Delayed administration of low-dose NPC18915 ameliorates lung ischemia-reperfusion injury.
BACKGROUND
NPC18915, a member of new antiinflammatory agent called nactins (neutrophil activation inhibitors), has been shown to reduce reperfusion injury in rat lung transplantation at high dosage. In vitro studies have demonstrated effectiveness of this compound even at low dosage. We hypothesized that this compound ameliorates lung ischemia reperfusion injury even at low dosage levels if administration is optimally timed. The aim of this study was to determine the efficacy and the best timing for administration of low-dose NPC18915.


METHODS
Forty syngeneic rat left lung transplantations were performed. All isografts were flushed with low-potassium dextran-1% glucose solution 20 ml and preserved for 18 hours at 4 degrees C. Animals were divided into four groups. Group I animals (n = 10) served as control subjects. In groups II (n = 10), III (n = 10), and IV (n = 10), NPC18915 (0.04 mg) was added to the flush solution and was administered intravenously (0.4 mg/kg) immediately before reperfusion (group II) and 60 minutes (group III) and 120 minutes (group IV) after reperfusion. Pulmonary function was assessed 24 hours after reperfusion.


RESULTS
In group III, oxygenation improved in comparison to group I (247.2 +/- 59.8 versus 76.6 +/- 16.0 mm Hg, p < 0.002). Wet-to-dry weight ratio and graft myeloperoxidase activity were significantly improved (group III versus group I, 6.02 +/- 0.21 versus 7.19 +/- 0.41, p = 0.013) (group III versus group I, 0.093 +/- 0.019 versus 0.207 +/- 0.023 delta optical density/min/mg, p < 0.002). There were no significant differences in CD11b expression.


CONCLUSIONS
These data suggest that delayed administration of NPC18915, 60 minutes after reperfusion, dramatically improves pulmonary graft function.
Yano
M
M
Department of Surgery, Washington University School of Medicine, Barnes Hospital, St. Louis, MO, USA.
Ando
K
K
Fujino
S
S
Liu
D Y
DY
Cooper
J D
JD
Patterson
G A
GA
D000818:Animals; D001565:Benzoates / Q000008:administration & dosage*; D001572:Benzofurans / Q000008:administration & dosage*; D005434:Flow Cytometry; D008168:Lung / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D016040:Lung Transplantation; D016177:Macrophage-1 Antigen / Q000032:analysis; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009926:Organ Preservation; D010100:Oxygen / Q000097:blood; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*
D001565:Benzoates; D001572:Benzofurans; D016177:Macrophage-1 Antigen; D009195:Peroxidase; C112691:NPC 18915; D010100:Oxygen