HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption.
HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption.
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DOI：
10.1016/j.mvr.2010.11.010
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发表时间：
2011-03
影响因子：
3.1
通讯作者：
Garcia JG
中科院分区：
文献类型：
--
作者：
Wolfson RK;Chiang ET;Garcia JG
急性肺损伤（ALI）是由于肺泡-毛细血管屏障完整性丧失和高渗透性肺水肿的发展导致肺泡灌流和显著的发病率和死亡率。HMGB 1是脓毒症的晚期介质，其独特地参与脓毒症和脓毒症诱导的ALI的演变。HMGB 1导致ALI的分子事件仍然缺乏特征性。我们的特点是HMGB 1在内皮细胞（EC）细胞骨架重排和血管通透性，事件必不可少的细胞间隙形成和屏障功能障碍的特征性ALI的作用。最初的实验表明，HMGB 1介导的人肺动脉EC中跨内皮细胞电阻（TER）的剂量依赖性（5-20 μg/ml）降低，反映了屏障完整性的丧失。此外，HMGB 1产生的剂量依赖性增加，与周边有组织的肌动蛋白纤维的损失，细胞-细胞连接钙粘蛋白的解离，和中央应力纤维的发展，与增加收缩活性和EC通透性增加的表型变化的音乐会旁细胞间隙的形成。使用针对已知HMGB 1受体（EGFR，TLR 2，TLR 4）的siRNA策略，我们系统地确定了晚期糖基化终产物（EGFR）受体是通过p38 MAP激酶激活和肌动蛋白结合蛋白Hsp 27磷酸化来传递HMGB 1诱导的TER降低和细胞旁间隙形成的主要受体。这些研究增加了对HMGB 1诱导的炎症事件和血管屏障破坏的了解，并为脓毒症诱导的ALI的临床干预提供了可能。
Acute lung injury (ALI) results from loss of alveolar-capillary barrier integrity and the evolution of high-permeability pulmonary edema resulting in alveolar flooding and significant morbidity and mortality. HMGB1 is a late mediator of sepsis which uniquely participates in the evolution of sepsis and sepsis-induced ALI. The molecular events by which HMGB1 contributes to ALI remain poorly characterized. We characterized the role of HMGB1 in endothelial cell (EC) cytoskeletal rearrangement and vascular permeability, events essential to paracellular gap formation and barrier dysfunction characteristic of ALI. Initial experiments demonstrated HMGB1-mediated dose-dependent (5–20 μg/ml) decreases in transendothelial cell electrical resistance (TER) in human pulmonary artery EC, a reflection of loss of barrier integrity. Furthermore, HMGB1 produced dose-dependent increases in paracellular gap formation in concert with loss of peripheral organized actin fibers, dissociation of cell-cell junctional cadherins, and development of central stress fibers, a phenotypic change associated with increased contractile activity and increased EC permeability. Using siRNA strategies directed against known HMGB1 receptors (RAGE, TLR2, TLR4), we systematically determined that the receptor for advanced glycation end products (RAGE) is the primary receptor signaling HMGB1-induced TER decreases and paracellular gap formation via p38 MAP kinase activation and phosphorylation of the actin-binding protein, Hsp27. These studies add to understanding of HMGB1-induced inflammatory events and vascular barrier disruption and offer the potential for clinical intervention in sepsis-induced ALI.
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HMGB1：内源性危险信号。
影响因子：
5.7
作者：
Klune, John R.;Dhupar, Rajeev;Cardinal, Jon;Billiar, Timothy R.;Tsung, Allan
通讯作者：
Tsung, Allan
影响因子：
5.3
作者：
LAVOIE, JN;LAMBERT, H;LANDRY, J
通讯作者：
LANDRY, J
影响因子：
5.5
作者：
Park, JS;Gamboni-Robertson, F;Abraham, E
通讯作者：
Abraham, E
DOI：
10.1152/ajplung.00359.2004
发表时间：
2005-05-01
影响因子：
4.9
作者：
Kim, JY;Park, JS;Abraham, E
通讯作者：
Abraham, E
影响因子：
4.8
作者：
Garcia, JGN;Wang, PY;Verin, AD
通讯作者：
Verin, AD