Intracapillary leucocyte accumulation as a novel antihaemorrhagic mechanism in acute pancreatitis in mice
- E Ryschich1,
- V Kerkadze1,
- O Deduchovas1,
- O Salnikova1,
- A Parseliunas1,
- A Märten1,
- W Hartwig1,
- M Sperandio2,
- J Schmidt1
- 1Department of Surgery, University of Heidelberg, Germany
- 2Walter-Brendel-Center for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany
- Correspondence to Dr E Ryschich, Department of Surgery, Im Neuenheimer Feld 110, University of Heidelberg, 69120 Heidelberg, Germany;
- Revised 23 March 2009
- Accepted 28 April 2009
- Published Online First 20 May 2009
Background: Pancreatic infiltration by leucocytes represents a hallmark in acute pancreatitis. Although leucocytes play an active role in the pathophysiology of this disease, the relation between leucocyte activation, microvascular injury and haemorrhage has not been adequately addressed.
Methods: We investigated intrapancreatic leucocyte migration, leucocyte extravasation and pancreatic microperfusion in different models of oedematous and necrotising acute pancreatitis in lys-EGFP-ki mice using fluorescent imaging and time-lapse intravital microscopy.
Results: In contrast to the current paradigm of leucocyte recruitment, the initial event of leucocyte activation in acute pancreatitis was represented through a dose- and time-dependent occlusion of pancreatic capillaries by intraluminally migrating leucocytes. Intracapillary leucocyte accumulation (ILA) resulted in dense filling of almost all capillaries close to the area of inflammation and preceded transvenular leucocyte extravasation. ILA was also initiated by isolated exposure of the pancreas to interleukin 8 or fMLP, demonstrating the causal role of chemotactic stimuli in the induction of ILA. The onset of intracapillary leucocyte accumulation was strongly inhibited in LFA-1−/− and ICAM-1−/− mice, but not in Mac-1−/− mice. Moreover, prevention of intracapillary leucocyte accumulation led to the development of massive capillary haemorrhages and transformed mild pancreatitis into lethal haemorrhagic disease.
Conclusions: ILA represents a novel protective and potentially lifesaving mechanism of haemostasis in acute pancreatitis. This process depends on expression of LFA-1 and ICAM-1 and precedes the classical steps of the leucocyte recruitment cascade.
Funding The study was supported by the Manfred-Lautenschläger-Foundation (to ER and AM), and German Research Foundation Grant SP621/3-1 (to MS).
Competing interests None.
Provenance and Peer review Not commissioned; externally peer reviewed.
See Commentary, p 1440
Ethics approval Experimental protocols were reviewed and approved by the local Animal Care Committee.
▸ Seven supplementary video files (1A,B; 2A,B; and 3A–C) are published online only at http://gut.bmj.com/content/vol58/issue11