Background & Aims: Pancreatic infiltration by leukocytes represents a hallmark in acute pancreatitis. Although leukocytes play an active role in the pathophysiology of this disease, the relation between leukocyte activation, microvascular injury and hemorrhage has not been adequately addressed.
Methods: We investigated intrapancreatic leukocyte migration, leukocyte extravasation and pancreatic microperfusion in different models of edematous and necrotizing acute pancreatitis in lys-EGFP-ki mice using fluorescent imaging and time-lapse intravital microscopy.
Results: In contrast to the current paradigm of leukocyte recruitment, the initial event of leukocyte activation in acute pancreatitis was represented through a dose- and time-dependent occlusion of pancreatic capillaries by intraluminally migrating leukocytes. Intracapillary leukocyte accumulation (ILA) resulted in dense filling of almost all capillaries close to the area of inflammation and preceded transvenular leukocyte extravasation. ILA was also initiated by isolated exposure of the pancreas to IL-8 or fMLP demonstrating the causal role of chemotactic stimuli in the induction of ILA. The onset of intracapillary leukocyte accumulation was strongly inhibited in LFA-1-/- and ICAM-1-/- mice, but not in Mac-1-/- mice. Moreover, prevention of intracapillary leukocyte accumulation led to the development of massive capillary hemorrhages and transformed mild pancreatitis into lethal hemorrhagic disease.
Conclusions: ILA represents a novel protective and potentially lifesaving mechanism of hemostasis in acute pancreatitis. This process depends on expression of LFA-1 and ICAM-1 and precedes the classical steps of the leukocyte recruitment cascade.