Recombinant Factor Xiii Diminishes Multiple Organ Dysfunction in Rats Caused by Gut Ischemia-Reperfusion Injury

Abstract

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.

Factor XIII and inflammatory cells

“…Such monocyte specific chemotactic factor(s) formed during clotting could be involved in recruiting monocytes/inflammatory macrophages to the site of injury. FXIII might also affect PMN leukocytes, since neutrophils from FXIII-treated rats had lower respiratory burst activity [19].…”

Recombinant Factor XIII Mitigates Hemorrhagic Shock-Induced Organ Dysfunction

“…[24, 25]. In vitro experiments have shown that activated FXIII is able to stabilize the endothelial barrier function and decrease endothelial permeability, presumably by interacting with extracellular matrix proteins in the paracellular spaces and/or minimizing disruption of adherens junctions, the protein complexes that occur at cell-cell junctions [13, 15, 16]. …”

“…The vehicle (1.0 mL/kg) or rFXIII (1.0 mg/kg) was given intravenously after 90 min of THS and re-infusion of shed blood (in THS groups) or after 90 min of TSS (in sham groups). The chosen dose of rFXIII was in alignment with the available literature data and our previous studies [13, 18]. …”

“…Previously, we have shown that recombinant factor XIII (rFXIII) limits MOD in an experimental model of isolated gut ischemia-reperfusion injury (superior mesenteric artery occlusion) [13]. FXIII or fibrin stabilizing factor is a transglutaminase involved in the final stage of blood coagulation.…”

“…Additionally, there is evidence that FXIII modulates the inflammatory response by retardation of macrophage migration [17]. Having previously demonstrated that treatment with rFXIII diminishes superior mesenteric artery occlusion-induced MODS [13], the present study aims to test the protective role of rFXIII in a more relevant clinical model of THS.…”