By use of intravital microscopy, we could document a direct and dominating role of LFA-1 in supporting firm adhesion of leucocytes in the postcapillary venules of the microcirculation kinase inhibitor Perifosine in AP. Systemic depletion of neutrophils abolished leucocyte-endothelium interactions in the pancreas, suggesting that neutrophils constitute the main leucocyte subtype interacting with the microvascular endothelium in AP (not shown). Although our findings show that LFA-1 is the predominant adhesion molecule supporting pancreatic adhesion and infiltration of neutrophils, these data do not exclude the possibility that other ��2-integrins may also be important in AP. For example, Hentzen et al. (2000) have shown that Mac-1 and LFA-1 cooperate for optimal recruitment of inflammatory cells, that is, LFA-1 initiates first stable contact and Mac-1 establishes a more sustainable adhesion onto the endothelium of inflamed organs.

In this context, it is interesting to note that one previous study has reported that inhibition of LFA-1 decreases neutrophil formation of ROS in AP (Inoue et al., 1996). Thus, considered collectively, these data suggest that LFA-1 may be of importance at several steps in the pathophysiology of AP, including both tissue leucocyte recruitment and ROS-mediated organ damage. Activation and extravascular navigation of neutrophils are orchestrated by secreted CXC chemokines, such as CXCL2 (Bacon and Oppenheim, 1998). In the present study, we found that both pancreatic and systemic levels of CXCL2 were markedly enhanced after taurocholate challenge.

Interestingly, taurocholate-induced formation of CXCL2 was significantly decreased in LFA-1-deficient animals. Similarly, inhibition of LFA-1 function also attenuated tissue formation of CXCL2 in AP. These observations are somewhat surprising considering that CXC chemokines are largely secreted by cells resident in the tissue of the pancreas (Bradley et al., 1999). Nonetheless, our findings indicate that LFA-1 exerts an early feature in the pathophysiology of pancreatitis upstream of CXC chemokine formation. Thus, our data suggest that LFA-1-mediated functions regulate subsequent formation of CXCL2 in AP. The link between LFA-1 function and CXCL2 production is speculative but may be related to pro-inflammatory compounds secreted from activated leucocytes, which in turn may activate tissue-resident cells in the pancreas.

For example, LFA-1-depedent formation of ROS may be involved as ROS have been shown to have the capacity to stimulate chemokine formation (Riaz et al., 2003; Kina et al., 2009). Inflammation and trypsinogen activation are recognized Batimastat as central components in the pathophysiology of AP. However, the relationship between neutrophil recruitment on one hand and protease activation on the other hand in the pancreas is not known.