期刊
CIRCULATION RESEARCH
卷 87, 期 3, 页码 254-260出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.87.3.254
关键词
neutrophil; CD11 antigen; CD18 antigen; endothelial cell; E-selectin
资金
- NHLBI NIH HHS [HL27016, HL45638, HL60678] Funding Source: Medline
Interaction of CD11/CD18 beta(2) integrins on polymorphonuclear leukocytes (PMNs) with their counterreceptor, intercellular adhesion molecule-1, on the surface of vascular endothelial cells is a critical event mediating stable PMN adhesion and mi,oration across the pulmonary vascular endothelial barrier. Neutrophil inhibitory factor (NIF), a 41-kDa glycoprotein isolated from the canine hookworm (Ancylostoma caninum), binds to the I domain of CD11a and CD11b and inhibits beta(2) integrin-dependent PMN adhesion. We describe a novel strategy using the endothelial cell-specific E-selectin promoter to induce NIF expression in an inflammation-specific manner in pulmonary vascular endothelial cells. A construct containing NIF cDNA driven by the inducible endothelial cell-specific E-selectin promoter (pESNIF) was transfected into human pulmonary artery endothelial cells (HPAECs). Lipopolysaccharide challenge (known to activate E-selectin) resulted in NIF mRNA and protein expression in transfected HPAECs. NIF expression induced by the E-selectin promoter prevented PMN adhesion to the activated HPAECs, whereas PMNs adhered avidly to activated HPAECs in the absence of NIF expression To address the utility of this approach in conditionally preventing in vivo PMN sequestration, we injected mice intravenously with cationic liposomes containing the pESNIF construct. Analysis of lung tissue showed that intraperitoneal challenge of Escherichia call resulted in NIF expression. Inflammation-specific NIF expression induced by the E-selectin promoter prevented lung PMN sequestration and vascular injury induced by E coli challenge. These studies suggest the feasibility of conditionally blocking beta(2) integrin function at sites where the endothelium is activated and thereby of locally preventing PMN activation and migration responses that lead to tissue inflammation.
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