Endobronchial gene transfer of soluble type I interleukin-1 receptor ameliorates lung graft ischemia-reperfusion injury.
BACKGROUND
Soluble type I interleukin-1 receptor is a competitive inhibitor of interleukin-1 and may reduce its proinflammatory actions. The objective of this experiment was to demonstrate that endobronchial gene transfer of soluble type I interleukin-1 receptor IgG to donor lung grafts reduces posttransplant ischemia-reperfusion injury.


METHODS
All experiments utilized an orthotopic left lung isograft transplant model. Donors were divided into three groups (n = 6 each) for endobronchial transfection: group I received 2 x 10(7) plaque-forming units of adenovirus encoding soluble type I interleukin-1 receptor IgG; group II received 2 x 10(7) plaque-forming units of nonfunctional control adenovirus encoding beta-galactosidase; and group III received 0.1 mL of saline. Left lungs were harvested 24 hours after transfection and stored for 18 hours before transplantation. Graft function was assessed 24 hours after reperfusion using three measurements: isolated graft oxygenation, wet-to-dry lung weight ratio, and tissue myeloperoxidase activity. Transgene expression of soluble type I interleukin-1 receptor IgG was also evaluated using enzyme-linked immunosorbent assay and immunohistochemistry.


RESULTS
Isolated graft arterial oxygenation was significantly improved in group I compared with groups II and III (281.8 +/- 134.8 versus 115.7 +/- 121.5 and 88.0 +/- 58.9 mm Hg, p = 0.0197 and p = 0.0081, respectively). Myeloperoxidase activity was also significantly reduced in group I compared with groups II and III (0.083 +/- 0.044 versus 0.155 +/- 0.043 and 0.212 +/- 0.079 optical density units per minute per milligram protein, p = 0.0485 and p = 0.0016, respectively). Expression of soluble type I interleukin-1 receptor IgG was detected only in lungs from group I.


CONCLUSIONS
Endobronchial gene transfer of soluble type I interleukin-1 receptor IgG to donor lung grafts subjected to prolonged cold ischemia ameliorates ischemia-reperfusion injury by improving graft oxygenation and reducing lung edema and neutrophil sequestration.
Tagawa
Tsutomu
T
Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110-1013, USA.
Dharmarajan
Sekhar
S
Hayama
Makio
M
Ishiyama
Takaaki
T
Suda
Takashi
T
Itano
Hideki
H
Patterson
G Alexander
GA
D000818:Animals; D018014:Gene Transfer Techniques; D016040:Lung Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D015427:Reperfusion Injury / Q000517:prevention & control*; D014162:Transfection; D019076:Transgenes
D017472:Receptors, Interleukin-1