Regulation of hepatobiliary transport activity and noninvasive identification of cytokine-dependent liver inflammation.
Many diseases are associated with cytokine release after inflammatory infiltration, which perturbs organ function. Radioligands capable of noninvasive tracking to assess the integrity of specific biochemical pathways offer potent ways to establish such perturbing mechanisms.


METHODS
To demonstrate regulation of hepatobiliary transport in disease, we used (99m)Tc-mebrofenin in a carbon tetrachloride-induced liver injury model in Fischer 344 rats. Healthy rats served as control animals. Image analysis was used to determine (99m)Tc-mebrofenin handling. Liver tests and histologic analysis were used for grading liver injury and hepatic fibrosis. To address the role of inflammatory cytokines, we used in vitro assays with (99m)Tc-mebrofenin-loaded primary rat hepatocytes.


RESULTS
In healthy rats, (99m)Tc-mebrofenin was promptly excreted, and after 1 h only 20% +/- 5% (mean +/- SD) of peak (99m)Tc-mebrofenin activity remained in the liver. In contrast, rats treated with carbon tetrachloride for 1 or 3 mo showed 84% +/- 5% and 80% +/- 7% (mean +/- SD), respectively, of peak (99m)Tc-mebrofenin activity in the liver after 1 h (P < 0.001). Abnormal (99m)Tc-mebrofenin transport was associated with necroinflammatory activity and not hepatic fibrosis. This was examined directly in animals, where withdrawal of carbon tetrachloride for 2 wk after significant liver injury produced loss of inflammatory activity without affecting hepatic fibrosis. In this situation, (99m)Tc-mebrofenin transport returned to normal, indicating a central role of inflammatory activity in this process. In vitro assays showed impairment in (99m)Tc-mebrofenin excretion after incubation of cultured hepatocytes with interleukin-6 and further impairment with interleukin-6 plus tumor necrosis factor-alpha.


CONCLUSIONS
The findings indicate that inflammatory cytokines regulate (99m)Tc-mebrofenin transport. This cytokine-mediated process establishes a paradigm for identifying and monitoring organ inflammation, including in viral or alcoholic hepatitis, fatty liver disease, allograft rejection, and responses to gene therapy vectors.
Joseph
Brigid
B
Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Bhargava
Kuldeep K
KK
Tronco
Gene G
GG
Kumaran
Vinay
V
Palestro
Christopher J
CJ
Gupta
Sanjeev
S
D000814:Aniline Compounds; D000818:Animals; D001652:Bile Ducts / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D001693:Biological Transport, Active; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D005998:Glycine; D007098:Imino Acids / Q000493:pharmacokinetics*; D008099:Liver / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D000814:Aniline Compounds; D016207:Cytokines; D007098:Imino Acids; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D002251:Carbon Tetrachloride; C034837:technetium Tc 99m mebrofenin; D005998:Glycine