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

Abstract

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.

Figure 1

A) There were no differences in the volume of blood required to be withdrawn to induce and maintain shock. B) The average MAP post resuscitation was significantly higher in the 1mg/kg FTY720 dose group compared with the vehicle group. All FTY720 doses were effective in limiting T/HS-induced C) lung injury Data expressed as Mean ± SD except for Figure 1b, where the mean value without SD was used for clarity. n=6–9 rats per group; # p<0.05 vs. all other groups; * p<0.05 vs. THS + Vehicle; PR=Post Resuscitation.

Figure 2

All FTY720 doses were effective in limiting T/HS-induced A) neutrophil priming and B) red cell dysfunction. Data expressed as Mean ± SD. n=6–9 rats per group; # p<0.05 vs. all other groups

Figure 3

T/HS lymph from FTY720-treated rats manifested less ability to A) increase RBC rigidity, B) increase RCB adhesion to endothelium, C) induce RBC CD36 expression or D) induce neutrophil priming. Data is expressed as Mean ± SD with lymph samples from 9–11 rats tested in each group. # p<0.05 vs. sham groups; * p<0.05 vs. all other groups; + p<0.05 vs. T/SS+FTY720 group

Figure 4

FTY720 did not prevent T/HS-induced increases in A) gut permeability or limit the extent of B) morphologic gut injury. Data is expressed as Mean ± SD with n=6 rats per group; * p<0.05 vs. the respective T/SS group.

Figure 5

A) Both the T/HS + Vehicle and T/HS + FTY720 groups did not manifest acute lung injury when lymph was prevented from entering the systemic circulation. B) Likewise there was no difference in the post shock neutrophil respiratory burst priming or C) RBC deformability between the groups. Data is expressed as Mean ± SD with n=9–10 rats per group; * p<0.05 vs. respective Pre-operative group.