Intracapillary leucocyte accumulation as a novel antihaemorrhagic mechanism in acute pancreatitis in mice

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.