Proper engagement of leukocyte and endothelial cell
selectins with their counterreceptors is an initial step in neutrophil trafficking to sites of
inflammation. Certain fucosylated
carbohydrate determinants such as
sialyl Lewis-x are proposed to act as these counterreceptors. We studied the effects of a synthetic
sialyl Lewis-x analog,
CY-1503, on the course of hemodynamic derangements and
acute lung injury during experimental gram-negative
sepsis. Anesthetized ventilated swine were made septic with an infusion of live Pseudomonas aeruginosa. A treatment group received an initial bolus of
CY-1503 (60 mg/kg) before
sepsis, followed by continuous infusion of
CY-1503 (15 mg.kg-1.h-1). Treatment with
CY-1503 did not prevent the development of
pulmonary hypertension, systemic
hypotension, decline in cardiac output, or severe
neutropenia. However,
CY-1503 significantly attenuated
lung injury, demonstrated by decreased bronchoalveolar lavage
protein content and neutrophil influx, lowered lung
myeloperoxidase activity, and improved arterial oxygenation. Neutrophils from septic and
CY-1503 animals showed significant activation, reflected by upregulated CD18 expression and priming for
oxidant burst compared with control animals. This study suggests blockade of
selectin interactions as a potential therapeutic intervention in
sepsis-induced
lung injury.