The selective and superoxide-independent disruption of intestinal epithelial tight junctions during leukocyte transmigration.
Polymorphonuclear leukocyte (PMN) transmigration across cultured intestinal epithelial monolayers has been shown to be associated with a decrease in transepithelial resistance to the passive flow of ions. Using flux techniques, we show that this effect reflects selective, PMN induced alterations in paracellular, as opposed to transcellular, ion permeability. Enhancement of paracellular permeability due to PMN transmigration is not simply due to expansion of the paracellular space resulting from cell death as cytotoxicity does not occur during this process. Thus, permeability alterations accompanying PMN transmigration can be specifically attributed to altered permeability of the rate limiting barrier of the paracellular pathway, the intercellular tight junction. We have also explored the mechanism by which PMN induce transient tight junction dissolution during transmigration. Use of inhibitors of toxic oxygen metabolites or use of PMN from patients with chronic granulomatous disease show that oxygen metabolites are neither required for transmigration or for the permeability abnormality accompanying transmigration. Similarly, use of protease inhibitors suggest that release of proteases by PMN during transmigration is not the basis by which PMN are able to cross tight junctions. Structural studies show that transient intimate PMN-epithelial cell plasma membrane associations and cytoskeletal specializations preceed junctional impalement by PMN. We speculate that such putative adhesion sites serve as the foothold from which PMN may generate the mechanical force necessary to cross tight junctions during transmigration.
Nash
S
S
Department of Pathology (Gastrointestinal Pathology), Brigham and Women's Hospital, Boston, Massachusetts.
Stafford
J
J
Madara
J L
JL
D001693:Biological Transport, Active; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D004848:Epithelium / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000648:ultrastructure; D008353:Mannitol / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D010539:Permeability; D012964:Sodium / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D013481:Superoxides; D008353:Mannitol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D012964:Sodium