Yang H M, Barger M W, Castranova V, Ma J K, Yang J J, Ma J Y
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA.
J Toxicol Environ Health A. 1999 Nov 12;58(5):261-78. doi: 10.1080/009841099157232.
The effects of diesel exhaust particle (DEP) exposure on alveolar macrophage (AM) response to ex vivo and in vivo lipopolysaccharide (LPS) challenge were determined by monitoring LPS-stimulated production of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). The roles of the insoluble particulate and the organic compounds of DEP in altering pulmonary responses were evaluated by comparing the DEP-induced pulmonary responses to those of carbon black (CB), a carbonaceous particle with few adsorbed organic compounds, or to silica, a known pneumotoxic dust. Male Sprague-Dawley rats were exposed to a single intratracheal dose (5 or 35 mg/kg body weight) of DEP, CB, or silica, or to saline vehicle. Rats were sacrificed 1, 3, or 7 d postexposure. To study the responsiveness to the bacterial product LPS, AM isolated from particle-exposed rats were challenged ex vivo with LPS (0.1 microg/10(6) AM) and LPS-stimulated cytokine release was monitored. In addition, rats were exposed intratracheally to a single dose of DEP (5 mg/kg) and 3 d later exposed in vivo to 1 mg/kg LPS for 3 h prior to measurement of cytokine production by AM. DEP exposure resulted in neutrophil infiltration and elevated levels of albumin and lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage fluid; these responses were not substantially different from those elicited by CB or silica exposure. AM from DEP-exposed rats showed increased spontaneous production of IL-1, but not TNF-alpha, while the opposite was true for CB or silica. Upon ex vivo challenge with LPS, AM from DEP-exposed rats showed a significant decrease in the secretion of TNF-alpha and, to a lesser extent, IL-1, compared to the sum of the DEP and LPS effects. In contrast, AM from CB- or silica-exposed rats did not show this decreased responsiveness to subsequent LPS challenge. This inhibitory action of DEP on LPS-stimulated AM production of IL-1 and TNF-alpha was further confirmed by the results obtained from rats exposed to both DEP and LPS in vivo. In summary, these results indicate that while DEP, CB, and silica all induce pulmonary inflammatory responses due to particle stimulation, only DEP suppress AM cytokine release in response to LPS stimulation. The contrasting cellular response with respect to DEP and CB exposures may be due to the presence of adsorbed organic compounds on DEP, which may contribute to the increased susceptibility of hosts to pulmonary infections after DEP exposure.
通过监测脂多糖（LPS）刺激的白细胞介素-1（IL-1）和肿瘤坏死因子-α（TNF-α）的产生，确定柴油废气颗粒（DEP）暴露对肺泡巨噬细胞（AM）对离体和体内LPS刺激反应的影响。通过比较DEP诱导的肺反应与炭黑（CB，一种吸附有机化合物很少的碳质颗粒）或二氧化硅（一种已知的肺毒性粉尘）的肺反应，评估DEP的不溶性颗粒和有机化合物在改变肺反应中的作用。将雄性Sprague-Dawley大鼠经气管内给予单次剂量（5或35mg/kg体重）的DEP、CB或二氧化硅，或给予生理盐水载体。在暴露后1、3或7天处死大鼠。为了研究对细菌产物LPS的反应性，用LPS（0.1μg/10⁶个AM）对从颗粒暴露大鼠分离的AM进行离体刺激，并监测LPS刺激的细胞因子释放。此外，大鼠经气管内给予单次剂量的DEP（5mg/kg），3天后在体内给予1mg/kg LPS 3小时，然后测量AM产生的细胞因子。DEP暴露导致支气管肺泡灌洗液中中性粒细胞浸润以及白蛋白和乳酸脱氢酶（LDH）活性水平升高；这些反应与CB或二氧化硅暴露引起的反应没有实质性差异。来自DEP暴露大鼠的AM显示IL-1的自发产生增加，但TNF-α没有，而CB或二氧化硅的情况则相反。在用LPS进行离体刺激时，与DEP和LPS的联合作用相比,来自DEP暴露大鼠的AM显示TNF-α分泌显著减少，IL-1分泌减少程度较小。相比之下，来自CB或二氧化硅暴露大鼠的AM对随后的LPS刺激没有显示出这种反应性降低。从体内同时暴露于DEP和LPS的大鼠获得的结果进一步证实了DEP对LPS刺激的AM产生IL-1和TNF-α的抑制作用。总之，这些结果表明，虽然DEP、CB和二氧化硅都因颗粒刺激而诱导肺部炎症反应，但只有DEP抑制AM对LPS刺激的细胞因子释放。DEP和CB暴露在细胞反应方面的差异可能是由于DEP上存在吸附的有机化合物，这可能导致宿主在DEP暴露后对肺部感染的易感性增加。
