Document Detail

Direct visualization of nitric oxide release by liver cells after the arrest of metastatic tumor cells in the hepatic microvasculature.
MedLine Citation:
PMID:  15126078     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Our previous studies have shown that the injection of B16F1 melanoma cells into the mesenteric vein can induce the rapid local release of nitric oxide (NO) in the liver, causing apoptosis of the melanoma cells in the liver sinusoids and inhibiting the subsequent formation of hepatic metastases. In this study, we have investigated the distribution and cellular source of NO in this model. MATERIALS AND METHODS: In situ liver perfusion was established in both wild-type (wt) and endothelial nitric oxide synthase knockout (eNOS KO) C57BL/6 mice. A specific fluorescent NO probe, 4,5-diaminofluorescein diacetate (DAF-2 DA) (5 micromol/L), was perfused into the portal venous system to label the liver tissue. Then, a MitoTracker Orange labeled B16F1 melanoma cell suspension (2 x 10(6) cells/ml) was injected through a portal vein catheter by a peristaltic pump. Images of the liver tissue were taken by confocal microscopy from a selected area to determine the cellular source of NO. For quantification, the fluorescence intensity of this area was measured over time by Fluoview software. RESULTS: Diaminotriazolofluorescein (DAF-2T) fluorescence (indicating NO generation) was detected in hepatic parenchymal cells located in the periportal region in both wt C57BL/6 and eNOS KO C57BL/6 mice and was intensified by increased flow rate in the portal venous system. The B16F1 cells arrested in the periportal sinusoids, corresponding to zone 1 of the hepatic acinus. DAF-2T fluorescence was expressed by both sinusoidal lining cells and hepatocytes at the site of tumor cell arrest. The fluorescence intensity of these cells increased approximately 2-fold over a time of 500 s. In contrast, there was no increase in the fluorescence intensity of the sinusoidal lining cells and hepatocytes in mice perfused with buffer or in eNOS KO mice perfused with B16F1 cells. CONCLUSION: This study demonstrates that NO is produced by hepatic parenchymal cells mainly located in the periportal zones and that the arrest of the B16F1 melanoma cells causes an eNOS-dependent local burst of NO by the sinusoidal lining cells and hepatocytes in the periportal areas.
Ke Qi; Hongming Qiu; John Rutherford; Yanshu Zhao; Dwight M Nance; F William Orr
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of surgical research     Volume:  119     ISSN:  0022-4804     ISO Abbreviation:  J. Surg. Res.     Publication Date:  2004 Jun 
Date Detail:
Created Date:  2004-05-05     Completed Date:  2004-06-07     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0376340     Medline TA:  J Surg Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  29-35     Citation Subset:  IM    
Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
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MeSH Terms
Cell Line, Tumor
Fluoresceins / pharmacokinetics
Fluorescent Dyes / pharmacokinetics
Image Processing, Computer-Assisted
Liver / metabolism*,  pathology
Liver Circulation*
Liver Neoplasms / pathology,  secondary*
Melanoma / pathology,  secondary*
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Neoplastic Cells, Circulating*
Nitric Oxide / metabolism*
Nitric Oxide Synthase / deficiency
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Stress, Mechanical
Time Factors
Tissue Distribution
Reg. No./Substance:
0/Fluoresceins; 0/Fluorescent Dyes; 10102-43-9/Nitric Oxide; EC Oxide Synthase; EC Oxide Synthase Type II; EC Oxide Synthase Type III; EC protein, mouse

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