Selectin blockade worsened lipopolysaccharide-induced lung injury in a swine model.
BACKGROUND
Polymorphonuclear leukocytes have been reported to play an important role in various acute lung injuries. Neutrophil recruitment into tissues is a multistep process involving sequential engagement of adhesion molecules. The objective of this study was to determine the effect of selectin inactivation with Sulfo Lewis C (SO3-3betaGal1-3betaGlcNAc-O(CH2)8-COOMe) on the pulmonary response to lipopolysaccharide (LPS) infusion.


METHODS
All animals (n = 11) were pretreated with an intramuscular injection of a priming dose of Escherichia coli LPS (10 microg/kg). Eighteen hours later, animals received an intravenous infusion of LPS (20 microg/kg) over 20 minutes. All animals were resuscitated with a lactated Ringer's solution. Group I (G1; n = 5) received no additional treatment. Group II (G2; n = 6) received a bolus injection of Sulfo Lewis C (10 mg/kg) 10 minutes before LPS insult followed by a continuous infusion (1 mg/kg per hour) for the rest of the study. Animals were observed for 5 hours from initiation of the LPS infusion and killed. Cardiopulmonary variables and blood gases were measured serially. The multiple inert gas elimination technique (MIGET) was used to evaluate the matching of air flow and blood flow in the lung 5 hours after LPS infusion. Histologic evaluation of the parenchymal injury was performed by using light microscopy. The number of polymorphonuclear leukocytes and red blood cells in the alveolar spaces per field at 400x magnification were counted in 10 randomly selected fields.


RESULTS
Hypoxemia, indexed as Pao2/FIO2, was exacerbated by the administration of Sulfo Lewis C (G1:437+/-33 vs. G2: 241+/-63 mm Hg at 5 hours, p<0.03). This finding is supported by the multiple inert gas elimination technique analysis, which demonstrated significantly greater blood flow to true shunt in G2 (G1:4.42+/-1.75 vs. G2:23.2+/-5.69, p<0.02). There was no difference between the two groups in red blood cell counts in the alveolar spaces. However, polymorphonuclear leukocyte counts were significantly greater in G2 (G1:1.8+/-0.58 vs. G2:9.9+/-2.34, p<0.01).


CONCLUSIONS
Selectin blockade significantly worsened lung injury induced by LPS infusion, and greater numbers of neutrophils were observed in alveolar spaces in the group treated with Sulfo Lewis C. These findings are supported by the multiple inert gas elimination technique analysis, which demonstrated significantly greater blood flow to the true shunt compartment in treated animals. Further studies are required to determine the role of selectins in sepsis-induced lung injury.
Tasaki
O
O
United States Army Institute of Surgical Research, Fort Sam Houston, San Antonio, Texas 78234-6315, USA.
Goodwin
C
C
Mozingo
D W
DW
Cioffi
W G
WG
Ishihara
S
S
Brinkley
W W
WW
Dubick
M A
MA
Smith
R H
RH
Srivastava
O
O
Pruitt
B A
BA
D000818:Animals; D001772:Blood Cell Count; D005260:Female; D006439:Hemodynamics; D007983:Lewis Blood Group Antigens; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008168:Lung / Q000503:physiopathology*; D009844:Oligosaccharides / Q000494:pharmacology*; D019087:Selectins / Q000502:physiology*; D013552:Swine
D007983:Lewis Blood Group Antigens; D008070:Lipopolysaccharides; D009844:Oligosaccharides; D019087:Selectins; C113506:sulfo Lewis C