Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation.
Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation.
复制标题
DOI：
10.1186/s12989-021-00427-w
复制
发表时间：
2021-09-08
影响因子：
10
通讯作者：
Campen MJ
中科院分区：
文献类型：
--
作者：
Young TL;Mostovenko E;Denson JL;Begay JG;Lucas SN;Herbert G;Zychowski K;Hunter R;Salazar R;Wang T;Fraser K;Erdely A;Ottens AK;Campen MJ
多壁碳纳米管 (MWCNT) 是一种越来越多使用的工程纳米材料，可能会带来与暴露相关的健康结果的重大风险。多壁碳纳米管诱导的肺外部位毒性的机制仍在研究中。多壁碳纳米管诱导的血清生物活性似乎会失调全身内皮细胞功能。多壁碳纳米管暴露后血清成分的变化已被确定为碎片化内源肽的激增，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，通过口咽抽吸对 C57BL/6 小鼠进行 Marimastat 或媒介物治疗。肺中性粒细胞浸润和支气管肺泡灌洗液总蛋白增加，与 MMP 阻断无关。 MWCNT 暴露后，主要炎症标志物（IL-1β、IL-6 和 TNF-α）的肺细胞因子谱同样增加，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 阻断消除了 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。 MWCNT 治疗小鼠的血清会引起内皮细胞的炎症反应，而马马司他治疗小鼠的血清可显着减弱这种炎症反应。因此，MWCNT 暴露诱导的肺部炎症在很大程度上独立于 MMP 活性，但主要通过 MMP 依赖性途径产生循环生物活性肽。这种多壁碳纳米管诱导的肺源性生物活性导致内皮炎症和屏障破坏的病理后果。
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.
登录
查看更多内容
由多壁碳纳米管暴露引起的MMP-9依赖性血清传播生物活性通过CD36清道夫受体诱导血管功能障碍。
DOI：
10.1093/toxsci/kfw015
发表时间：
2016-04
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
--
作者：
Aragon M;Erdely A;Bishop L;Salmen R;Weaver J;Liu J;Hall P;Eye T;Kodali V;Zeidler-Erdely P;Stafflinger JE;Ottens AK;Campen MJ
通讯作者：
Campen MJ
影响因子：
16.6
作者：
Akthar S;Patel DF;Beale RC;Peiró T;Xu X;Gaggar A;Jackson PL;Blalock JE;Lloyd CM;Snelgrove RJ
通讯作者：
Snelgrove RJ
影响因子：
10
作者：
Fraser K;Kodali V;Yanamala N;Birch ME;Cena L;Casuccio G;Bunker K;Lersch TL;Evans DE;Stefaniak A;Hammer MA;Kashon ML;Boots T;Eye T;Hubczak J;Friend SA;Dahm M;Schubauer-Berigan MK;Siegrist K;Lowry D;Bauer AK;Sargent LM;Erdely A
通讯作者：
Erdely A
影响因子：
24.3
作者：
Dagouassat, M.;Lanone, S.;Boczkowski, J.
通讯作者：
Boczkowski, J.
影响因子：
--
作者：
Eatemadi A;Daraee H;Karimkhanloo H;Kouhi M;Zarghami N;Akbarzadeh A;Abasi M;Hanifehpour Y;Joo SW
通讯作者：
Joo SW