Extended cold preservation of the graft liver enhances neutrophil-mediated pulmonary injury after liver transplantation.
OBJECTIVE
The precise mechanisms of pulmonary injury after liver transplantation, especially those associated with cold ischemia time, are not yet clear.


METHODS
We histologically evaluated the number of accumulated polymorphonuclear neutrophils (PMNs) in lungs, and pulmonary injury after liver transplantation with varying periods of cold ischemia (1, 6 and 24h in University of Wisconsin solution at 4 degrees C). Pulmonary expression of cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) mRNA were investigated by quantitative reverse-transcription polymerase chain reaction. The levels of tumor necrosis factor-alpha (TNFalpha), which stimulates these chemokine productions, were also monitored after liver transplantation.


RESULTS
The accumulated PMN number, and lung edema, quantified by wet to dry weight ratio, significantly increased in the 24-hr cold-ischemia group after 3h of reperfusion, compared with the 1-hr and 6-hr cold-ischemia groups. Both pulmonary MIP-2 and CINC mRNA expression in the 24-hr group were remarkably upregulated at this time. According to the histological examination, pulmonary injury in the 24-hr group was prominent, characterized by interstitial edema, and alveolar hemorrhage. Furthermore, TNF in the hepatic vein was detected only in the 24-hr group.


CONCLUSIONS
Cold ischemia time prolongation upregulates pulmonary MIP-2 and CINC expression via hepatic-derived TNFalpha, and promotes PMN accumulation, resulting in increased pulmonary injury after liver transplantation.
Shimizu
Hiroaki
H
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. h-shimizu@umin.ac.jp
Kataoka
Masaaki
M
Ohtsuka
Masayuki
M
Ito
Hiroshi
H
Kimura
Fumio
F
Togawa
Akira
A
Yoshidome
Hiroyuki
H
Kato
Atsushi
A
Miyazaki
Masaru
M
D000818:Animals; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D003080:Cold Temperature; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007958:Leukocyte Count; D016031:Liver Transplantation; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000502:physiology; D009926:Organ Preservation / Q000379:methods*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger