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Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation
Particle and Fibre Toxicology ( IF 10 ) Pub Date : 2021-09-08 , DOI: 10.1186/s12989-021-00427-w
Tamara L Young 1 , Ekaterina Mostovenko 2 , Jesse L Denson 1 , Jessica G Begay 1 , Selita N Lucas 1 , Guy Herbert 1 , Katherine Zychowski 3 , Russell Hunter 1 , Raul Salazar 1 , Ting Wang 4 , Kelly Fraser 5 , Aaron Erdely 5 , Andrew K Ottens 2 , Matthew J Campen 1
Affiliation  

Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

中文翻译:

广谱基质金属蛋白酶抑制剂 marimastat 的肺部递送可减少多壁碳纳米管诱导的循环生物活性,但不会减少肺部炎症

多壁碳纳米管 (MWCNT) 是一种越来越多使用的工程纳米材料,可能会导致与暴露相关的健康后果的重大风险。MWCNT 诱导的肺外位点毒性的潜在机制仍在定义中。MWCNT 诱导的血清生物活性似乎会失调全身内皮细胞功能。MWCNT 暴露后血清成分的变化已被确定为片段化内源性肽的激增,可能源自基质金属蛋白酶 (MMP) 活性。在本研究中,我们利用广谱 MMP 抑制剂 Marimastat 以及先前描述的 MWCNT 给药的口咽抽吸模型来研究 MMP 在 MWCNT 衍生的血清肽生成和内皮生物活性中的作用。在 MWCNT 治疗前 1 小时,通过口咽抽吸用 Marimastat 或载体对 C57BL/6 小鼠进行治疗。肺中性粒细胞浸润和总支气管肺泡灌洗液蛋白增加,与 MMP 阻断无关。主要炎症标志物(IL-1β、IL-6 和 TNF-α)的 MWCNT 暴露后,肺细胞因子谱类似地增加,而 MMP 抑制的影响最小。然而,血清肽组学分析揭示了不同的肽组成特征,MMP 阻断取消了 MWCNT 衍生的血清肽片段。反过来,当与原代鼠脑血管内皮细胞一起孵育时,血清在炎症生物活性方面表现出不同的效力。来自 MWCNT 处理的小鼠的血清导致内皮细胞的炎症反应,而 Marimastat 处理的小鼠的血清显着减弱了这些反应。因此,MWCNT 暴露诱导的肺部炎症很大程度上独立于 MMP 活性,但主要通过 MMP 依赖途径产生循环生物活性肽。这种 MWCNT 诱导的肺源性生物活性导致内皮炎症和屏障破坏的病理结果。
更新日期:2021-09-08
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