Therapeutic Effects of an Anti-Sialyl Lewis x Antibody in a Murine Model of Acute Lung Injury.

Abstract

Acute respiratory distress syndrome is a life-threatening acute lung injury (ALI) characterized by the destruction of alveoli leading to pulmonary edema. The infiltration and activation of inflammatory cells and production of inflammatory cytokines are both involved in the pathogenesis of ALI. Here, we show that the infiltration of neutrophils, major inflammatory cells causing ALI, into the lung is mediated by sialyl Lewis x (sLe^x) glycans, which can be efficiently suppressed by a monoclonal antibody (mAb) against these glycans. In fucosyltransferase-IV and -VII double-deficient mice lacking sLe^x expression, neutrophil infiltration into the lung was significantly suppressed compared with that observed in wild-type mice in a lipopolysaccharide (LPS)-induced ALI model. Administration of a highly specific anti-sLe^x mAb F2 3 hours after LPS administration significantly suppressed pulmonary neutrophil infiltration, accompanied by the reduced induction of inflammatory cytokines. It was consistently indicated from ex vivo cell rolling assay that mAb F2 blocked the rolling of mouse neutrophils on P-selectin-expressing cells. Overall, these results indicate that the sLe^x glycan could serve as a therapeutic target against ALI, and also that mAb F2 would be useful for specific targeting of this glycan.