Leukocyte recruitment in hepatic injury: selectin-mediated leukocyte rolling is a prerequisite for CD18-dependent firm adhesion.
OBJECTIVE
This study was designed to examine the role of selectins and CD18 in leukocyte recruitment in hepatic injury induced by tumor necrosis factor-alpha (TNF-alpha) and galactosamine (Gal) in vivo.


METHODS
Intravital fluorescence microscopy of the hepatic microcirculation was used to quantify leukocyte-endothelium interactions provoked by 24 h of systemic TNF-alpha/Gal challenge in rats. Hepatic injury was evaluated with liver enzymes.


RESULTS
When administered after 24 h of TNF-alpha/Gal challenge, fucoidan, a selectin-function inhibitor, reduced leukocyte rolling by 69%, whereas firm adhesion was unaltered. In contrast, passive immunization against CD18 decreased leukocyte adhesion by 60%, whereas rolling remained unchanged. Notably, when administered prior to TNF-alpha/Gal, fucoidan attenuated both leukocyte rolling and adhesion, by 57 and 69%, respectively. Pretreatment with an anti-CD18 antibody decreased TNF-alpha/Gal-induced rolling and firm adhesion by 25 and 90%, respectively. Moreover, pretreatment with fucoidan and the anti-CD18 antibody both protected against TNF-alpha/Gal-induced increases in liver enzymes. For example, the pretreatments reduced alanine aminotransferase by 59 and 87%, respectively.


CONCLUSIONS
Our data suggest that TNF-alpha/Gal-induced leukocyte rolling is selectin-mediated and a precondition for CD18-dependent firm adhesion in hepatic venules. Thus, reducing leukocyte recruitment by inhibition of selectins or CD18 may be useful to control TNF-alpha-induced liver injury.
Klintman
Daniel
D
Department of Surgery, Malmö University Hospital, Lund University, S-205 02 Malmo, Sweden.
Schramm
René
R
Menger
Michael D
MD
Thorlacius
Henrik
H
D000818:Animals; D000970:Antineoplastic Agents; D018821:CD18 Antigens / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D005688:Galactosamine; D007962:Leukocytes / Q000166:cytology; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000276:immunology*; D008102:Liver Circulation / Q000276:immunology; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley; D019087:Selectins / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D014699:Venules / Q000166:cytology
D000970:Antineoplastic Agents; D018821:CD18 Antigens; D019087:Selectins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine