能在免疫调节柯德兰暴露中发挥重要作用。 IHC揭示了细支气管上皮，AM和ATII中Ccl3，Il1-alpha和TNF-alpha的表达说明了这些细胞在识别和响应葡聚糖方面的重要免疫调节作用。总的来说，这些结果证实了凝胶多糖的炎性并且证明了由（1-3）-β-d葡聚糖以三重螺旋形式诱导的与炎症相关的基因应答的复合物。这些观察结果还为在实验研究中在人和动物中观察到的对凝胶多糖的刺激和炎性反应提供了生物学基础。

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