A dual-binding antibody to E- 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 anti-E- and anti-L-selectin monoclonal antibody (EL-246) on a porcine model of sepsis-induced lung injury. Four groups were studied for 5 h. Group 1 (control animals) received intravenous saline only. Group 2 (septic) received a 1-h infusion of Pseudomonas aeruginosa. Group 3 (EL-246 pretreatment) received EL-246 (1 mg/kg) prior to Pseudomonas infusion. Group 4 (EL-246 controls) received EL-246 infusion only. Group 2 animals showed rapid, significant decline in arterial pH and oxygen tension whereas, in Group 3, physiologic deterioration was significantly attenuated. Bronchoalveolar lavage at 5 h showed a significant increase 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 content at 5 h was significantly reduced in Group 3 compared with Group 2. There was no significant difference in pulmonary and systemic hemodynamics between Groups 2 and 3. Group 4 animals exhibited a transient neutropenia, but otherwise no other differences in measured parameters were 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Ridings
P C
PC
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
Windsor
A C
AC
Jutila
M A
MA
Blocher
C R
CR
Fisher
B J
BJ
Sholley
M M
MM
Sugerman
H J
HJ
Fowler
A A
AA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000502:physiology; D019040:E-Selectin; D019041:L-Selectin; D008168:Lung / Q000201:enzymology; D051379:Mice; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D011292:Premedication; D011552:Pseudomonas Infections / Q000503:physiopathology / Q000517:prevention & control*; D012128:Respiratory Distress Syndrome / Q000503:physiopathology / Q000517:prevention & control*; D013552:Swine; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000503:physiopathology*
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D019041:L-Selectin; D009195:Peroxidase