A sphingosine-1 phosphate agonist (FTY720) limits trauma/hemorrhagic shock-induced multiple organ dysfunction syndrome.

BACKGROUND: Trauma/hemorrhagic shock (T/HS) is one of the major consequences of battlefield injury as well as civilian trauma. FTY720 (sphingosine-1-phosphate agonist) has the capability to decrease the activity of the innate and adaptive immune systems and, at the same time, maintain endothelial cell barrier function and vascular homeostasis during stress. For this reason, we hypothesize that FTY720, as part of resuscitation therapy, would limit T/HS-induced multiple organ dysfunction syndrome in a rodent T/HS model. METHODS: Rats subjected to trauma/sham shock (T/SS) or T/HS (30 mm Hg × 90 min) were administered FTY720 (1 mg/kg) post-T/HS during volume resuscitation. Lung injury (permeability to Evans blue dye), polymorphonuclear leukocyte (PMN) priming (respiratory burst activity), and red blood cell (RBC) rigidity were measured. In addition, lymph duct-cannulated rats were used to quantify the effect of FTY720 on gut injury (permeability and morphology) and the biologic activity of T/HS versus T/SS lymph on PMN-RBC and RBC deformability. RESULTS: Trauma/hemorrhagic shock-induced increased lung permeability, PMN priming, and RBC rigidity were all abrogated by FTY720. The systemic protective effect of FTY720 was only partially at the gut level, because FTY720 did not prevent T/HS-induced gut injury (morphology or permeability); however, it did abrogate T/HS lymph-induced increased respiratory burst and RBC rigidity. CONCLUSIONS: FTY720 limited T/HS-induced multiple organ dysfunction syndrome (lung injury, red cell injury, and neutrophil priming) as well as T/HS lymph bioactivity, although it did not limit gut injury.

Oral pretreatment with recombinant human lactoferrin limits trauma-hemorrhagic shock-induced gut injury and the biological activity of mesenteric lymph.

BACKGROUND: Lactoferrin (LF) is a pleiotropic glycoprotein that is found in bodily secretions and is postulated to enhance the gastrointestinal barrier and promote mucosal immunity. Thus, the ability of talactoferrin, an oral recombinant form of human LF, to limit gut injury and the production of biologically active gut-derived products was tested using a rat model of trauma-hemorrhagic shock (T/HS). METHODS: Male rats were orally dosed with vehicle or talactoferrin (1000 mg/kg, every day) for 5 d before being subjected to T/HS or trauma-sham shock (T/SS). Subsequently, rats were subjected to a laparotomy (trauma) and hemorrhagic shock (mean arterial pressure, 30-35 mm Hg × 90 min) or to T/SS, followed by resuscitation with their shed blood. Before inducing shock, the mesenteric lymphatic duct was catheterized for collection of mesenteric lymph. Four hours after the end of the shock or sham-shock period, rats were sacrificed, a segment of the distal ileum was collected for morphologic analysis, and lymph samples were processed and frozen. Subsequently, lymph samples were tested in several pharmacodynamic assays, including endothelial cell permeability, neutrophil respiratory burst activity, and red blood cell (RBC) deformability. Total white blood cell counts in lymph samples were also quantified. RESULTS: Pretreatment with talactoferrin reduced the incidence of T/HS-induced morphologic injury of ileum to T/SS levels. Post-T/HS lymph from vehicle-treated rats increased endothelial monolayer permeability and neutrophil priming for an augmented respiratory burst, and induced loss of RBC deformability, compared with T/SS groups. Talactoferrin pretreatment significantly reduced the biological activity of T/HS lymph on respiratory burst activity and RBC deformability, but had no effect on the lymph cell count or endothelial cell permeability. CONCLUSIONS: These results provide a proof of principle that prophylactic dosing of oral talactoferrin can potentially protect the gut in a T/HS model and limit the production of biologically active factors in rat gastrointestinal tissue subjected to ischemia-reperfusion-type injuries.