Does recombinant factor XIII eliminate early manifestations of multiple-organ injury after experimental burn similarly to gut ischemia-reperfusion injury or trauma-hemorrhagic shock?

The authors have previously shown that recombinant factor XIII (rFXIII) eliminates early manifestations of multiple-organ injury caused by experimental superior mesenteric artery occlusion or trauma-hemorrhagic shock. The aim of the present study was to test the hypothesis that rFXIII provides similar protective effect in experimental burn injury. Rats were randomly divided into five groups (eight animals per group): group 1: burn + placebo treatment; group 2: burn + rFXIII pretreatment; group 3: burn + rFXIII treatment; group 4: sham burn + placebo treatment, and group 5: sham burn + rFXIII treatment. Burn (40% of TBSA) was achieved by immersing the back and abdomen of a rat into 97°C water for 10 and 5 seconds, respectively. Infusion of rFXIII (1 mg/kg) or placebo was performed immediately after burn/sham burn in treatment groups or 24 hours before burn and repeated immediately after it in pretreatment group. Endpoint parameters measured 3 hours after burn/sham burn included muscle blood flow and PO2, lung permeability, gut histology, lung and gut myeloperoxidase activity, neutrophil respiratory burst, and FXIII activity. Both treatment and pretreatment with rFXIII partially preserved microvascular blood flow in the muscle. Muscle PO2 in pretreated rats did not differ from that in shams. Pretreatment but not treatment with rFXIII preserved lung permeability. rFXIII did not have any protective effect on other endpoint parameters. In contrast to superior mesenteric artery occlusion and trauma-hemorrhagic shock experimental models, rFXIII at the doses tested has a limited effect on preventing early manifestations of multiple-organ injury after experimental burn.

Listeria monocytogenes (Lm)-LLO immunotherapies reduce the immunosuppressive activity of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment.

Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) are major components of the immune suppressive cells that potentially limit the effectiveness of an immunotherapy-based treatment. Both of these suppressive cell types have been shown to expand in tumor models and promote T-cell dysfunction that in turn favors tumor progression. This study demonstrates that Listeria monocytogenes (Lm)-LLO immunotherapies effect on the suppressive ability of MDSC and Treg in the tumor microenvironment (TME), resulting in a loss in the ability of these cells to suppress T cells. This alteration of immunosuppression in the TME was an inherent property of all Lm-LLO immunotherapies tested and was independent of the tumor model. The virtually total loss in the suppressive ability of these cells in the TME was linked to the reduction in the expression of arginase I in MDSC and IL-10 in Treg. The results presented here provide insight into a novel mechanism of Lm-LLO immunotherapies that potentially contributes to therapeutic antitumor responses.

Recombinant factor XIII mitigates hemorrhagic shock-induced organ dysfunction.

BACKGROUND: Plasma factor XIII (FXIII) is responsible for stabilization of fibrin clot at the final stage of blood coagulation. Since FXIII has also been shown to modulate inflammation, endothelial permeability, as well as diminish multiple organ dysfunction (MOD) after gut ischemia-reperfusion injury, we hypothesized that FXIII would reduce MOD caused by trauma-hemorrhagic shock (THS). MATERIALS AND METHODS: Rats were subjected to a 90 min THS or trauma sham shock (TSS) and treated with either recombinant human FXIII A(2) subunit (rFXIII) or placebo immediately after resuscitation with shed blood or at the end of the TSS period. Lung permeability, lung and gut myeloperoxidase (MPO) activity, gut histology, neutrophil respiratory burst, microvascular blood flow in the liver and muscles, and cytokine levels were measured 3 h after the THS or TSS. FXIII levels were measured before THS or TSS and after the 3-h post-shock period. RESULTS: THS-induced lung permeability as well as lung and gut MPO activity was significantly lower in rFXIII-treated than in placebo-treated animals. Similarly, rFXIII-treated rats had lower neutrophil respiratory burst activity and less ileal mucosal injury. rFXIII-treated rats also had a higher liver microvascular blood flow compared with the placebo group. Cytokine response was more favorable in rFXIII-treated animals. Trauma-hemorrhagic shock did not cause a drop in FXIII activity during the study period. CONCLUSIONS: Administration of rFXIII diminishes THS-induced MOD in rats, presumably by preservation of the gut barrier function, limitation of polymorphonuclear leukocyte (PMN) activation, and modulation of the cytokine response.

Recombinant factor XIII diminishes multiple organ dysfunction in rats caused by gut ischemia-reperfusion injury.

Plasma factor XIII (FXIII) is responsible for stabilization of fibrin clot at the final stage of blood coagulation. Because FXIII has also been shown to modulate inflammation and endothelial permeability, we hypothesized that FXIII diminishes multiple organ dysfunction caused by gut I/R injury. A model of superior mesenteric artery occlusion (SMAO) was used to induce gut I/R injury. Rats were subjected to 45-min SMAO or sham SMAO and treated with recombinant human FXIII A2 subunit (rFXIII) or placebo at the beginning of the reperfusion period. Lung permeability, lung and gut myeloperoxidase activity, gut histology, neutrophil respiratory burst, and microvascular blood flow in the liver and muscles were measured after a 3-h reperfusion period. The effect of activated rFXIII on transendothelial resistance of human umbilical vein endothelial cells was tested in vitro. Superior mesenteric artery occlusion-induced lung permeability as well as lung and gut myeloperoxidase activity was significantly lower in rFXIII-treated versus untreated animals. Similarly, rFXIII-treated rats had lower neutrophil respiratory burst activity and ileal mucosal injury. Rats treated with rFXIII also had higher liver microvascular blood flow compared with the placebo group. Superior mesenteric artery occlusion did not cause FXIII consumption during the study period. In vitro, activated rFXIII caused a dose-dependent increase in human umbilical vein endothelial cell monolayer resistance to thrombin-induced injury. Thus, administration of rFXIII diminishes SMAO-induced multiple organ dysfunction in rats, presumably by preservation of endothelial barrier function and the limitation of polymorphonuclear leukocyte activation.

Identification of novel mediators of NF-kappaB through genome-wide survey of monocyte adherence-induced genes.

The transcription factor nuclear factor (NF)-kappaB controls the expression of genes involved in inflammation, cell proliferation, apoptosis, and differentiation. Impaired regulation of NF-kappaB has been associated with many diseases; thus, there is significant interest in therapeutic approaches based on modulation of this transcription factor. NF-kappaB activity is controlled by numerous signaling molecules, many of which are potentially to be identified. Monocytes are principal effectors of the immune system, and monocyte adherence is the first step leading to their activation and differentiation. Adherence induces activation of NF-kappaB, resulting in the induction of proinflammatory genes as well as anti-inflammatory genes, which counterbalance and limit the intensity and duration of NF-kappaB activation. Here, to identify novel mediators of NF-kappaB signaling, we used the model of monocyte adherence to perform a systematic, genome-wide survey of adherence-induced genes. Having isolated mRNAs from nonadherent and adherent primary human monocytes, we constructed suppressive subtraction hybridization libraries containing cDNAs, which were differentially regulated by adherence. Of 366 identified differentially expressed genes, most were found to be up-regulated by adherence. Having analyzed a subset of these genes, we found that the library was enriched with inhibitors of NF-kappaB. Three of those (an orphan nuclear receptor NUR77, a guanosine 5'-diphosphate/guanosine 5'-triphosphate exchange factor RABEX5, and a PRK1-associated protein AWP1) were particularly potent inhibitors of NF-kappaB activation. Thus, the collection of monocyte adherence-regulated genes represents a rich source for the identification of novel components of the machinery that controls NF-kappaB activation.