Am J Surg. 2013 Jan 30. pii: S0002-9610(13)00023-8. doi: 10.1016/j.amjsurg.2012.10.027. [Epub ahead of print]
Tumor necrosis factor-related apoptosis-inducing ligand promotes microvascular endothelial cell hyperpermeability through phosphatidylinositol 3-kinase pathway.
Stagg HW, Bowen KA, Sawant DA, Rodriguez M, Tharakan B, Childs EW.
Department of Surgery, Texas A&M Health Science Center College of Medicine and Scott & White Memorial Hospital, 702 SW H.K. Dodgen Loop, Temple, TX 76504, USA.
BACKGROUND:
Microvascular hyperpermeability that occurs in hemorrhagic shock and burn trauma is regulated by the apoptotic signaling pathway. We hypothesized that tumor necrosis factor-a (TNF-a)-related apoptosis-inducing ligand (TRAIL) would promote hyperpermeability directly or by interacting with other signaling pathways.
METHODS:
Rat lung microvascular endothelial cells (RLMECs) grown on Transwell membranes (Corning Life Sciences, Lowell, MA) were treated with recombinant human TRAIL (10, 50, and 100 ng/mL) for 6 hours or TRAIL (100 ng/mL) + LY294002 (a PI3K inhibitor; 20 µmol/L), Z-DEVD-FMK (a caspase-3 inhibitor; 10 µmol/L), or the inhibitors alone. Fluorescein isothiocyanate (FITC)-albumin flux was an indicator of permeability. Caspase-3 activity was measured fluorometrically. Adherens junction integrity was studied using ß-catenin immunofluorescence.
RESULTS:
TRAIL + LY294002, but not TRAIL alone, induced monolayer hyperpermeability (P < .05), and caspase-3 activity (P < .05), and disrupted the adherens junctions. Z-DEVD-FMK attenuated hyperpermeability and protected the adherens junctions.
CONCLUSIONS:
TRAIL-induced microvascular hyperpermeability is phosphatidylinositol 3-kinase (PI3K)-dependent and may be mediated by caspase-3 cleavage of the endothelial adherens junctional complex.
hmmmm..... never would have put that up here, but I thought I could find another abstract, to accompany that above, relating to sepsis/pi3k. Can't find it. So.... sorry! |
