DUAL-BINDING ANTIBODY TO E-SELECTIN AND L-SELECTIN ATTENUATES SEPSIS-INDUCED LUNG INJURY

Many studies indicate a pivotal role for neutrophil adhesion in sepsis -associated lung injury. Neutrophil adhesion to endothelium depends on activation and expression of selectin and integrin adhesion receptors . We studied the effects of pretreatment with a dual-binding porcine a nti-G and anti-L-selectin monoclonal antibody (EL-246) on a porcine mo del of sepsis-induced lung injury. Four groups were studied for 5 h. G roup 1 (control animals) received intravenous saline only. Group 2 (se ptic) received a 1-h infusion of Pseudomonas aeruginosa. Group 3 (EL-2 46 pretreatment) received EL-246 (1 mg/kg) prior to Pseudomonas infusi on. Group 4 (EL-246 controls) received EL-246 infusion only. Group 2 a nimals showed rapid, significant decline in arterial pH and oxygen ten sion whereas, in Group 3, physiologic deterioration was significantly attenuated. Bronchoalveolar lavage at 5 h showed a significant increas e in neutrophil count and protein content in Group 2. Group 3, however , showed no significant differences in these parameters compared with control animals. Despite severe neutropenia, lung myeloperoxidase cont ent at 5 h was significantly reduced in Group 3 compared with Group 2. There was no significant difference in pulmonary and systemic hemodyn amics between Groups 2 and 3. Group 4 animals exhibited a transient ne utropenia, but otherwise no other differences in measured parameters w ere found compared with Group 1 control animals. In conclusion, EL-246 significantly reduced neutrophil accumulation in lung and attenuated sepsis-induced lung injury, but failed to attenuate deranged pulmonary and systemic hemodynamics. These results suggest that EL-246 reduced neutrophil/endothelial adhesion in organs of high flow, such as lung, thus preventing formation of a microenviroment for injury between neut rophils and endothelium.