Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice.
Neutrophils can cause parenchymal cell injury in the liver during ischemia-reperfusion and endotoxemia. Neutrophils relevant for the injury accumulate in sinusoids, transmigrate, and adhere to hepatocytes. To investigate the role of E- and L-selectin in this process, C3Heb/FeJ mice were treated with 700 mg/kg galactosamine and 100 microgram/kg endotoxin (Gal/ET). Immunogold labeling verified the expression of E-selectin on sinusoidal endothelial cells 4 hours after Gal/ET injection. In addition, Gal/ET caused up-regulation of Mac-1 (CD11b/CD18) and shedding of L-selectin from circulating neutrophils. Gal/ET induced hepatic neutrophil accumulation (422 +/- 32 polymorphonuclear leukocytes [PMN]/50 high power fields [HPF]) and severe liver injury (plasma alanine transaminase [ALT] activities: 4,120 +/- 960 U/L; necrosis: 44 +/- 3%) at 7 hours. Treatment with an anti-E-selectin antibody (3 mg/kg, intravenously) at the time of Gal/ET administration did not significantly affect hepatic neutrophil accumulation and localization. However, the anti-E-selectin antibody significantly attenuated liver injury as indicated by reduced ALT levels (-84%) and 43% less necrotic hepatocytes. In contrast, animals treated with an anti-L-selectin antibody or L-selectin gene knock out mice were not protected against Gal/ET-induced liver injury. However, E-, L-, and P-selectin triple knock out mice showed significantly reduced liver injury after Gal/ET treatment as indicated by lower ALT levels (-65%) and reduced necrosis (-68%). Previous studies showed that circulating neutrophils of E-selectin-overexpressing mice are primed and activated similar to neutrophils adhering to E-selectin in vitro. Therefore, we conclude that blocking E-selectin or eliminating this gene may have protected against Gal/ET-induced liver injury in vivo by inhibiting the full activation of neutrophils during the transmigration process.
Lawson
J A
JA
Department of Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, MI, USA.
Burns
A R
AR
Farhood
A
A
Lynn Bajt
M
M
Collins
R G
RG
Smith
C W
CW
Jaeschke
H
H
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D019040:E-Selectin / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications*; D005688:Galactosamine; D019041:L-Selectin / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D008107:Liver Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D000906:Antibodies; D019040:E-Selectin; D019041:L-Selectin; D005688:Galactosamine