Systemic inhibition of NF-kappaB activation protects from silicosis.
Systemic inhibition of NF-kappaB activation protects from silicosis.
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DOI：
10.1371/journal.pone.0005689
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发表时间：
2009-05-25
期刊：
影响因子：
3.7
通讯作者：
Ortiz LA
中科院分区：
文献类型：
--
作者：
Di Giuseppe M;Gambelli F;Hoyle GW;Lungarella G;Studer SM;Richards T;Yousem S;McCurry K;Dauber J;Kaminski N;Leikauf G;Ortiz LA
矽肺是一种复杂的肺部疾病，目前尚无成功的治疗方法，因此肺移植是一种潜在的替代方法。肿瘤坏死因子α（TNFα）在矽肺的发病机制中起着重要作用。TNFα信号传导由转录因子核因子（NF）-κB介导，其调节控制若干生理过程（包括先天免疫应答、细胞死亡和炎症）的基因。因此，抑制NF-κB活化是矽肺潜在的治疗策略。在目前的工作中，我们评估了肺移植数据库（1986年5月至2007年7月）在匹兹堡大学，研究肺移植的矽肺患者（n = 11）的疗效。 我们将这些患者的总生存率和移植物排斥率与特发性肺纤维化（IPF，n = 79）患者进行了对比，特发性肺纤维化患者被选为对照组，因为肺移植对这些患者的生存有益。 在肺移植时，我们发现暴露于二氧化硅的受试者的肺含有多个炎性细胞灶和硅肺结节，近端TNFα表达巨噬细胞和上皮细胞中的NF-κB活化。与IPF患者（5.3年; CI：2.8-15年; p = 0.07）相比，矽肺患者的生存率较低（中位生存期2.4年;置信区间（CI）：0.16-7.88年），并且在肺移植（2.4年; CI：1.5-3.6年; p<0.05）后发生了肺移植物早期排斥反应（0.9年; CI：0.22-0.9年）。 使用小鼠实验模型，气管内滴注二氧化硅重现了在人体中观察到的二氧化硅诱导的肺损伤，我们发现，用IκBα磷酸化的药理学抑制剂（BAY 11-7085）全身抑制NF-κB活化可减少二氧化硅诱导的炎症和胶原沉积。相反，在上皮细胞特异性启动子的控制下表达显性负性IκBα突变蛋白的转基因小鼠在对二氧化硅的反应中表现出肺中细胞凋亡和胶原沉积的增强。尽管受其大小的限制，我们的数据支持矽肺患者肺移植后的预后不佳。实验数据表明，虽然全身抑制NF-κB可保护二氧化硅诱导的肺损伤，但上皮细胞特异性NF-κB抑制似乎加重了实验性矽肺的结果。
Silicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFα) plays a central role in the pathogenesis of silicosis. TNFα signaling is mediated by the transcription factor, Nuclear Factor (NF)-κB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-κB activation represents a potential therapeutic strategy for silicosis. In the present work we evaluated the lung transplant database (May 1986–July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFα expressing macrophage and NF-κB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16–7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8–15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22–0.9 yr) following lung transplantation (2.4 yr; CI:1.5–3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-κB activation with a pharmacologic inhibitor (BAY 11-7085) of IκBα phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IκBα mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica. Although limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-κB protects from silica-induced lung injury, epithelial cell specific NF-κB inhibition appears to aggravate the outcome of experimental silicosis.
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影响因子：
15.9
作者：
Hashimoto, N;Jin, H;Phan, SH
通讯作者：
Phan, SH
影响因子：
3.8
作者：
Kang, JL;Pack, IS;Castranova, V
通讯作者：
Castranova, V
DOI：
10.1165/rcmb.2003-0284oc
发表时间：
2004-06-01
影响因子：
6.4
作者：
Langley, RJ;Kalra, R;Sopori, ML
通讯作者：
Sopori, ML
影响因子：
56.9
作者：
Hoffmann, A;Levchenko, A;Baltimore, D
通讯作者：
Baltimore, D
影响因子：
24.3
作者：
Cavarra, E;Martorana, PA;Lungarella, G
通讯作者：
Lungarella, G