Notably, Afatinib a previous investigation has shown that levels of TAP correlate with disease severity in the early phases of AP (Frossard, 2001). Indeed, we observed that taurocholate challenge markedly increased the levels of TAP in the pancreas. However, taurocholate-induced levels of TAP were not altered in LFA-1 gene-targeted animals or in mice treated with a blocking antibody directed against LFA-1. These findings indicate that trypsinogen activation is independent of LFA-1-mediated neutrophil accumulation in the pancreas. Thus, pancreatic infiltration of neutrophils seems not to be a precondition for protease activation in AP. Whether neutrophils may exert intravascular functions, such as secretion of pro-inflammatory compounds, which may trigger intrapancreatic activation of trypsinogen cannot be excluded by our present findings.

It should be noted that trypsin is a potent activator of proteinase-activated receptor-2 (PAR2), which is a 7-transmembrane G-protein-coupled receptor expressed by pancreatic acinar and ductal cells (Nguyen et al., 1999). A recent study reported that taurocholate-triggered calcium transients, kinase activation and acinar cell injury is markedly reduced in isolated pancreatic acini from PAR2 gene-deficient mice, suggesting that PAR2 activation may support acinar cell damage in AP (Laukkarinen et al., 2008). Whether trypsin-mediated activation of PAR2 may explain LFA-1-independent effects, such as trypsinogen activation, in the present study is a matter of future studies.

Nonetheless, considering that activation of trypsinogen seems to be an early process, neutrophil recruitment and inflammation in the pancreas persists longer and targeting LFA-1 might be a more favourable strategy for specific therapeutic interventions (Regn��r et al., 2008). In conclusion, our novel data demonstrate not only that neutrophil adhesion and infiltration in AP are mediated by LFA-1 but also that LFA-1-dependant recruitment of neutrophils regulates tissue damage in the pancreas. In addition, these findings also indicate that trypsinogen activation is independent of LFA-1-mediated neutrophil accumulation in the pancreas. Taken together, we conclude that LFA-1 may be a useful target to antagonize pathological inflammation in AP.

Acknowledgments This work was supported by grants from the Swedish Medical Research Council (2009-4872), Crafoordska stiftelsen, Einar och Inga Nilssons stiftelse, Harald och Greta Jaenssons stiftelse, Greta och Johan Kocks stiftelser, Fr?ken Agnes Nilssons stiftelse, Franke och Margareta Bergqvists stiftelse f?r fr?mjande av cancerforskning, Magnus Bergvalls stiftelse, Batimastat Lundgrens stiftelse, Mossfelts stiftelse, Nanna Svartz stiftelse, Ruth och Richard Julins stiftelse, Svenska L?kares?llskapet, Allm?na sjukhusets i Malm? stiftelse f?r bek?mpande av cancer, MAS fonder, Malm? University Hospital and Lund University.