Myeloid ABCG1 Deficiency Enhances Apoptosis and Initiates Efferocytosis in Bronchoalveolar Lavage Cells of Murine Multi-Walled Carbon Nanotube-Induced Granuloma Model.
Myeloid ABCG1 Deficiency Enhances Apoptosis and Initiates Efferocytosis in Bronchoalveolar Lavage Cells of Murine Multi-Walled Carbon Nanotube-Induced Granuloma Model.
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DOI：
10.3390/ijms23010047
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发表时间：
2021-12-21
影响因子：
5.6
通讯作者：
Thomassen MJ
中科院分区：
文献类型：
--
作者：
Soliman E;Bhalla S;Elhassanny AEM;Malur A;Ogburn D;Leffler N;Malur AG;Thomassen MJ
在过去的几十年里，碳纳米管的使用有所增加。碳纳米管与肺结节病（一种慢性肉芽肿性炎症）的发病机制有关。我们利用多壁碳纳米管（MWCNT）建立了慢性肉芽肿性炎症小鼠模型，以研究肉芽肿形成的机制。使用该模型，我们证明了骨髓ATP结合盒（ABC）胆固醇转运蛋白（ABCG 1）的缺乏促进了多壁碳纳米管滴注的肉芽肿形成和纤维化;然而，其机制仍不清楚。我们以前的研究表明，多壁碳纳米管诱导野生型（C57 BL/6）小鼠支气管肺泡灌洗液（BAL）细胞的凋亡。鉴于持续的细胞凋亡导致持续的严重肺部炎症，我们假设ABCG 1缺乏会增加MWCNT诱导的细胞凋亡，从而促进肉芽肿性炎症和纤维化。为了验证我们的假设，我们利用骨髓特异性ABCG 1敲除（ABCG 1 KO）小鼠。我们的研究结果表明，多壁碳纳米管滴注增强肺纤维化的ABCG 1基因敲除小鼠相比，野生型对照。增强的纤维化通过肺中增加的三色染色和转化生长因子-β（TGF-β）表达以及TGF-β相关信号传导分子白细胞介素-13（IL-13）和Smad-3的增加的表达来指示。MWCNT诱导ABCG 1基因敲除小鼠BAL细胞凋亡增多。细胞凋亡的启动最有可能是由外源性途径介导的，因为与野生型相比，MWCNT灌注ABCG 1 KO小鼠中的caspase 8活性和Fas表达显著更高。此外，TUNEL染色显示，与WT对照相比，用MWCNT滴注的ABCG 1 KO小鼠具有更高百分比的TUNEL阳性BAL细胞和更多的红细胞增多症。此外，输注MWCNT的ABCG 1 KO小鼠的BAL细胞显示出红细胞增多标志物、乳脂球-EGF因子8（MFG-E8）和整联蛋白β3增加。因此，我们的观察结果表明，ABCG 1缺陷促进肺纤维化的多壁碳纳米管，这种影响可能是由于在BAL细胞的凋亡和巨噬细胞的增加。
The use of carbon nanotubes has increased in the past few decades. Carbon nanotubes are implicated in the pathogenesis of pulmonary sarcoidosis, a chronic granulomatous inflammatory condition. We developed a murine model of chronic granulomatous inflammation using multiwall carbon nanotubes (MWCNT) to investigate mechanisms of granuloma formation. Using this model, we demonstrated that myeloid deficiency of ATP-binding cassette (ABC) cholesterol transporter (ABCG1) promotes granuloma formation and fibrosis with MWCNT instillation; however, the mechanism remains unclear. Our previous studies showed that MWCNT induced apoptosis in bronchoalveolar lavage (BAL) cells of wild-type (C57BL/6) mice. Given that continual apoptosis causes persistent severe lung inflammation, we hypothesized that ABCG1 deficiency would increase MWCNT-induced apoptosis thereby promoting granulomatous inflammation and fibrosis. To test our hypothesis, we utilized myeloid-specific ABCG1 knockout (ABCG1 KO) mice. Our results demonstrate that MWCNT instillation enhances pulmonary fibrosis in ABCG1 KO mice compared to wild-type controls. Enhanced fibrosis is indicated by increased trichrome staining and transforming growth factor-beta (TGF-β) expression in lungs, together with an increased expression of TGF-β related signaling molecules, interleukin-13 (IL-13) and Smad-3. MWCNT induced more apoptosis in BAL cells of ABCG1 KO mice. Initiation of apoptosis is most likely mediated by the extrinsic pathway since caspase 8 activity and Fas expression are significantly higher in MWCNT instilled ABCG1 KO mice compared to the wild type. In addition, TUNEL staining shows that ABCG1 KO mice instilled with MWCNT have a higher percentage of TUNEL positive BAL cells and more efferocytosis than the WT control. Furthermore, BAL cells of ABCG1 KO mice instilled with MWCNT exhibit an increase in efferocytosis markers, milk fat globule-EGF factor 8 (MFG-E8) and integrin β3. Therefore, our observations suggest that ABCG1 deficiency promotes pulmonary fibrosis by MWCNT, and this effect may be due to an increase in apoptosis and efferocytosis in BAL cells.
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影响因子：
37.8
作者：
Kojima Y;Weissman IL;Leeper NJ
通讯作者：
Leeper NJ
DOI：
10.1165/rcmb.2010-0401oc
发表时间：
2011-10-01
影响因子：
6.4
作者：
Huizar, Isham;Malur, Anagha;Thomassen, Mary Jane
通讯作者：
Thomassen, Mary Jane
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
24.3
作者：
Kunitake, R;Kuwano, K;Hara, N
通讯作者：
Hara, N
影响因子：
9
作者：
Grabiec AM;Hussell T
通讯作者：
Hussell T