Indeed, one clear example of neutrophil-induced monolayer disruption is provided by Gautum et al., who demonstrated both a decrease in transendothelial electrical resistance (TEER) and an increase in the albumin permeability of unstimulated human umbilical vein endothelial cells (HUVECs) when N-Formylmethionyl-leucyl-phenylalanine (fMLP) was introduced in the trans compartment of a membrane-based chemotactic chamber. Thus, the controversy in the literature may be a matter of degrees: experimental circumstances involving a large number of simultaneous leukocyte engagements will show concurrent molecular transmission in bulk permeability assays, while the same assays will not be sensitive to less numerous and/or asynchronous events. 48 The fact that the junctions quickly reseal following the leukocyte exit is cited as an explanation for the ability of endothelial monolayers to maintain a barrier to molecular transmission despite leukocyte transmigration, 19, 29 however the same images suggest that some local molecular leakage will likely accompany transmigration events. Live cell movies of leukocytes transmigrating across endothelium clearly show short-lived disruptions of endothelial junctions. Developing a better understanding of the specific role neutrophils play in vascular barrier disruption will facilitate the development of novel anti-inflammatory therapeutics capable of modulating this off-target response. However, there are counter examples both in vivo 53 and in vitro 13, 17 where the engagement of endothelium by leukocytes is the only plausible stimulus responsible for a subsequent increase in molecular permeability. 46 The common view that these two forms of permeability are uncoupled is based on many examples of leukocyte adhesion without accompanying permeability and vice versa (reviewed in Refs. 10 Despite the fact that both leukocyte and plasma ‘permeability’ have been known since the observations of Cohnheim, 9, 23, 24 the extent to which leukocyte engagement contributes to microvascular permeability remains unclear. ![]() ![]() Alterations in microvascular barrier integrity are implicated in a variety of inflammatory diseases, including sepsis. The increased permeability of the microvasculature to both leukocytes and plasma components are hallmarks of inflammation.
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