Acute-phase protein α-1-acid glycoprotein mediates neutrophil migration failure in sepsis by a nitric oxide-dependent mechanism
Acute-phase protein α-1-acid glycoprotein mediates neutrophil migration failure in sepsis by a nitric oxide-dependent mechanism
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DOI：
10.1073/pnas.0709681104
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发表时间：
2007-12-04
影响因子：
11.1
通讯作者：
Cunha, F. Q.
中科院分区：
文献类型：
--
作者：
Mestriner, F. L. A. C.;Spiller, F.;Cunha, F. Q.
循环中性粒细胞迁移到感染部位的减少与严重脓毒症的不良结局相关。用高效液相色谱和丙烯酰胺凝胶电泳从严重脓毒症患者血清中分离出α 1-酸性糖蛋白（AGP），并经质谱鉴定。当以每只大鼠4.0 μ g（每只大鼠95 pmol）的剂量静脉内给药时，分离的蛋白质和商业AGP都抑制角叉菜胶诱导的中性粒细胞迁移到大鼠腹膜腔中。活体显微镜分析表明，这两种蛋白质抑制白细胞在肠系膜微循环中的滚动和粘附。抑制活性被50 mg/kg氨基胍s.c.阻断，并且在诱导型一氧化氮合酶（iNOS）敲除小鼠中不明显。与健康人中性粒细胞孵育的AGP诱导NO的产生，并通过iNOS/NO/环鸟苷3，5-单磷酸依赖的途径抑制中性粒细胞的趋化性。此外，AGP诱导中性粒细胞释放L-选择素。对轻度盲肠结扎穿孔脓毒症大鼠给予AGP可抑制中性粒细胞迁移，并使7天存活率从约80%降至20%。这些数据表明，AGP，急性时相蛋白，抑制中性粒细胞迁移的NO依赖的过程，并表明，AGP也参与了人类败血症。
The reduction of circulating neutrophil migration to infection sites is associated with a poor outcome of severe sepsis. alpha-1-Acid glycoprotein (AGP) was isolated from the sera of severely septic patients by HPLC and acrylamide gel electrophoresis and identified by mass spectrometry. Both the isolated protein and commercial AGP inhibited carrageenin-induced neutrophil migration into the rat peritoneal cavity when administered i.v. at a dose of 4.0 mu g per rat (95 pmol per rat). Analysis by intravital microscopy demonstrated that both proteins inhibited the rolling and adhesion of leukocytes in the mesenteric microcirculation. The inhibitory activity was blocked by 50 mg/kg aminoguanidine, s.c., and was not demonstrable in inducible nitric oxide synthase (iNOS) knockout mice. Incubation of AGP with neutrophils from healthy subjects induced the production of NO and inhibited the neutrophil chemotaxis by an iNOS/NO/cyclic guanosine 3,5-monophosphate-dependent pathway. In addition, AGP induced the L-selectin shedding by neutrophils. The administration of AGP to rats with mild cecal ligation puncture sepsis inhibited neutrophil migration and reduced 7-day survival from approximate to 80% to 20%. These data demonstrate that AGP, an acute-phase protein, inhibits neutrophil migration by an NO-dependent process and suggest that AGP also participates in human sepsis.