Effects of the 5-lipoxygenase inhibitor A-64077 on intestinal hypothermic organ preservation injury.
The effects of the orally active selective 5-lipoxygenase inhibitor Zileuton (A-64077, (N-1(1-benzo{b}thien-2-ylethyl)-N-hydroxyurea) were studied in a canine model of hypothermic intestinal organ ischemia-reperfusion (I/R) injury (transplant preservation injury). Forty-eighty hours of hypothermic intestinal ischemia utilizing Collin's flush, followed by 1 hr of reperfusion (transplantation) in A-64077-treated animals, resulted in a 3-fold increase in intestinal oxygen uptake and blood flow relative to the untreated controls. The postreperfusion movement of fluid from the microcirculation into the intestinal lumen significantly increased in the control animals at reperfusion, and A-64077 treatment dramatically exacerbated this phenomenon. Mucosal neutrophil infiltration, or the processes leading to infiltration, significantly increased after 48 hr of cold ischemia and 1 hr of normothermic reperfusion in the untreated animals. A similar response was observed in A-64077-treated dogs, but the absolute levels of MPO were 10-fold less relative to untreated animals, including intestinal tissue obtained before I/R. Hypothermic I/R injury in this model resulted in severe histologic injury. A-64077-treated dogs, however, demonstrated significant improvements in histologic injury. Mucosal synthesis of LTB4 rose significantly after cold I/R injury and was abrogated by A-64077 treatment. The synthesis of PGE2 significantly increased after cold I/R in both untreated and A-64077-treated dogs. The increase in PGE2 production after hypothermic I/R in the A-64077-treated animals was higher relative to the untreated control animals. In conclusion, this study indicates that arachidonic acid metabolism via the 5-lipoxygenase pathway plays a significant role in the pathophysiology of hypothermic intestinal I/R injury. Furthermore, the 5-lipoxygenase inhibitor A-64077 possesses favorable pharmacologic and biologic responses in this intestinal injury and should be considered in the clinical amelioration of intestinal transplantation preservation injury.
Mangino
M J
MJ
Department of Critical Care Medicine, Miami Children's Hospital, Florida, USA.
Mangino
J E
JE
Kotadia
B
B
Sielczak
M
M
D000818:Animals; D015925:Cryopreservation; D015232:Dinoprostone / Q000096:biosynthesis; D004285:Dogs; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007082:Ileum / Q000201:enzymology / Q000293:injuries / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009926:Organ Preservation / Q000009:adverse effects*; D009195:Peroxidase / Q000378:metabolism
D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D009195:Peroxidase; D015232:Dinoprostone; C063449:zileuton; D006918:Hydroxyurea