Rho-kinase signalling regulates CXC chemokine formation and leukocyte recruitment in colonic ischemia–reperfusion

Santen, Stefan; Yusheng Wang; Laschke, Matthias W.; Menger, Michael D.; Jeppsson, Bengt; Thorlacius, Henrik
September 2010
International Journal of Colorectal Disease;Sep2010, Vol. 25 Issue 9, p1063
Academic Journal
Leukocyte recruitment is a key feature in ischemia–reperfusion (I/R)-induced tissue injury. The aim of the present study was to investigate the effect of Rho-kinase inhibition on I/R-provoked leukocyte recruitment in the colon. C57BL/6 mice were subjected to 30 min of ischemia by clamping of the superior mesenteric artery followed by 120 min of reperfusion. Intraperitoneal pretreatment with the selective Rho-kinase inhibitors fasudil (4–40 mg/kg) and Y-27632 (1–10 mg/kg) was administered prior to induction of colonic I/R. Leukocyte–endothelium interactions were analyzed by intravital fluorescence microscopy. Colonic content of tumour necrosis factor-α (TNF-α) and the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) were determined by ELISA. Additionally, colonic activity of myeloperoxidase (MPO), a marker of leukocyte infiltration, and malondialdehyde (MDA), were quantified. Fasudil and Y-27632 pretreatment decreased I/R-induced leukocyte rolling and adhesion by 76% and 96%, respectively. Moreover, Rho-kinase interference reduced formation of TNF-α, MIP-2 and KC by more than 68% in the reperfused colon. Additionally, the reperfusion-provoked increase in the levels of MPO and MDA in the colon decreased after Rho-kinase inhibition by 69% and 42%, respectively. Our data demonstrate that inhibition of Rho-kinase activity decrease I/R-induced leukocyte rolling, adhesion and recruitment in the colon. Moreover, these findings show that Rho-kinase signalling regulates TNF-α and CXC chemokine formation as well as lipid peroxidation in the reperfused colon. Thus, targeting Rho-kinase signalling may be a useful strategy in order to protect against pathological inflammation in the colon.


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