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1 Department of General Surgery, Muenster University Hospital, Muenster, Germany
2 Institute of Cell Biology, ZMBE, University of Muenster and Max-Planck-Institute of Vascular Biology, Muenster, Germany
* To whom correspondence should be addressed. E-mail: krieglstein{at}uni-muenster.de.
Background: Recruitment of circulating leukocytes into the colonic tissue is a key feature of intestinal inflammation. P-Selectin Glycoprotein Ligand-1 (PSGL-1) and Very Late Antigen-4 (VLA-4) are expressed on leukocytes and play an important role in leukocyte/endothelial cell adhesive interactions. We examined the effects of immunoneutralization of PSGL-1 and VLA-4 on leukocyte recruitment in vivo in the development and treatment of experimental colitis. Methods: Chronic colitis was induced in balb/c mice by oral administration of dextran sodium sulfate (DSS). Monoclonal antibodies 2PH1 (anti-PSGL-1) and PS/2 (anti- VLA-4) or the combination of both were injected i.v. and leukocyte adhesion was observed for 60 minutes in colonic submucosal venules by intravital microscopy (IVM) under isoflurane / N2O anesthesia. In addition, mice with established colitis were treated by daily i.p. injections of 2PH1, PS/2 or the combination of both over 5 days. Disease Activity Index (DAI), histology and MPO-levels were compared with sham-treated DSS-controls. Results: 2PH1 reduced the number of rolling leukocytes (148.7 ± 29.8 vs. 36.9 ± 8.7 /0.01mm2/30s, P<0.05), while leukocyte velocity was increased (24.0 ± 3.6 vs. 127.8 ± 11.7 µm/s P<0.05). PS/2 reduced leukocyte rolling to a lesser extend. Leukocyte firm adhesion was not influenced by 2PH1, but strongly reduced by PS/2 (24.1 ± 2 vs. 4.4 ± 0.9 /0.01mm2/30s, P<0.05). Combined application did not cause additional effects on leukocyte adhesion. Treatment of chronic colitis with 2PH1 or PS/2 reduced DAI, mucosal injury and MPO-levels significantly. Combined treatment led to a significant better reduction of DAI (0.4 ± 0.1 vs. 2.1 ± 0.2 pts.) and histology (9.7 ± 0.9 vs. 21.4 ± 4.6 pts.). Conclusions: PSGL-1 and VLA-4 play an important role for leukocyte recruitment during intestinal inflammation. Therapeutic strategies designed to disrupt interactions mediated by PSGL-1 and/or VLA-4 may prove beneficial in treatment of chronic colitis.
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