HMGB1 promotes the development of pulmonary arterial hypertension in rats.
HMGB1 promotes the development of pulmonary arterial hypertension in rats.
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DOI：
10.1371/journal.pone.0102482
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Maruyama I
中科院分区：
文献类型：
--
作者：
Sadamura-Takenaka Y;Ito T;Noma S;Oyama Y;Yamada S;Kawahara K;Inoue H;Maruyama I
肺动脉高压（PAH）的特点是肺血管阻力增加导致右心室衰竭和死亡。最近的研究表明，慢性炎症过程参与了PAH的发病机制。然而，驱动炎症的分子和细胞机制尚未完全阐明。目的：阐明高迁移率组框1蛋白（HMGB1）在PAH大鼠模型中的作用。HMGB1是一种普遍存在的具有细胞外促炎活性的dna结合蛋白。给雄性Sprague-Dawley大鼠注射MCT。观察支气管肺泡灌洗液（BALF）和血清中HMGB1的浓度，以及HMGB1在肺中的定位。检测抗hmgb1中和抗体对mct诱导的多环芳烃的保护作用。注射MCT后1周，BALF中HMGB1水平升高，且此升高发生在其他促炎细胞因子（如TNF-α）升高和PAH发生之前。相比之下，注射MCT后4周血清HMGB1水平升高，此时大鼠开始死亡。免疫组化分析表明，HMGB1在mct注射大鼠动脉周围浸润细胞、肺泡巨噬细胞和支气管上皮细胞中易位至核外间隙。抗hmgb1中和抗体对mct诱导的肺炎症、肺动脉壁增厚、右心室收缩压升高具有保护作用，并显著提高mct诱导的PAH大鼠的生存率。我们的研究结果确定细胞外HMGB1是mct诱导的多环芳烃的促进因子。阻断HMGB1活性可提高mct诱导的PAH大鼠的存活率，因此可能是治疗PAH的一种有希望的治疗方法。
Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated. To elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH. Male Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested. HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats. Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH.
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DOI：
10.1165/rcmb.2007-0330oc
发表时间：
2008-10-01
影响因子：
6.4
作者：
Hamada, Naoki;Maeyama, Takashige;Nakanishi, Yoichi
通讯作者：
Nakanishi, Yoichi
影响因子：
64.8
作者：
Scaffidi, P;Misteli, T;Bianchi, ME
通讯作者：
Bianchi, ME
影响因子：
6.7
作者：
Hatada, T;Wada, H;Maruyama, I
通讯作者：
Maruyama, I
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
DOI：
10.1073/pnas.161272598
发表时间：
2001-07-17
影响因子：
11.1
作者：
Minamino, T;Christou, H;Kourembanas, S
通讯作者：
Kourembanas, S