Regulatory role of heme oxygenase-1 in silica-induced lung injury.
Regulatory role of heme oxygenase-1 in silica-induced lung injury.
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DOI：
10.1186/s12931-018-0852-6
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发表时间：
2018-08-01
影响因子：
5.8
通讯作者：
Kaneko T
中科院分区：
文献类型：
--
作者：
Nakashima K;Sato T;Shigemori S;Shimosato T;Shinkai M;Kaneko T
矽肺病是一种进行性炎性肺病，主要归因于职业性接触二氧化硅粉尘，即使在停止接触后仍表现出肺功能丧失。除了传统的评估方法，如胸部x线、计算机断层扫描和肺活量测定法，我们发现血红素加氧酶(HO)-1，一种诱导抗氧化剂，作为识别高危患者的潜在生物标志物。我们发现HO-1在减轻矽肺疾病进展中起关键作用；然而，关键的信号通路尚未被阐明。在这里，我们报道了二氧化硅暴露后的关键途径，重点关注二氧化硅衍生的活性氧（ROS）信号的作用及其衰减，这是由HO-1诱导介导的，在体内和体外。本研究使用正常支气管上皮细胞和巨噬细胞系，以及气管内给药2.5 mg结晶二氧化硅产生的小鼠矽肺模型。研究人员检测了二氧化硅暴露激活的途径，包括丝裂原活化蛋白激酶（MAPK）信号通路，并比较了HO-1超诱导和非超诱导的情况。首先对小鼠矽肺模型进行评估，以评估二氧化硅暴露后的激活途径，重点关注ROS-MAPK的激活。在小鼠模型中，二氧化硅注入后肺组织中HO-1的表达增加。此外，二氧化硅药物对肺细胞外信号调节激酶（ERK）的激活在二氧化硅诱导的HO-1上调中减弱。其他MAPKs，如p38和c-Jun n -末端激酶途径的激活，在二氧化硅暴露后没有显著差异，而与HO-1诱导无关。进一步的体外研究表明，1)二氧化硅诱导的HO-1通过抑制ERK的激活而显著减弱，2)HO-1的最终副产物一氧化碳和胆红素可以抑制ERK的激活。综上所述，二氧化硅诱导的HO-1上调是由ERK激活介导的，HO-1通过其最终副产物一氧化碳和胆红素进一步调节ERK的激活。这是首次证实HO-1在矽肺中的调节作用的研究。这一发现可能有助于开发一种监测HO-1水平作为治疗干预标志的治疗策略。本文的在线版本（10.1186/s12931-018-0852-6）包含补充材料，授权用户可使用。
Silicosis, a progressive inflammatory lung disease attributed mainly to occupational exposure to silica dust, shows loss of lung function even after cessation of exposure. In addition to conventional evaluation methods such as chest X-ray, computed tomography, and spirometry, we identified heme oxygenase (HO)-1, an inducible antioxidant, as a potential biomarker to identify at-risk patients. We found that HO-1 was critical in attenuating the disease progression of silicosis; however, the key signaling pathway has not yet been elucidated. Here, we report the critical pathway after silica exposure, focusing on the role of silica-derived reactive oxygen species (ROS) signaling and its attenuation, which is mediated by HO-1 induction, in vivo and in vitro. Normal bronchial epithelial cells and a macrophage cell line, as well as a murine silicosis model generated by intratracheal administration of 2.5 mg of crystalline silica, were used in this study. The pathways activated in response to silica exposure, including the mitogen-activated protein kinase (MAPK) signaling pathway, were examined and compared with or without super-induction of HO-1. The murine silicosis model was first assessed for the evaluation of activated pathways after silica exposure, focusing on ROS-MAPK activation. In the murine model, increased expression of HO-1 in the lungs was observed after silica-instillation. Moreover, silica-medicated activation of extracellular signal-regulated kinase (ERK) in the lungs was attenuated in response to silica-induced HO-1 upregulation. Activation of other MAPKs, such as p38 and c-Jun N-terminal kinase pathways, after silica exposure was not significantly different irrespective of HO-1 induction. Further in vitro studies showed that 1) silica-induced HO-1 was significantly attenuated by inhibiting ERK activation, and 2) carbon monoxide and bilirubin as final byproducts of HO-1 could inhibit ERK activation. Taken together, silica-induced HO-1 upregulation was mediated by ERK activation, and HO-1 further regulates ERK activation via its final byproducts, carbon monoxide and bilirubin. This is the first study to demonstrate the regulatory role of HO-1 in silicosis. This finding could contribute to the development of a treatment strategy of monitoring HO-1 levels as a marker of therapeutic intervention. The online version of this article (10.1186/s12931-018-0852-6) contains supplementary material, which is available to authorized users.
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影响因子：
5.1
作者：
Hashiba, T;Suzuki, M;Ishigatubo, Y
通讯作者：
Ishigatubo, Y
影响因子：
3.5
作者：
Hong, Hye-Young;Jeon, Woo-Kwang;Kim, Byung-Chul
通讯作者：
Kim, Byung-Chul
DOI：
10.1124/jpet.106.102699
发表时间：
2006-10-01
影响因子：
3.5
作者：
Kinobe, Robert T.;Dercho, Ryan A.;Nakatsu, Kanji
通讯作者：
Nakatsu, Kanji
影响因子：
3.3
作者：
Fujimura, N
通讯作者：
Fujimura, N
影响因子：
4.2
作者：
Inoue, S;Suzuki, M;Ishigatsubo, Y
通讯作者：
Ishigatsubo, Y