Acute lung injury after hepatic cryoablation: correlation with NF-kappa B activation and cytokine production.
BACKGROUND
Previous clinical reports have documented multisystem organ injury after hepatic cryoablation. We hypothesized that hepatic cryosurgery, but not partial hepatectomy, induces a systemic inflammatory response characterized by distant organ injury and overproduction of nuclear factor kappa B (NF-kappa B)-dependent, proinflammatory cytokines.


METHODS
In this study, rats underwent either cryoablation of 35% of liver parenchyma or a similar resection of left hepatic tissue. Serum tumor necrosis factor-alpha and macrophage inflammatory protein-2 levels and NF-kappa B activation were assessed by electrophoretic mobility shift assay at 30 minutes 1, 2, 6, and 24 hours after either procedure.


RESULTS
Cryoablation of 35% of liver (n = 22 rats) resulted in lung injury and a 45% mortality rate within 24 hours of surgery, whereas 7% treated with 35% hepatectomy (n = 15 rats) died during the 24 hours after surgery (P < .05, cryoablation vs hepatectomy). Serum tumor necrosis factor-alpha and macrophage inflammatory protein-2 levels were markedly increased in rats (n = 10 rats) 1 hour after hepatic cryoablation compared with rats that underwent partial hepatectomy (P < .005). We evaluated NF-kappa B activation by electrophoretic mobility shift assay in nuclear extracts of liver and lung after cryosurgery and found that NF-kappa B activation was strikingly increased in the liver but not the lung at 30 minutes and in both organs 1 hour after cryosurgery, and returned to baseline in both organs by 2 hours. In rats undergoing 35% hepatectomy, no increase in NF-kappa B activation was detected in nuclear extracts of either liver or lung at any time point.


CONCLUSIONS
These data show that hepatic cryosurgery results in systemic inflammation with activation of NF-kappa B and increased production of NF-kappa B-dependent cytokines. Our data suggest that lung injury and death in this animal model is mediated by an exaggerated inflammatory response to cryosurgery.
Blackwell
T S
TS
Division of Hepatobiliary Surgery, Vanderbilt University Medical Center, Nashville, Tenn. 37232-4753, USA.
Debelak
J P
JP
Venkatakrishnan
A
A
Schot
D J
DJ
Harley
D H
DH
Pinson
C W
CW
Williams
P
P
Washington
K
K
Christman
J W
JW
Chapman
W C
WC
D000208:Acute Disease; D000818:Animals; D054426:Chemokine CXCL2; D003452:Cryosurgery / Q000009:adverse effects*; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D006498:Hepatectomy / Q000009:adverse effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000601:surgery*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D015846:Monokines / Q000097:blood; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D054426:Chemokine CXCL2; D016207:Cytokines; D018836:Inflammation Mediators; D015846:Monokines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha