University of Chicago, Department of Pediatrics, IL, USA.
Microvasc Res. 2011 Mar;81(2):189-97. doi: 10.1016/j.mvr.2010.11.010. Epub 2010 Dec 10.
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 the 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 the 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 the understanding of HMGB1-induced inflammatory events and vascular barrier disruption and offer the potential for clinical intervention in sepsis-induced ALI.
急性肺损伤（ALI）是由肺泡毛细血管屏障完整性丧失和高通透性肺水肿的发展引起的，导致肺泡积水和高发病率和死亡率。HMGB1 是败血症的晚期介质，独特地参与败血症和败血症引起的 ALI 的发展。HMGB1 导致 ALI 的分子事件仍未得到很好的描述。我们描述了 HMGB1 在血管内皮细胞（EC）细胞骨架重排和血管通透性中的作用，这些事件对于细胞旁间隙形成和 ALI 特征性的屏障功能障碍至关重要。初步实验表明，HMGB1 介导的剂量依赖性（5-20μg/ml）降低人肺动脉内皮细胞的跨内皮细胞电阻（TER），反映出屏障完整性的丧失。此外，HMGB1 还产生剂量依赖性的细胞旁间隙形成增加，伴随着周围有组织的肌动蛋白纤维丧失、细胞-细胞连接钙粘蛋白解离以及中央应激纤维的形成，这种表型变化与收缩活性增加和 EC 通透性增加有关。使用针对已知 HMGB1 受体（RAGE、TLR2、TLR4）的 siRNA 策略，我们系统地确定了晚期糖基化终产物受体（RAGE）是主要的受体，通过 p38 MAP 激酶的激活和肌动蛋白结合蛋白 Hsp27 的磷酸化，信号转导 HMGB1 诱导的 TER 降低和细胞旁间隙形成。这些研究增加了对 HMGB1 诱导的炎症事件和血管屏障破坏的理解，并为败血症引起的 ALI 的临床干预提供了潜力。
