Lung Biology Center, University of California San Francisco, San Francisco, CA 94121, USA.
Am J Respir Crit Care Med. 2012 Jan 1;185(1):58-66. doi: 10.1164/rccm.201108-1381OC.
Sepsis and acute lung injury (ALI) have devastatingly high mortality rates. Both are associated with increased vascular leak, a process regulated by complex molecular mechanisms.
We hypothesized that integrin αvβ3 could be an important determinant of vascular leak and endothelial permeability in sepsis and ALI.
β3 subunit knockout mice were tested for lung vascular leak after endotracheal LPS, and systemic vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. Possible contributory effects of β3 deficiency in platelets and other hematopoietic cells were excluded by bone marrow reconstitution experiments. Endothelial cells treated with αvβ3 antibodies were evaluated for sphingosine-1 phosphate (S1P)–mediated alterations in barrier function, cytoskeletal arrangement, and integrin localization.
β3 knockout mice had increased vascular leak and pulmonary edema formation after endotracheal LPS, and increased vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. In endothelial cells, αvβ3 antibodies inhibited barrier-enhancing and cortical actin responses to S1P. Furthermore, S1P induced translocation of αvβ3 from discrete focal adhesions to cortically distributed sites through Gi- and Rac1-mediated pathways. Cortical αvβ3 localization after S1P was decreased by αvβ3 antibodies, suggesting that ligation of the αvβ3 with its extracellular matrix ligands is required to stabilize cortical αvβ3 focal adhesions.
Our studies identify a novel mechanism by which αvβ3 mitigates increased vascular leak, a pathophysiologic function central to sepsis and ALI. These studies suggest that drugs designed to block αvβ3 may have the unexpected side effect of intensifying sepsis- and ALI-associated vascular endothelial leak.
脓毒症和急性肺损伤（ALI）的死亡率极高。两者均与血管通透性增加有关，而这一过程受复杂的分子机制调节。
我们假设整合素 αvβ3 可能是脓毒症和 ALI 中血管渗漏和内皮通透性的重要决定因素。
通过气管内 LPS 检测β3 亚基敲除小鼠的肺血管渗漏，通过腹腔内 LPS 和盲肠结扎穿刺检测系统性血管渗漏和死亡率。通过骨髓重建实验排除了血小板和其他造血细胞中β3 缺乏的可能促成作用。用 αvβ3 抗体处理内皮细胞，评估其对鞘氨醇-1-磷酸（S1P）介导的屏障功能、细胞骨架排列和整合素定位的改变。
β3 敲除小鼠经气管内 LPS 处理后血管通透性增加和肺水肿形成，经腹腔内 LPS 和盲肠结扎穿刺后血管通透性增加和死亡率增加。在内皮细胞中，αvβ3 抗体抑制 S1P 增强的屏障和皮质肌动蛋白反应。此外，S1P 通过 Gi 和 Rac1 介导的途径诱导αvβ3 从离散的焦点黏附转移到皮质分布的部位。S1P 后，αvβ3 抗体减少了 S1P 诱导的皮质 αvβ3 定位，表明αvβ3 与其细胞外基质配体的结合是稳定皮质 αvβ3 焦点黏附所必需的。
我们的研究确定了一种新的机制，即αvβ3 减轻血管通透性增加，这是脓毒症和 ALI 的病理生理功能的核心。这些研究表明，设计用于阻断 αvβ3 的药物可能会产生意想不到的副作用，加剧与脓毒症和 ALI 相关的血管内皮渗漏。
