The effects of FR167653 on pulmonary ischemia-reperfusion injury in dogs.
BACKGROUND
Ischemia-reperfusion injury may result in the local release of proinflammatory cytokines. A newly synthesized organic compound, FR167653, has been characterized as a potent suppressant of interleukin-1 beta and tumor necrosis factor-alpha. We investigated the effects of FR167653 on ischemia-reperfusion injury of the lung by using an in situ warm lung ischemia model in dogs.


METHODS
Thirteen dogs were divided into two groups; seven dogs were assigned to the control group, and six were assigned to the FR167653-treated group. The latter group was administered FR167653 (1 mg/kg/hr) continuously beginning 30 minutes before induced ischemia and ending 2 hours after reperfusion. Warm ischemia was induced for 3 hours by clamping the pulmonary artery and veins. The left main bronchus was bisected and anastomosed 3 hours later. Arterial oxygen saturation, left pulmonary vascular resistance, and cardiac output were measured. Blood was collected to measure interleukin-1 beta level, and the lung specimen was harvested for histologic study.


RESULTS
Arterial oxygen saturation levels after 30 minutes and 2 hours of reperfusion were significantly (p < 0.05) higher in the FR167653-treated group than in the control group. After 30 minutes of reperfusion, cardiac output deterioration was significantly (p < 0.05) greater in the control group than in the FR167653-treated group, and left pulmonary vascular resistance was significantly (p < 0.05) lower in the FR167653-treated group than in the control group. The 3-day survival rate was 67% in the FR167653-treated group and 14% in the control group. There were statistically significant differences (p < 0.05) between the survival rates of the two groups. Alveolar damage with interstitial edema and hyaline membranes localized along the alveolar duct were observed in the control group; whereas reduced interstitial edema was observed in the FR167653-treated group. Blood levels of IL-1 beta were lower in the FR167653-treated group than in the control group.


CONCLUSIONS
FR167653 seems to generate a protective effect relative to ischemia-reperfusion injury of the lung in the early stage of tissue damage.
Kamoshita
N
N
Second Department of Surgery, Gunma University School of Medicine, Japan.
Takeyoshi
I
I
Ohwada
S
S
Iino
Y
Y
Morishita
Y
Y
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D006818:Hyalin; D007262:Infusions, Intravenous; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000097:blood; D007511:Ischemia; D016040:Lung Transplantation / Q000276:immunology / Q000473:pathology; D009926:Organ Preservation; D010100:Oxygen / Q000097:blood; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011651:Pulmonary Artery / Q000502:physiology; D011654:Pulmonary Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000517:prevention & control*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects
D016207:Cytokines; C104334:FR 167653; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen