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.

• Authors: Joyce A Bonitz, Julie Y Son, Benjamin Chandler, Jacquelyn N Tomaio, Yong Qin, Lauriston M Prescott, Eleonora Feketeova, Edwin A Deitch
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 42 Issue 5 Pg. 448-55 (Nov 2014) ISSN: 1540-0514 [Electronic] United States
• PMID: 25004059 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Immunosuppressive Agents
• Propylene Glycols
• Fingolimod Hydrochloride
• Sphingosine

Topics

• Acute Lung Injury (etiology, prevention & control)
• Animals
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Erythrocyte Deformability (drug effects, physiology)
• Fingolimod Hydrochloride
• Immunosuppressive Agents (administration & dosage, therapeutic use)
• Male
• Multiple Organ Failure (blood, etiology, prevention & control)
• Neutrophil Activation (drug effects)
• Propylene Glycols (administration & dosage, therapeutic use)
• Rats, Sprague-Dawley
• Respiratory Burst (drug effects)
• Shock, Hemorrhagic (blood, complications, drug therapy)
• Sphingosine (administration & dosage, analogs & derivatives, therapeutic use)