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Inhibition of Fas-Fas ligand interaction attenuates microvascular hyperpermeability following hemorrhagic shock.

ABSTRACT: Hemorrhagic shock (HS)-induced microvascular hyperpermeability poses a serious challenge in the management of trauma patients. Microvascular hyperpermeability occurs mainly because of the disruption of endothelial cell adherens junctions, where the "intrinsic" apoptotic signaling plays a regulatory role. The purpose of this study was to understand the role of the "extrinsic" apoptotic signaling molecules, particularly Fas-Fas ligand interaction in microvascular endothelial barrier integrity. Rat lung microvascular endothelial cells (RLMECs) were exposed to HS serum in the presence or absence of the Fas ligand inhibitor, FasFc. The effect of HS serum on Fas receptor and Fas ligand expression on RLMECs was determined by flow cytometry. Endothelial cell permeability was determined by monolayer permeability assay and the barrier integrity by ?-catenin immunofluorescence. Mitochondrial reactive oxygen species formation was determined using dihydrorhodamine 123 probe by fluorescent microscopy. Mitochondrial transmembrane potential was studied by fluorescent microscopy as well as flow cytometry. Caspase 3 enzyme activity was assayed fluorometrically. Rat lung microvascular endothelial cells exposed to HS serum showed increase in Fas receptor and Fas ligand expression levels. FasFc treatment showed protection against HS serum-induced disruption of the adherens junctions and monolayer hyperpermeability (P < 0.05) in the endothelial cells. Pretreatment with FasFc also decreased HS serum-induced increase in mitochondrial reactive oxygen species formation, restored HS serum-induced drop in mitochondrial transmembrane potential, and reduced HS serum-induced caspase 3 activity in RLMECs. These findings open new avenues for drug development to manage HS-induced microvascular hyperpermeability by targeting the Fas-Fas ligand-mediated pathway.

SUBMITTER: Sawant DA

PROVIDER: S-EPMC3640556 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Inhibition of Fas-Fas ligand interaction attenuates microvascular hyperpermeability following hemorrhagic shock.

Sawant Devendra A DA Tharakan Binu B Tobin Richard P RP Stagg Hayden W HW Hunter Felicia A FA Newell M Karen MK Smythe W Roy WR Childs Ed W EW

Shock (Augusta, Ga.) 20130201 2

Hemorrhagic shock (HS)-induced microvascular hyperpermeability poses a serious challenge in the management of trauma patients. Microvascular hyperpermeability occurs mainly because of the disruption of endothelial cell adherens junctions, where the "intrinsic" apoptotic signaling plays a regulatory role. The purpose of this study was to understand the role of the "extrinsic" apoptotic signaling molecules, particularly Fas-Fas ligand interaction in microvascular endothelial barrier integrity. Rat ...[more]

PMID: 23324886

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Project description:BACKGROUND:Tourniquet is the most widely used and effective first-aid equipment for controlling hemorrhage of injured limb in battlefield. However, time-out application of tourniquets leads to ischemic-necrosis of skeletal muscles and ischemia-reperfusion injury. Regional hypothermia (RH) on wounded limb can relieve the injury on local tissue and distant organs. We aimed to investigate the protective effects of RH on rabbits' limbs injured by a steel-ball combined with hemorrhagic-shock, and then employed tourniquet over-time, tried to identify the optimal treatment RH. METHODS:Thirty rabbits were randomly divided into 5 groups. All rabbits were anesthetized, intubated femoral artery and vein in right-hind limbs. Sham operation group (Sham): only femoral arteriovenous cannula in right-hind limb. None RH group (NRH): rabbits were intubated as Sham group, then the soft tissues of rabbits' left-hinds were injured by a steel-ball shooting, and were exsanguinated until shock, then bundled with rubber tourniquets for 4 h. Three RH subgroups: rabbits were injured as mentioned above, the injured limbs were bundled with rubber tourniquets and treated with different temperature (5 ± 1 °C, 10 ± 1 °C, and 20 ± 1 °C, respectively) for 4 h. The injury severity of lung and regional muscle was assessed by histologic examination. Activity of adenosine triphosphatase (ATPase) and content of malondialdehyde (MDA) in muscle, inflammatory cytokines, myoglobin, creatine kinase-MM (CK-MM), Heme, Heme oxygenase 1 (HO-1), lactic acid (Lac), and lectrolyte ion in serum were detected. RESULTS:Following with RH treatment, the injury of lung and local muscle tissue was alleviated evidencing by mitigation of histopathological changes, significant decrease of water-content and MDA content, and increase of ATPase activity. Lower level of Lac, Potassium (K+), inflammatory cytokines, Heme, CK-MM, myoglobin content, and higher level of Calcium (Ca2+), HO-1 content were shown in RH treatment. 10 °C was the most effective RH to increase ATPase activity, and decrease MDA, myoglobin, CK-MM content. CONCLUSION:Transient RH (4 h) had a "long-term mitigation effects" (continued for 6 h) on time-out application of tourniquet with the fluid resuscitation and core temperature maintenance, and the most effective temperature for reducing the side effects on tourniquet time-out application was 10 °C.

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Inhibition of Fas-Fas ligand interaction attenuates microvascular hyperpermeability following hemorrhagic shock.

Publications

Inhibition of Fas-Fas ligand interaction attenuates microvascular hyperpermeability following hemorrhagic shock.

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