Attenuation of lung injury in allograft rejection using NF-kappaB decoy transfection-novel strategy for use in lung transplantation.
OBJECTIVE
Increased production of nitric oxide (NO) is known to be a marker of lung allograft rejection and lung injury. NO production is up-regulated directly or indirectly by nuclear factor-kappa B (NF-kappaB), a transcriptional factor of inflammatory cytokines and iNOS. We attempted to determine whether transfection of an NF-kappaB decoy into allografts could reduce NO production and ameliorate acute lung injury during allograft rejection.


METHODS
Left lung transplantation was performed in pairs of Brown Norway (RT1n) and Lewis (RT1) rats. In Group NF (n=6), the allografts were flushed with 20 ml of PBS solution containing a hemagglutinating virus of Japan (HVJ) liposome-ODN complex as an NF-kappaB decoy and preserved for 60 min at 4 degrees C. A scramble decoy was used in the positive control (Group S, n=5) and simple PBS solution in the negative control (Group C, n=5). Five days after transplantation without use of immuno-suppressants, exhaled NO, gas exchange, and graft histological rejection score were determined.


RESULTS
The exhaled NO level was significantly reduced in Group NF as compared with Group S (445+/-162 vs 1305+/-123 ppb, P<0.02), while improvements in PaO2 (197+/-28 vs. 60+/-18 mmHg, P<0.02) and rejection score (1.8+/-0.3 vs. 2.5+/-0.4) were also observed. There were no differences in these parameters between Groups S and C.


CONCLUSIONS
Inhibition of NF-kappaB activation in the allograft by ODN decoy transfection into the donor lung ameliorated lung injury during acute allograft rejection. Our results imply a possible therapeutic target for the inflammation process in lung transplantation clinical settings.
Ohmori
Kenichi
K
Department of Surgery (E1), Osaka University Graduate School of Medicine, Yamada-oka 2-2, Suita City, Osaka 565-0871, Japan. omorik@kure-nh.go.jp
Takeda
Shin-ichi
S
Miyoshi
Shinichiro
S
Minami
Masato
M
Nakane
Shigeru
S
Ohta
Mitsunori
M
Sawa
Yoshiki
Y
Matsuda
Hikaru
H
D000208:Acute Disease; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000503:physiopathology / Q000517:prevention & control*; D006084:Graft Rejection / Q000378:metabolism / Q000503:physiopathology*; D008081:Liposomes; D008168:Lung / Q000503:physiopathology; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013873:Thionucleotides / Q000008:administration & dosage; D014162:Transfection / Q000379:methods
D008081:Liposomes; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D009569:Nitric Oxide