Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation.
Hemorrhagic shock and resuscitation cause endotoxemia and hepatocellular damage. Because lipopolysaccharide-binding protein (LBP) enhances cellular responses to endotoxin, our aim was to determine whether LBP contributes to hemorrhage/resuscitation-induced injury by comparing LBP knockout and wild-type mice. Under pentobarbital anaesthesia, wild-type and LBP-deficient mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer solution. Serum alanine aminotransferase (ALT) necrosis, neutrophil infiltration, and 4-hydroxynonenal by histology/cytochemistry and stress kinase activation by immunoblot analysis were then determined. ALT in wild-type mice was 2,461 +/- 383 and 1,418 +/- 194 IU/l (means +/- SE), respectively, at 2 and 6 h after resuscitation versus sham ALT of 102 +/- 6 IU/l. In LBP-deficient mice, ALT was blunted at both time points to 1,108 +/- 340 and 619 +/- 171 IU/l (P < 0.05). Liver necrosis after 6 h was also attenuated from 3.5 +/- 0.8% in wild-type mice to 1.3 +/- 0.5% in LBP-deficient mice (P < 0.05). After hemorrhage/resuscitation, neutrophil infiltration increased 71% more in wild-type than LBP knockout mice. Similarly, hepatic 4-hydroxynonenal staining, indicative of lipid peroxidation, decreased from 33.8 +/- 4.5% in wild-type mice to 11.6 +/- 1.9% in knockout mice (P < 0.05). After hemorrhage/resuscitation, activation of MAPKs, JNK and ERK, occurred in wild-type mice, which was largely blocked in LBP-deficient mice. However, endotoxin in portal blood after resuscitation was not significantly different between wild-type and knockout mice. In conclusion, hemorrhagic shock and resuscitation to mice cause severe, LBP-mediated hepatocellular damage. An absence of LBP blunts hepatocellular injury with decreased neutrophil infiltration, oxidative stress, and c-Jun and ERK activation.
Lehnert
Mark
M
Medical Univ. of South Carolina, 280 Calhoun St., PO Box 250140, Charleston, SC 29425, USA.
Uehara
Tetsuya
T
Bradford
Blair U
BU
Lind
Henrik
H
Zhong
Zhi
Z
Brenner
David A
DA
Marzi
Ingo
I
Lemasters
John J
JJ
D000209:Acute-Phase Proteins / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D007155:Immunologic Factors / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000517:prevention & control; D018836:Inflammation Mediators / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000276:immunology* / Q000628:therapy*; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D007155:Immunologic Factors; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein