Fundamental and distinct roles of P-selectin and LFA-1 in ischemia/reperfusion-induced leukocyte-endothelium interactions in the mouse colon.
OBJECTIVE
To study the adhesive mechanisms underlying ischemia/reperfusion (I/R)-induced leukocyte-endothelium interactions in the colon.


BACKGROUND
Leukocyte recruitment is a key feature in I/R-induced tissue injury, but the mechanisms regulating leukocyte rolling and adhesion in the colon are not known. The authors recently developed a new model to study the molecular mechanisms of I/R-provoked leukocyte-endothelium interactions in the colon microcirculation using inverted intravital fluorescence microscopy.


METHODS
The superior mesenteric artery was occluded for 30 minutes and leukocyte responses were analyzed after 120 minutes of reperfusion in colonic venules in mice. The adhesive mechanisms underlying I/R-induced leukocyte rolling and adhesion were investigated using monoclonal antibodies against L-, E- and P-selectin, and CD11a gene-targeted mice were used to examine the role of lymphocyte function antigen-1 (LFA-1, CD11a/CD18).


RESULTS
Reperfusion provoked a clear-cut increase in leukocyte rolling and adhesion in colonic venules compared to negative controls. Both P- and E-selectin mRNA were expressed in the colon after this I/R insult. Pretreatment with an anti-P-selectin antibody reduced leukocyte rolling and adhesion by 88% and 85%, respectively, whereas antibodies against L- and E-selectin had no effect. Moreover, I/R-induced leukocyte adhesion in LFA-1-deficient mice was reduced by more than 95%.


CONCLUSIONS
This study provides evidence that leukocyte rolling is exclusively and nonredundantly mediated by P-selectin and that firm adhesion is supported by LFA-1 in I/R-induced leukocyte recruitment in the colon. Taken together, both P-selectin and LFA-1 may be important targets to control pathologic inflammation in I/R-induced tissue injury in the colon.
Riaz
Amjid Ali
AA
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Wan
Ming Xiu
MX
Schaefer
Thilo
T
Schramm
Rene
R
Ekberg
Henrik
H
Menger
Michael D
MD
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001483:Base Sequence; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003108:Colonic Diseases / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007413:Intestinal Mucosa / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D007958:Leukocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019007:P-Selectin / Q000378:metabolism*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis*; D011897:Random Allocation; D012016:Reference Values; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D019007:P-Selectin; D012333:RNA, Messenger