Yano Kiichiro, Liaw Patricia C, Mullington Janet M, Shih Shu-Ching, Okada Hitomi, Bodyak Natalya, Kang Peter M, Toltl Lisa, Belikoff Bryan, Buras Jon, Simms Benjamin T, Mizgerd Joseph P, Carmeliet Peter, Karumanchi S Ananth, Aird William C
Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
J Exp Med. 2006 Jun 12;203(6):1447-58. doi: 10.1084/jem.20060375. Epub 2006 May 15.
Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus-sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.
脓毒症是机体对感染的全身性炎症反应，是发病和死亡的主要原因。脓毒症病理生理学机制尚不清楚，但可能涉及炎症和凝血途径介质之间的复杂相互作用。更好地理解这些机制应为开发新疗法提供重要基础。在本研究中，我们发现，在脓毒症的动物和人类模型中，脓毒症与循环血管内皮生长因子（VEGF）和胎盘生长因子（PlGF）水平随时间增加有关。在内毒素血症小鼠模型中，腺病毒介导的可溶性Flt-1（sFlt-1）过表达减弱了VEGF和PlGF水平的升高，并阻断了内毒素血症对心脏功能、血管通透性和死亡率的影响。同样，在盲肠结扎穿刺（CLP）模型中，腺病毒-sFlt-1可预防心脏功能障碍和死亡。在内毒素血症或CLP发作后1小时开始的治疗方案中给予sFlt肽，可显著改善心脏生理功能和存活率。全身给予抗跨膜受体Flk-1而非Flt-1的抗体可预防脓毒症死亡。腺病毒介导的VEGF而非PlGF过表达加剧了脂多糖介导的毒性作用。总之，这些数据支持VEGF在介导脓毒症表型中的病理生理作用。
