A MONOCLONAL ANTIBODY AGAINST RAGE ALTERS GENE EXPRESSION AND IS PROTECTIVE IN EXPERIMENTAL MODELS OF SEPSIS AND PNEUMOCOCCAL PNEUMONIA

被引：57

作者：

Christaki, Eirini ^{[1
]}

Opal, Steven M. ^{[1
]}

Keith, James C., Jr. ^{[2
]}

Kessimian, Nubar ^{[1
]}

Palardy, John E. ^{[1
]}

Parejo, Nicolas A. ^{[1
]}

Tan, Xiang Yang ^{[2
]}

Piche-Nicholas, Nicole ^{[2
]}

Tchistiakova, Lioudmila ^{[2
]}

Vlasuk, George P. ^{[2
]}

Shields, Kathleen M. ^{[2
]}

Feldman, Jeffrey L. ^{[2
]}

LaVallie, Edward R. ^{[2
]}

Arai, Maya ^{[2
]}

Mounts, William ^{[2
]}

Pittman, Debra D. ^{[2
]}

机构：

[1] Brown Univ, Div Infect Dis, Mem Hosp RI, Warren Alpert Sch Med, Providence, RI 02912 USA

[2] Pfizer Res Labs, Cambridge, MA USA

来源：

SHOCK | 2011年 / 35卷 / 05期

关键词：

Sepsis; septic shock; pneumococcal pneumonia; receptor for advanced glycation end products (RAGE); monoclonal antibody; transcriptomics; GLYCATION END-PRODUCTS; CELL-SURFACE RECEPTOR; NF-KAPPA-B; MULTILIGAND RECEPTOR; UNITED-STATES; HOST-DEFENSE; INFLAMMATION; ACTIVATION; IMMUNE; A20;

D O I：

10.1097/SHK.0b013e31820b2e1c

中图分类号：

R4 [临床医学];

学科分类号：

100218 [急诊医学];

摘要：

The RAGE (receptor for advanced glycation end products) is believed to play a role in sepsis by perpetuating inflammation. The interaction of RAGE with a variety of host-derived ligands that accumulate during stress and inflammation further induces the expression of RAGE. It was previously shown that a rat anti-RAGE monoclonal antibody protected mice from lethality in a cecal ligation and puncture model. We studied the effects of a humanized anti-RAGE monoclonal antibody in the murine pneumococcal pneumonia model of sepsis. Moreover, a gene expression analysis was performed in lung tissue of animals that underwent cecal ligation and puncture and treated with the rat anti-RAGE monoclonal antibody, compared with controls. Administration of humanized anti-RAGE mAb 6 h after intratracheal infection with Streptococcus pneumoniae improved mortality in BALB/c mice whether a 7.5 mg/kg (P < 0.01) or a 15 mg/kg dose (P < 0.01) was administered in combination with antibiotics. Gene expression analysis showed that many of the genes modulated by treatment with the anti-RAGE antibody were those that play an important role in regulating inflammation. Anti-RAGE monoclonal antibody offered a survival advantage to septic mice. This protective role in treated animals is supported by the observed gene expression profile changes of genes involved in sepsis and inflammation.

引用

页码：492 / 498

页数：7

共 35 条

[1]

Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care [J].