Antibody to E- and L-selectin does not prevent lung injury or mortality in septic baboons.
Recruitment of polymorphonuclear leukocytes (PMN) through upregulation of cellular adhesion molecules is a proposed mechanism of injury in sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that pretreatment of baboons with a monoclonal antibody to human E- and L-selectin (EL-246) during sepsis would decrease PMN influx into tissues and result in less organ injury during gram-negative sepsis. We studied 14 anesthetized, ventilated adult baboons; six animals received 1 mg/kg of EL-246 before infusion of an LD100 of live Escherichia coli and six received the E. coli infusion without antibody therapy. Two other animals received 1 mg/kg of EL-246 intravenously without an infusion of bacteria. Intermittent measurements were made of circulatory pressures, cardiac output, urine output, arterial blood gases, ventilation:perfusion ratio (VA/Q), and hematologic status. The experiments were ended at 48 h or at the time of death. Tissues were harvested for pathology and biochemical measurements. The E. coli infusions were associated with a hyperdynamic state, pulmonary hypertension, systemic hypotension, decreased urine output (UOP), and metabolic acidosis. The antibody partly blocked PMN migration, but there were few significant physiologic or biochemical differences between the EL-246-treated and untreated animals. In the antibody-treated animals, UOP was decreased, metabolic acidosis was worsened, and median survival time was decreased significantly. We conclude that treatment with an antibody to E- and L-selectin in gram-negative sepsis does not improve gas exchange or protect against lung injury, and is associated with decreased survival time in primates.
Carraway
M S
MS
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Welty-Wolf
K E
KE
Kantrow
S P
SP
Huang
Y C
YC
Simonson
S G
SG
Que
L G
LG
Kishimoto
T K
TK
Piantadosi
C A
CA
D000138:Acidosis / Q000382:microbiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001794:Blood Pressure; D002245:Carbon Dioxide / Q000097:blood; D002302:Cardiac Output; D015815:Cell Adhesion Molecules / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D019040:E-Selectin / Q000276:immunology*; D004927:Escherichia coli Infections / Q000150:complications*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000382:microbiology; D007022:Hypotension / Q000382:microbiology; D007275:Injections, Intravenous; D019041:L-Selectin / Q000276:immunology*; D008297:Male; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology; D010100:Oxygen / Q000097:blood; D010215:Papio; D011659:Pulmonary Gas Exchange; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000382:microbiology / Q000517:prevention & control*; D018805:Sepsis / Q000150:complications*; D015996:Survival Rate; D015854:Up-Regulation; D014556:Urine; D014692:Ventilation-Perfusion Ratio
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D019041:L-Selectin; D002245:Carbon Dioxide; D010100:Oxygen