Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes.
Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes.
复制标题
DOI：
10.1186/1743-8977-8-27
复制
发表时间：
2011-09-06
影响因子：
10
通讯作者：
Donaldson K
中科院分区：
文献类型：
--
作者：
Cho WS;Duffin R;Howie SE;Scotton CJ;Wallace WA;Macnee W;Bradley M;Megson IL;Donaldson K
大量生产氧化锌纳米颗粒（ZnONP）可能会造成职业甚至消费者环境中意外吸入的风险。我们进一步研究了ZnONP引起的病理改变及其可能的作用机制。将两种剂量的ZnONP（50和150 cm2/大鼠）经气管灌注到大鼠肺中，并在注射后24小时、1周和4周进行评估，以评估剂量和时间过程反应。评估包括支气管肺泡灌洗（BAL）液分析、组织学分析、透射电镜、血清和BAL液中的IgE和IgA测定。为探讨其作用机制，大鼠同时灌胃ZnONP、不含ZnONP的支气管肺泡灌洗液和溶解Zn2+ （92.5 μg/大鼠）。用吖啶橙染色法对培养的巨噬细胞评价NP对溶酶体膜的破坏作用。ZnONP诱导嗜酸性粒细胞增多、气道上皮细胞增殖、杯状细胞增生和肺纤维化。慢性期支气管中心性间质性肺纤维化与肌成纤维细胞积累增加和转化生长因子-β阳性相关。ZnONP可上调血清IgE水平，同时下调血清IgA水平。ZnONP在酸性条件下（pH 4.5）迅速溶解，而在中性（pH 7.4）周围保持完整。溶解后的Zn2+注入大鼠肺也出现了类似的病理变化(如：，嗜酸性粒细胞增多，支气管中心性间质纤维化)，由ZnONP引起。ZnONP处理巨噬细胞后，溶酶体稳定性降低，细胞死亡。我们假设吞噬体内ZnONP的快速、ph依赖性溶解是ZnONP诱导的各种进行性严重肺损伤的主要原因。
Large production volumes of zinc oxide nanoparticles (ZnONP) might be anticipated to pose risks, of accidental inhalation in occupational and even in consumer settings. Herein, we further investigated the pathological changes induced by ZnONP and their possible mechanism of action. Two doses of ZnONP (50 and 150 cm2/rat) were intratracheally instilled into the lungs of rats with assessments made at 24 h, 1 wk, and 4 wks after instillation to evaluate dose- and time-course responses. Assessments included bronchoalveolar lavage (BAL) fluid analysis, histological analysis, transmission electron microscopy, and IgE and IgA measurement in the serum and BAL fluid. To evaluate the mechanism, alternative ZnONP, ZnONP-free bronchoalveolar lavage exudate, and dissolved Zn2+ (92.5 μg/rat) were also instilled to rats. Acridine orange staining was utilized in macrophages in culture to evaluate the lysosomal membrane destabilization by NP. ZnONP induced eosinophilia, proliferation of airway epithelial cells, goblet cell hyperplasia, and pulmonary fibrosis. Bronchocentric interstitial pulmonary fibrosis at the chronic phase was associated with increased myofibroblast accumulation and transforming growth factor-β positivity. Serum IgE levels were up-regulated by ZnONP along with the eosinophilia whilst serum IgA levels were down-regulated by ZnONP. ZnONP are rapidly dissolved under acidic conditions (pH 4.5) whilst they remained intact around neutrality (pH 7.4). The instillation of dissolved Zn2+ into rat lungs showed similar pathologies (eg., eosinophilia, bronchocentric interstitial fibrosis) as were elicited by ZnONP. Lysosomal stability was decreased and cell death resulted following treatment of macrophages with ZnONP in vitro. We hypothesise that rapid, pH-dependent dissolution of ZnONP inside of phagosomes is the main cause of ZnONP-induced diverse progressive severe lung injuries.
登录
查看更多内容
影响因子：
3.8
作者：
Dong, CC;Yin, XJJ;Ma, JKH
通讯作者：
Ma, JKH
影响因子：
10.4
作者：
Hirshon JM;Shardell M;Alles S;Powell JL;Squibb K;Ondov J;Blaisdell CJ
通讯作者：
Blaisdell CJ
影响因子：
2.7
作者：
Filipe, P.;Silva, J. N.;Pinheiro, T.
通讯作者：
Pinheiro, T.
影响因子：
5.8
作者：
Conroy DM;Williams TJ
通讯作者：
Williams TJ
影响因子：
2.8
作者：
Evaldsson, Chamilly;Ryden, Ingvar;Uppugunduri, Srinivas
通讯作者：
Uppugunduri, Srinivas