肺部颗粒诱导的发病机制仍然知之甚少。肺中的嗜中性粒细胞炎症和氧化应激是毒性的标志。一些研究人员推测,粉尘上颗粒表面活性氧(psROS)的氧化应激会在暴露于粉尘的动物的肺部产生毒理病理学。该假设与阐明月球尘埃(LD)毒性的研究同时进行了测试,由于高速微流星体轰击使月球表面风化层破裂和粉化,据信其中含有psROS。用三种LD(由阿波罗14号月球风化石制备)气管内滴注(ITI)的大鼠的研究结果,PSROS的水平相差14倍,和两个毒性参考粉尘(TiO2和石英)表明psROS对肺中的粉尘毒性没有显着贡献。此处报道了LD毒性研究小组对5粉尘ITI研究中的大鼠和暴露于空气中LD4周的大鼠收获的肺泡中性粒细胞中氧化剂的毒理学作用的进一步研究结果。每个中性粒细胞和所有中性粒细胞的氧化剂随剂量而增加,暴露时间和粉尘的细胞毒性。结果表明,肺泡中性粒细胞在粉尘暴露动物肺部颗粒诱导的损伤和毒性中起关键作用。基于这些结果,我们提出了颗粒相关性肺病的不良结局途径(AOP),该途径以肺泡中性粒细胞来源的氧化剂的关键作用为中心.对有关颗粒暴露和肺部疾病的毒理学文献的严格审查进一步支持了中性粒细胞中心机制在肺部疾病的发病机理中,并可能解释了先前报道的动物物种对难溶性颗粒的反应差异。毒理学文献的主要发现表明(1)暴露于相同数量的相同粉尘后,大鼠比仓鼠有更多的肺泡中性粒细胞;仓鼠从肺部清除更多的颗粒,因此导致较少的中性粒细胞和较不严重的肺部病变;(2)暴露于纳米尺寸TiO2的大鼠比暴露于相同质量浓度的微米尺寸TiO2的大鼠具有更多的中性粒细胞和更严重的肺部病变;与相同质量的微米尺寸的灰尘相比,纳米尺寸的灰尘具有更多的颗粒数量和更大的总颗粒-细胞接触表面积,这会触发更多的肺泡上皮细胞(AECs)合成并释放更多的细胞因子,从而招募更多的中性粒细胞,从而导致更严重的病变。因此,我们假设,在长期接触灰尘期间,颗粒引起的AECs持续释放细胞因子,招募嗜中性粒细胞并激活它们以产生氧化剂,从而导致长期持续的内源性氧化应激源,从而导致肺毒性。这种中性粒细胞驱动的肺发病机制解释了为什么灰尘暴露在大鼠中引起比仓鼠更严重的病变;为什么,在质量剂量基础上,纳米尺寸的粉尘比微米尺寸的粉尘毒性更大;为什么肺部病变会随着时间的推移而发展;以及为什么颗粒毒性的剂量反应曲线表现出具有阈值的曲棍球棒形状。以中性粒细胞为中心的AOP用于颗粒诱导的肺部疾病对人类暴露于灰尘颗粒和环境颗粒物的风险评估具有意义。
The mechanisms of particle-induced pathogenesis in the lung remain poorly understood. Neutrophilic inflammation and oxidative stress in the lung are hallmarks of toxicity. Some investigators have postulated that oxidative stress from particle surface reactive oxygen species (psROS) on the dust produces the toxicopathology in the lungs of dust-exposed animals. This postulate was tested concurrently with the studies to elucidate the toxicity of lunar dust (LD), which is believed to contain psROS due to high-speed micrometeoroid bombardment that fractured and pulverized lunar surface regolith. Results from studies of rats intratracheally instilled (ITI) with three LDs (prepared from an Apollo-14 lunar regolith), which differed 14-fold in levels of psROS, and two toxicity reference dusts (TiO2 and quartz) indicated that psROS had no significant contribution to the dusts\' toxicity in the lung. Reported here are results of further investigations by the LD toxicity study team on the toxicological role of
oxidants in alveolar neutrophils that were harvested from rats in the 5-dust ITI study and from rats that were exposed to airborne LD for 4 weeks. The
oxidants per neutrophils and all neutrophils increased with dose, exposure time and dust\'s cytotoxicity. The results suggest that alveolar neutrophils play a critical role in particle-induced injury and toxicity in the lung of dust-exposed animals. Based on these results, we propose an adverse outcome pathway (AOP) for particle-associated lung disease that centers on the crucial role of alveolar neutrophil-derived oxidant species. A critical
review of the toxicology literature on particle exposure and lung disease further supports a neutrophil-centric mechanism in the pathogenesis of lung disease and may explain previously reported animal species differences in responses to poorly soluble particles. Key findings from the toxicology literature indicate that (1) after exposures to the same dust at the same amount, rats have more alveolar neutrophils than hamsters; hamsters clear more particles from their lungs, consequently contributing to fewer neutrophils and less severe lung lesions; (2) rats exposed to nano-sized TiO2 have more neutrophils and more severe lesions in their lungs than rats exposed to the same mass-concentration of micron-sized TiO2; nano-sized dust has a greater number of particles and a larger total particle-cell contact surface area than the same mass of micron-sized dust, which triggers more alveolar epithelial cells (AECs) to synthesize and release more cytokines that recruit a greater number of neutrophils leading to more severe lesions. Thus, we postulate that, during chronic dust exposure, particle-inflicted AECs persistently release cytokines, which recruit neutrophils and activate them to produce
oxidants resulting in a prolonged continuous source of endogenous oxidative stress that leads to lung toxicity. This neutrophil-driven lung pathogenesis explains why dust exposure induces more severe lesions in rats than hamsters; why, on a mass-dose basis, nano-sized dusts are more toxic than the micron-sized dusts; why lung lesions progress with time; and why dose-response curves of particle toxicity exhibit a hockey stick like shape with a threshold. The neutrophil centric AOP for particle-induced lung disease has implications for risk assessment of human exposures to dust particles and environmental particulate matter.