title: Evidence for the involvement of Fas ligand and perforin in the induction of vascular leak syndrome.
abstract: Endothelial cell injury resulting in vascular leak syndrome (VLS) is one of the most widely noted phenomenons in a variety of clinical diseases. In the current study we used IL-2-induced VLS as a model to investigate the role of cytolytic lymphocytes in the cytotoxicity of endothelial cells. Administration of IL-2 (75,000 U/mouse, three times a day for 3 days) into BL/6 wild-type mice triggered significant VLS in the lungs, liver, and spleen. Interestingly, perforin-knockout (KO) mice exhibited a marked decrease in IL-2-induced VLS in all three organs tested. Also, Fas ligand-defective (gld) mice and Fas-deficient (lpr) mice exhibited decreased VLS in the liver and spleen, but not in the lungs. The decreased VLS seen in perforin-KO, gld, and lpr mice was not due to any defect in lymphocyte migration or homing to various organs because histopathologic studies in these mice demonstrated significant and often greater perivascular infiltration of lymphocytes compared with the IL-2-treated wild-type mice. Ultrastructural studies of the lungs demonstrated significant damage to the endothelial cells in IL-2-treated wild-type mice and decreased damage in perforin-KO mice. IL-2 administration caused up-regulation of CD44 in all strains of mice tested and triggered increased LAK activity against an endothelial cell line in wild-type and gld mice, but not in perforin-KO mice. The current study demonstrates for the first time that perforin and Fas ligand may actively participate in endothelial cell injury and induction of VLS in a variety of organs.
authors.affiliation: Department of Biology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg 24061, USA.
authors.forename: A Q
authors.initials: AQ
authors.lastname: Rafi
authors.forename: A
authors.initials: A
authors.lastname: Zeytun
authors.forename: M J
authors.initials: MJ
authors.lastname: Bradley
authors.forename: D P
authors.initials: DP
authors.lastname: Sponenberg
authors.forename: R L
authors.initials: RL
authors.lastname: Grayson
authors.forename: M
authors.initials: M
authors.lastname: Nagarkatti
authors.forename: P S
authors.initials: PS
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D019559:Capillary Leak Syndrome / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000276:immunology; D002461:Cell Line, Transformed; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D053222:Fas Ligand Protein; D005260:Female; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000098:blood supply / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000473:pathology; D018655:Lymphocyte Count / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin