Ja. Lawson et al., Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice, HEPATOLOGY, 32(5), 2000, pp. 990-998
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 mug/kg endotoxin (Gal/ET), Immunogold labe
ling 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 polymorphonucl
ear leukocytes [PMN]AO high power fields [HPF]) and severe liver injury (pl
asma 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, i
ntravenously) at the time of Gal/ET administration did not significantly af
fect hepatic neutrophil accumulation and localization. However, the anti-E-
selectin antibody significantly attenuated liver injury as indicated by red
uced ALT levels (-84%) and 43% less necrotic hepatocytes, In contrast, anim
als treated with an anti-l-selectin antibody or L-selectin gene knock out m
ice were not protected against Gal/ET-induced liver injury. However, E-, L-
, and P-selectin triple knock out mice showed significantly reduced liver i
njury after Gal/ELT treatment as indicated by lower ALT levels (-65%) and r
educed necrosis (-68%). Previous studies showed that circulating neutrophil
s of E-selectin-overexpressing mice are primed and activated similar to neu
trophils adhering to E-selectin in vitro. Therefore, we conclude that block
ing E-selectin or eliminating this gene may have protected against Gal/ET-i
nduced liver injury in vivo by inhibiting the full activation of neutrophil
s during the transmigration process.