Nature子刊：血管细胞中的关键受体快速激活与脓血症
研究人员在10月在线出版的《自然—免疫学》期刊中报告，血管细胞中的关键受体如何被快速激活将决定脓血症患者能否存活。
脓血症是一种对血源性感染所产生的威胁生命的免疫反应，它会引发血管功能的丧失，导致休克和多种器官功能的衰竭。Athan Kuliopulos希望了解激活或抑制一种名为 PAR1的受体是否能限制脓血症的严重程度。他们将细菌直接注入小鼠的血管中，小鼠发展出脓血症，最后死亡；然而，如果在细菌注入后4小时内再给小鼠注射PAR1抑制剂，那么小鼠就能存活。
但一个令人吃惊的发现是，如果PAR1在稍晚一些的时间里被抑制，那么这样做就不能保护这些小鼠；相反，如果在稍晚时激活PAR1，则能保护小鼠不会产生毒性休克。Athan Kuliopulos和同事还发现，PAR1的这种“晚期”激活能导致PAR1的受体也被激活，这样，通过引导血管内的细胞保持高度的连接性、阻止浮肿的扩散和血管内血液的凝结，一种保护机制产生了。
也许，这些新发现将有助于发明一种针对脓血症或其他系统性炎症反应的治疗方法。（科学时报）
原始出处:
Nature Immunology
Published online: 28 October 2007 | doi:10.1038/ni1525
'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage
Nicole C Kaneider1, Andrew J Leger1, Anika Agarwal1, Nga Nguyen1, George Perides2, Claudia Derian3, Lidija Covic1 & Athan Kuliopulos1
Abstract
Sepsis is a deadly disease characterized by considerable derangement of the proinflammatory, anti-inflammatory and coagulation responses. Protease-activated receptor 1 (PAR1), an important regulator of endothelial barrier function and blood coagulation, has been proposed to be involved in the lethal sequelae of sepsis, but it is unknown whether activation of PAR1 is beneficial or harmful. Using a cell-penetrating peptide (pepducin) approach, we provide evidence that PAR1 switched from being a vascular-disruptive receptor to a vascular-protective receptor during the progression of sepsis in mice. Unexpectedly, we found that the protective effects of PAR1 required transactivation of PAR2 signaling pathways. Our results suggest therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis.
- Departments of Medicine and Biochemistry, Molecular Oncology Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
- Department of Surgery, Tufts–New England Medical Center, Boston, Massachusetts 02111, USA.
- Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477, USA.
Correspondence to: Athan Kuliopulos1 e-mail: athan.kuliopulos@tufts.edu
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