EFFECTS OF THE 5-LIPOXYGENASE INHIBITOR A-64077 ON INTESTINAL HYPOTHERMIC ORGAN PRESERVATION INJURY

The effects of tile orally active selective 5-lipoxygenase inhibitor Z ileuton (A-64077, (N-1(1-benzo{b}thien-2-ylethyl)-N-hydroxyurea) were studied in a canine model of hypothermic intestinal organ ischemia-rep erfusion (I/R) injury (transplant preservation injury), Forty-eight ho urs of hypothermic intestinal ischemia utilizing Collin's flush, follo wed by 1 hr of reperfusion (transplantation) in A-64077-treated animal s, 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 signific antly increased in the control animals at reperfusion, and A-64077 tre atment dramatically exacerbated this phenomenon. Mucosal neutrophil in filtration, or the processes leading to infiltration, significantly in creased after 48 hr of cold ischemia and 1 hr of normothermic reperfus ion in the untreated animals. A similar response was observed in A-640 77-treated dogs, but the absolute levels of MPO were 10-fold less rela tive to untreated animals, including intestinal tissue obtained before I/R. Hypothermic I/R injury in this model resulted in severe histolog ic injury. A-64077-treated dogs, however, demonstrated significant imp rovements in histologic injury. Mucosal synthesis of LTB4 rose signifi cantly after cold I/R injury and was abrogated by A-64077 treatment. T he synthesis of PGE(2) significantly increased after cold I/R in both untreated and A-64077-treated dogs. The increase in PGE(2) production after hypothermic I/R in the A-64077-treated animals was higher relati ve to the untreated control animals. In conclusion, this study indicat es that arachidonic acid metabolism via the 5-lipoxygenase pathway pla ys a significant role in the pathophysiology of hypothermic intestinal I/R injury, Furthermore, the 5-lipoxygenase inhibitor A-64077 possess es favorable pharmacologic and biologic responses in this intestinal i njury and should be considered in the clinical amelioration of intesti nal transplantation preservation injury.