Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-kappaB.
A central role for nuclear factor-kappaB (NF-kappaB) in the induction of lung inflammatory injury is emerging. We hypothesized that NF-kappaB is a critical early regulator of the inflammatory response in lung ischemia-reperfusion injury, and inhibition of NF-kappaB activation reduces this injury and improves pulmonary graft function. With use of a porcine transplantation model, left lungs were harvested and stored in cold Euro-Collins preservation solution for 6 h before transplantation. Activation of NF-kappaB occurred 30 min and 1 h after transplant and declined to near baseline levels after 4 h. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-kappaB, given to the lung graft during organ preservation (40 mmol/l) effectively inhibited NF-kappaB activation and significantly improved lung function. Compared with control lungs 4 h after transplant, PDTC-treated lungs displayed significantly higher oxygenation, lower PCO(2), reduced mean pulmonary arterial pressure, and reduced edema and cellular infiltration. These results demonstrate that NF-kappaB is rapidly activated and is associated with poor pulmonary graft function in transplant reperfusion injury, and targeting of NF-kappaB may be a promising therapy to reduce this injury and improve lung function.
Ross
S D
SD
Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.
Kron
I L
IL
Gangemi
J J
JJ
Shockey
K S
KS
Stoler
M
M
Kern
J A
JA
Tribble
C G
CG
Laubach
V E
VE
D000818:Animals; D004247:DNA / Q000378:metabolism; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D016040:Lung Transplantation; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011183:Postoperative Complications / Q000517:prevention & control*; D011652:Pulmonary Circulation; D011654:Pulmonary Edema / Q000517:prevention & control; D011759:Pyrrolidines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013552:Swine; D013859:Thiocarbamates / Q000494:pharmacology
D020672:I-kappa B Proteins; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D004247:DNA; D009195:Peroxidase