研究人員在10月在線出版的《自然—免疫學(xué)》期刊中報(bào)告,，血管細(xì)胞中的關(guān)鍵受體如何被快速激活將決定膿血癥患者能否存活。
膿血癥是一種對(duì)血源性感染所產(chǎn)生的威脅生命的免疫反應(yīng),，它會(huì)引發(fā)血管功能的喪失，導(dǎo)致休克和多種器官功能的衰竭,。Athan Kuliopulos希望了解激活或抑制一種名為 PAR1的受體是否能限制膿血癥的嚴(yán)重程度,。他們將細(xì)菌直接注入小鼠的血管中，小鼠發(fā)展出膿血癥,，最后死亡,；然而，如果在細(xì)菌注入后4小時(shí)內(nèi)再給小鼠注射PAR1抑制劑,，那么小鼠就能存活,。
但一個(gè)令人吃驚的發(fā)現(xiàn)是，如果PAR1在稍晚一些的時(shí)間里被抑制,，那么這樣做就不能保護(hù)這些小鼠,；相反，如果在稍晚時(shí)激活PAR1,，則能保護(hù)小鼠不會(huì)產(chǎn)生毒性休克,。Athan Kuliopulos和同事還發(fā)現(xiàn)，PAR1的這種“晚期”激活能導(dǎo)致PAR1的受體也被激活,，這樣,，通過(guò)引導(dǎo)血管內(nèi)的細(xì)胞保持高度的連接性、阻止浮腫的擴(kuò)散和血管內(nèi)血液的凝結(jié),，一種保護(hù)機(jī)制產(chǎn)生了,。
也許，這些新發(fā)現(xiàn)將有助于發(fā)明一種針對(duì)膿血癥或其他系統(tǒng)性炎癥反應(yīng)的治療方法,。（科學(xué)時(shí)報(bào)）
原始出處:
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: [email protected]
