Hepatic injury from cryoablation has been associated with multisystem injury, including adult respiratory distress syndrome, renal insufficiency, and coagulopathy; but the responsible mechanisms have not been well defined. In the present study we investigated the role of the transcription factor NF-kappaB in the multiorgan inflammatory response to hepatic cryoablation utilizing a novel in vivo system for determining NF-kappaB activity. Using transgenic mice expressing photinus luciferase under the control of the 5' HIV-LTR (an NF-kappaB-dependent promoter), we measured luciferase activity in the liver, lungs, and kidneys as a marker for NF-kappaB activity. Luciferase production was determined by in vivo bioluminescence and by luciferase assays of tissue homogenates. After measurement of basal luciferase activity, mice were treated with 35% hepatic cryoablation or sham laparotomy and injected with luciferin (0.75 mg/mouse). Photon emission from the liver, lungs, and kidneys was measured at multiple time points. Hepatic cryoablation induced a significant increase in photon emission by the liver, lungs, and kidneys, which correlated with markedly increased luciferase activity measured from each organ after death. Lung lavage 4 hours after cryoablation showed neutrophilic lung inflammation with increased MIP-2 levels compared with sham surgery. These findings demonstrate that 35% hepatic cryoablation is associated with NF-kappaB activation in the remnant liver and multiple distant sites, and may be causally related to the multisystem injury that is seen after direct liver injury.