Pulmonary effects of inhaled diesel exhaust in young and old mice: a pilot project.

Debra L Laskin, Gediminas Mainelis, Barbara J Turpin, Kinal J Patel, Vasanthi R Sunil
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Abstract

It is well established that exposure to ambient fine particulate matter (PM), defined as PM < or = 2.5 microm in aerodynamic diameter (PM2.5), is associated with increased cardiovascular morbidity and mortality and that elderly persons are particularly susceptible to these effects. We speculated that the increased susceptibility of elderly persons to PM is due to altered production of inflammatory mediators and antioxidants in the lung. We performed pilot studies in an animal model to test this hypothesis. For these studies we used diesel exhaust (DE), a major component of urban PM, as a model. Two groups of male CB6F1 mice, 2 months and 18 months old, (referred to in this report as young and old mice, respectively) were exposed to DE at 300 or 1000 microg/m3 PM (referred to as low- or high-dose DE, respectively), or to filtered air as a control, for one 3-hour period (single exposure) or for 3 hours on each of three consecutive days (repeated exposure). Mice were killed and bronchoalveolar lavage (BAL) fluid, serum, and lung tissue were collected immediately after exposure (0 hours) and 24 hours after the final exposure. After single or repeated exposure to DE, persistent structural alterations and inflammation were observed in the lungs of old mice. These changes consisted of patchy thickening of alveolar septa and an increase in the number of neutrophils and macrophages in alveolar spaces. In the young mice, in contrast, no major alterations in lung histology were noted. In old but not in young mice, significant increases in messenger RNA (mRNA) expression of the oxidative-stress marker lipocalin 24p3 were also observed. In both young and old mice, exposure to DE was associated with increased expression of tumor necrosis factor alpha (TNF-alpha) mRNA in the lung. However, this response was attenuated in old mice. Exposure to high-dose DE resulted in significant increases in interleukin (IL)-6 and IL-8 mRNA expression in the lungs of old animals; these increases persisted for 24 hours. Whereas IL-6 was also up-regulated in young mice after DE exposure, no major effects were evident on the expression of IL-8 mRNA. Expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was decreased in lung tissue from young animals after single or repeated exposure to DE. In contrast, constitutive expression of MnSOD was not evident in lungs of old mice, and DE had no effect on the expression of this antioxidant. These preliminary data confirm that old mice are more sensitive to DE than young mice and that increased sensitivity is associated with altered expression of inflammatory cytokines and the antioxidant MnSOD. These aberrations may contribute to the increased susceptibility of old mice to inhaled PM.

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吸入柴油废气对年轻和年老小鼠肺部的影响:一个试点项目。
众所周知,暴露于环境细颗粒物(PM)(定义为空气动力学直径<或= 2.5微米的PM (PM2.5))与心血管发病率和死亡率增加有关,老年人特别容易受到这些影响。我们推测老年人对PM的易感性增加是由于肺部炎症介质和抗氧化剂的产生改变。我们在动物模型中进行了初步研究来验证这一假设。在这些研究中,我们使用柴油废气(DE)作为模型,这是城市PM的主要组成部分。两组2个月和18个月大的雄性CB6F1小鼠(在本报告中分别称为年轻小鼠和老年小鼠)暴露于300或1000微克/立方米PM的DE(分别称为低剂量或高剂量DE),或暴露于过滤空气中作为对照,为期3小时(单次暴露)或连续三天各3小时(重复暴露)。在暴露后(0小时)和最终暴露后24小时立即杀死小鼠,收集支气管肺泡灌洗液、血清和肺组织。在单次或多次暴露于DE后,在老年小鼠的肺部观察到持续的结构改变和炎症。这些变化包括肺泡间隔斑片状增厚,肺泡间隙中性粒细胞和巨噬细胞数量增加。相比之下,在年轻小鼠中,肺组织学没有发生重大变化。在年老而非年轻小鼠中,氧化应激标志物脂钙蛋白24p3的信使RNA (mRNA)表达也显著增加。在年轻和老年小鼠中,暴露于DE与肺中肿瘤坏死因子α (tnf - α) mRNA表达增加有关。然而,这种反应在老年小鼠中减弱。暴露于高剂量DE后,老龄动物肺组织中白细胞介素(IL)-6和IL-8 mRNA表达显著升高;这些增加持续了24小时。暴露于DE后,IL-6在幼鼠中也上调,但对IL-8 mRNA的表达没有明显影响。单次或多次暴露于DE后,幼龄动物肺组织中抗氧化酶锰超氧化物歧化酶(MnSOD)的表达降低,而老年小鼠肺组织中MnSOD的组成性表达不明显,DE对该抗氧化剂的表达没有影响。这些初步数据证实,老年小鼠比年轻小鼠对DE更敏感,并且敏感性的增加与炎症细胞因子和抗氧化剂MnSOD的表达改变有关。这些异常可能导致老年小鼠吸入PM的易感性增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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