Regulation of hepatobiliary transport activity and noninvasive identification of cytokine-dependent liver inflammation

Brigid Joseph, Kuldeep K. Bhargava, Gene G. Tronco, Vinay Kumaran, Christopher J. Palestro, Sanjeev Gupta

Research output: Contribution to journalArticle

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Abstract

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 99mTc-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 99mTc-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 99mTc- mebrofenin-loaded primary rat hepatocytes. Results: In healthy rats, 99mTc-mebrofenin was promptly excreted, and after 1 h only 20% ± 5% (mean ± SD) of peak 99mTc-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 99mTc-mebrofenin activity in the liver after 1 h (P < 0.001). Abnormal 99mTc-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, 99mTc-mebrofenin transport returned to normal, indicating a central role of inflammatory activity in this process. In vitro assays showed impairment in 99mTc- mebrofenin excretion after incubation of cultured hepatocytes with interleukin-6 and further impairment with interleukin-6 plus tumor necrosis factor-α. Conclusion: The findings indicate that inflammatory cytokines regulate 99mTc-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.

Original languageEnglish (US)
Pages (from-to)146-152
Number of pages7
JournalJournal of Nuclear Medicine
Volume46
Issue number1
StatePublished - 2005

Fingerprint

Cytokines
Inflammation
Liver
Carbon Tetrachloride
Fibrosis
Hepatocytes
Interleukin-6
Wounds and Injuries
Alcoholic Fatty Liver
technetium Tc 99m mebrofenin
Alcoholic Hepatitis
Inbred F344 Rats
Genetic Therapy
Allografts
Liver Diseases
Tumor Necrosis Factor-alpha

Keywords

  • T-mebrofenin
  • Cytokines
  • Inflammation
  • Liver

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Regulation of hepatobiliary transport activity and noninvasive identification of cytokine-dependent liver inflammation. / Joseph, Brigid; Bhargava, Kuldeep K.; Tronco, Gene G.; Kumaran, Vinay; Palestro, Christopher J.; Gupta, Sanjeev.

In: Journal of Nuclear Medicine, Vol. 46, No. 1, 2005, p. 146-152.

Research output: Contribution to journalArticle

Joseph, Brigid ; Bhargava, Kuldeep K. ; Tronco, Gene G. ; Kumaran, Vinay ; Palestro, Christopher J. ; Gupta, Sanjeev. / Regulation of hepatobiliary transport activity and noninvasive identification of cytokine-dependent liver inflammation. In: Journal of Nuclear Medicine. 2005 ; Vol. 46, No. 1. pp. 146-152.
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N2 - 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 99mTc-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 99mTc-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 99mTc- mebrofenin-loaded primary rat hepatocytes. Results: In healthy rats, 99mTc-mebrofenin was promptly excreted, and after 1 h only 20% ± 5% (mean ± SD) of peak 99mTc-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 99mTc-mebrofenin activity in the liver after 1 h (P < 0.001). Abnormal 99mTc-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, 99mTc-mebrofenin transport returned to normal, indicating a central role of inflammatory activity in this process. In vitro assays showed impairment in 99mTc- mebrofenin excretion after incubation of cultured hepatocytes with interleukin-6 and further impairment with interleukin-6 plus tumor necrosis factor-α. Conclusion: The findings indicate that inflammatory cytokines regulate 99mTc-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.

AB - 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 99mTc-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 99mTc-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 99mTc- mebrofenin-loaded primary rat hepatocytes. Results: In healthy rats, 99mTc-mebrofenin was promptly excreted, and after 1 h only 20% ± 5% (mean ± SD) of peak 99mTc-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 99mTc-mebrofenin activity in the liver after 1 h (P < 0.001). Abnormal 99mTc-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, 99mTc-mebrofenin transport returned to normal, indicating a central role of inflammatory activity in this process. In vitro assays showed impairment in 99mTc- mebrofenin excretion after incubation of cultured hepatocytes with interleukin-6 and further impairment with interleukin-6 plus tumor necrosis factor-α. Conclusion: The findings indicate that inflammatory cytokines regulate 99mTc-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.

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