Comprehensive Pneumology Center-Institute of Lung Biology and Disease and Focus Network Nanoparticles and Health, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Acc Chem Res. 2013 Mar 19;46(3):714-22. doi: 10.1021/ar300043r. Epub 2012 Sep 17.
Researchers need to study the biokinetics of inhaled biopersistent nano- and micrometer-sized particles (NPs and μPs) to assess their toxicity and to develop an understanding of their potential risks. When particles are inhaled, they do not necessarily remain at their sites of deposition in the respiratory tract. Instead they can undergo numerous transport processes within the various tissues of the lungs, including clearance from the lungs. In this context, we would like to understand how the biokinetic studies performed in animals can be extrapolated to humans. Interestingly, the particle retention is much shorter in rodent lungs and declines much faster than it does in human, simian, and canine lungs. The predominant long-term clearance pathway for both NPs and μPs in humans and other animal species is macrophage-mediated particle transport from the peripheral lungs toward ciliated airways and the larynx. However, the transport rate is 10 times higher in rodents than in other species. In addition to particle clearance out of the lung, we also observe particle redistribution from the epithelium toward and within the interstitium and lymph nodes of the lung and particle translocation to blood circulation leading to subsequent accumulation in secondary organs. While μPs have limited access to interstitial spaces in the rodent lungs, NPs rapidly relocate in the epithelium and the underlying interstitium. By contrast, indirect evidence shows that both NPs and μPs are relocated into the epithelium and interstitial spaces of the human, simian, and canine lungs. Only NPs translocate into the circulatory system and subsequently accumulate in the secondary organs and tissues of the body. Translocated NP fractions are rather low, but they depend strongly on the physicochemical properties of the NP and their surface properties. Growing evidence indicates that the binding and conjugation of proteins to NPs play an essential role in translocation across cellular membranes and organ barriers. In summary, particle biokinetics result from a multitude of highly dynamic processes, which depend not only on physicochemical properties of the particles but also on a multitude of cellular and molecular responses and interactions. Given the rather small accumulation in secondary organs after acute inhalation exposures, it appears likely that adverse effects caused by NPs accumulated in secondary organs may only occur after chronic exposure over extended time periods. Therefore adverse health effects in secondary organs such as the cardiovascular system that are associated with chronic exposure of ambient urban air pollution are less likely to result from particle translocation. Instead, chronic particle inhalation could trigger or modulate the autonomous nervous system or the release of soluble mediators into circulation leading to adverse health effects.
研究人员需要研究吸入的生物持久性纳米和微米级颗粒（NPs 和 μPs）的生物动力学，以评估它们的毒性，并了解它们的潜在风险。当颗粒被吸入时，它们不一定会停留在呼吸道的沉积部位。相反，它们可以在肺部的各种组织中经历许多转运过程，包括从肺部清除。在这种情况下，我们希望了解在动物中进行的生物动力学研究如何可以外推到人类。有趣的是，在啮齿动物肺部中，颗粒的保留时间要短得多，并且下降速度比人类、灵长类动物和犬类肺部快得多。NPs 和 μPs 在人类和其他动物物种中的主要长期清除途径是巨噬细胞介导的颗粒从外周肺部向纤毛气道和喉头的运输。然而，在啮齿动物中的转运速率比其他物种高 10 倍。除了从肺部清除颗粒外，我们还观察到颗粒从上皮细胞向肺的间质和淋巴结内以及从颗粒向血液循环的再分布，导致随后在次级器官中的积累。虽然 μPs 进入啮齿动物肺部的间质空间有限，但 NPs 会迅速在上皮细胞和下面的间质中重新定位。相比之下，间接证据表明，NPs 和 μPs 都被重新定位到人类、灵长类动物和犬类肺部的上皮细胞和间质空间中。只有 NPs 转移到血液循环系统中，随后在次级器官和身体组织中积累。转移的 NP 分数相当低，但它们强烈依赖于 NP 的物理化学性质及其表面性质。越来越多的证据表明，蛋白质与 NPs 的结合和缀合在跨细胞膜和器官屏障的转运中起着至关重要的作用。总之，颗粒的生物动力学是由许多高度动态的过程产生的，这些过程不仅取决于颗粒的物理化学性质，还取决于许多细胞和分子反应和相互作用。鉴于在急性吸入暴露后次级器官中的积累量相当小，似乎不太可能由次级器官中积累的 NPs 引起的不良反应仅在慢性暴露于延长时间后才会发生。因此，与慢性暴露于环境城市空气污染相关的心血管系统等次级器官中的不良健康影响不太可能是由于颗粒的转运引起的。相反，慢性颗粒吸入可能会触发或调节自主神经系统或可溶性介质释放到循环中，从而导致不良健康影响。
