Systemic and local release of inflammatory cytokines regulates hepatobiliary excretion of 99mTc-mebrofenin

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

OBJECTIVES: Imaging agents capable of providing cell compartment-specific information will facilitate studies of pathophysiological mechanisms, natural history of diseases, and therapeutic development. To demonstrate the effects of liver injury on the disposal of the organic anion mebrofenin, we performed animal studies. METHODS: Acute liver injury was induced in Fischer 344 rats with 0.25-1 ml/kg single doses of carbon tetrachloride followed by studies of animals over 4 weeks. The liver injury was analyzed by blood tests and histological grading. Additional rats were treated with lipopolysaccharide, interleukin-6 or tumor necrosis factor-α to activate inflammatory events. Hepatic clearance of Tc-mebrofenin was studied with dynamic imaging and fractional retention after 60 min of peak hepatic mebrofenin activity was determined. RESULTS: In healthy rats, only 24±2% of peak mebrofenin activity was retained in the liver after 60 min. By contrast, 24 h after carbon tetrachloride, virtually all mebrofenin activity was retained in the liver (P<0.001). Three weeks were required for mebrofenin excretion to become normal after carbon tetrachloride administration. In this situation, we found that Kupffer cell activity was increased. In addition, the abnormality in mebrofenin excretion was reproduced by lipopolysaccharide, which activates Kupffer cells. Moreover, mebrofenin excretion was highly sensitive to interleukin-6 and/or tumor necrosis factor-α, which help mediate the Kupffer cell response. CONCLUSION: Hepatobiliary excretion of mebrofenin was affected rapidly and over an extended period by inflammatory cytokines released after liver injury. The remarkable sensitivity of mebrofenin excretion to cytokines suggests that Tc-mebrofenin imaging will be helpful for assessing cytokine-mediated liver inflammation.

Original languageEnglish (US)
Pages (from-to)336-344
Number of pages9
JournalNuclear Medicine Communications
Volume29
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Cytokines
Liver
Kupffer Cells
Carbon Tetrachloride
Wounds and Injuries
Lipopolysaccharides
Interleukin-6
Tumor Necrosis Factor-alpha
Hepatobiliary Elimination
technetium Tc 99m mebrofenin
Inbred F344 Rats
Hematologic Tests
Anions
Inflammation

Keywords

  • Cytokine
  • Inflammation
  • Liver
  • Mebrofenin
  • Transport

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Systemic and local release of inflammatory cytokines regulates hepatobiliary excretion of 99mTc-mebrofenin. / Joseph, Brigid; Bhargava, Kuldeep K.; Tronco, Gene G.; Palestro, Christopher J.; Gupta, Sanjeev.

In: Nuclear Medicine Communications, Vol. 29, No. 4, 04.2008, p. 336-344.

Research output: Contribution to journalArticle

Joseph, Brigid ; Bhargava, Kuldeep K. ; Tronco, Gene G. ; Palestro, Christopher J. ; Gupta, Sanjeev. / Systemic and local release of inflammatory cytokines regulates hepatobiliary excretion of 99mTc-mebrofenin. In: Nuclear Medicine Communications. 2008 ; Vol. 29, No. 4. pp. 336-344.
@article{226edd273d1546f4bd05e81a39adda57,
title = "Systemic and local release of inflammatory cytokines regulates hepatobiliary excretion of 99mTc-mebrofenin",
abstract = "OBJECTIVES: Imaging agents capable of providing cell compartment-specific information will facilitate studies of pathophysiological mechanisms, natural history of diseases, and therapeutic development. To demonstrate the effects of liver injury on the disposal of the organic anion mebrofenin, we performed animal studies. METHODS: Acute liver injury was induced in Fischer 344 rats with 0.25-1 ml/kg single doses of carbon tetrachloride followed by studies of animals over 4 weeks. The liver injury was analyzed by blood tests and histological grading. Additional rats were treated with lipopolysaccharide, interleukin-6 or tumor necrosis factor-α to activate inflammatory events. Hepatic clearance of Tc-mebrofenin was studied with dynamic imaging and fractional retention after 60 min of peak hepatic mebrofenin activity was determined. RESULTS: In healthy rats, only 24±2{\%} of peak mebrofenin activity was retained in the liver after 60 min. By contrast, 24 h after carbon tetrachloride, virtually all mebrofenin activity was retained in the liver (P<0.001). Three weeks were required for mebrofenin excretion to become normal after carbon tetrachloride administration. In this situation, we found that Kupffer cell activity was increased. In addition, the abnormality in mebrofenin excretion was reproduced by lipopolysaccharide, which activates Kupffer cells. Moreover, mebrofenin excretion was highly sensitive to interleukin-6 and/or tumor necrosis factor-α, which help mediate the Kupffer cell response. CONCLUSION: Hepatobiliary excretion of mebrofenin was affected rapidly and over an extended period by inflammatory cytokines released after liver injury. The remarkable sensitivity of mebrofenin excretion to cytokines suggests that Tc-mebrofenin imaging will be helpful for assessing cytokine-mediated liver inflammation.",
keywords = "Cytokine, Inflammation, Liver, Mebrofenin, Transport",
author = "Brigid Joseph and Bhargava, {Kuldeep K.} and Tronco, {Gene G.} and Palestro, {Christopher J.} and Sanjeev Gupta",
year = "2008",
month = "4",
doi = "10.1097/MNM.0b013e3282f81460",
language = "English (US)",
volume = "29",
pages = "336--344",
journal = "Nuclear Medicine Communications",
issn = "0143-3636",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Systemic and local release of inflammatory cytokines regulates hepatobiliary excretion of 99mTc-mebrofenin

AU - Joseph, Brigid

AU - Bhargava, Kuldeep K.

AU - Tronco, Gene G.

AU - Palestro, Christopher J.

AU - Gupta, Sanjeev

PY - 2008/4

Y1 - 2008/4

N2 - OBJECTIVES: Imaging agents capable of providing cell compartment-specific information will facilitate studies of pathophysiological mechanisms, natural history of diseases, and therapeutic development. To demonstrate the effects of liver injury on the disposal of the organic anion mebrofenin, we performed animal studies. METHODS: Acute liver injury was induced in Fischer 344 rats with 0.25-1 ml/kg single doses of carbon tetrachloride followed by studies of animals over 4 weeks. The liver injury was analyzed by blood tests and histological grading. Additional rats were treated with lipopolysaccharide, interleukin-6 or tumor necrosis factor-α to activate inflammatory events. Hepatic clearance of Tc-mebrofenin was studied with dynamic imaging and fractional retention after 60 min of peak hepatic mebrofenin activity was determined. RESULTS: In healthy rats, only 24±2% of peak mebrofenin activity was retained in the liver after 60 min. By contrast, 24 h after carbon tetrachloride, virtually all mebrofenin activity was retained in the liver (P<0.001). Three weeks were required for mebrofenin excretion to become normal after carbon tetrachloride administration. In this situation, we found that Kupffer cell activity was increased. In addition, the abnormality in mebrofenin excretion was reproduced by lipopolysaccharide, which activates Kupffer cells. Moreover, mebrofenin excretion was highly sensitive to interleukin-6 and/or tumor necrosis factor-α, which help mediate the Kupffer cell response. CONCLUSION: Hepatobiliary excretion of mebrofenin was affected rapidly and over an extended period by inflammatory cytokines released after liver injury. The remarkable sensitivity of mebrofenin excretion to cytokines suggests that Tc-mebrofenin imaging will be helpful for assessing cytokine-mediated liver inflammation.

AB - OBJECTIVES: Imaging agents capable of providing cell compartment-specific information will facilitate studies of pathophysiological mechanisms, natural history of diseases, and therapeutic development. To demonstrate the effects of liver injury on the disposal of the organic anion mebrofenin, we performed animal studies. METHODS: Acute liver injury was induced in Fischer 344 rats with 0.25-1 ml/kg single doses of carbon tetrachloride followed by studies of animals over 4 weeks. The liver injury was analyzed by blood tests and histological grading. Additional rats were treated with lipopolysaccharide, interleukin-6 or tumor necrosis factor-α to activate inflammatory events. Hepatic clearance of Tc-mebrofenin was studied with dynamic imaging and fractional retention after 60 min of peak hepatic mebrofenin activity was determined. RESULTS: In healthy rats, only 24±2% of peak mebrofenin activity was retained in the liver after 60 min. By contrast, 24 h after carbon tetrachloride, virtually all mebrofenin activity was retained in the liver (P<0.001). Three weeks were required for mebrofenin excretion to become normal after carbon tetrachloride administration. In this situation, we found that Kupffer cell activity was increased. In addition, the abnormality in mebrofenin excretion was reproduced by lipopolysaccharide, which activates Kupffer cells. Moreover, mebrofenin excretion was highly sensitive to interleukin-6 and/or tumor necrosis factor-α, which help mediate the Kupffer cell response. CONCLUSION: Hepatobiliary excretion of mebrofenin was affected rapidly and over an extended period by inflammatory cytokines released after liver injury. The remarkable sensitivity of mebrofenin excretion to cytokines suggests that Tc-mebrofenin imaging will be helpful for assessing cytokine-mediated liver inflammation.

KW - Cytokine

KW - Inflammation

KW - Liver

KW - Mebrofenin

KW - Transport

UR - http://www.scopus.com/inward/record.url?scp=43149126600&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43149126600&partnerID=8YFLogxK

U2 - 10.1097/MNM.0b013e3282f81460

DO - 10.1097/MNM.0b013e3282f81460

M3 - Article

C2 - 18317297

AN - SCOPUS:43149126600

VL - 29

SP - 336

EP - 344

JO - Nuclear Medicine Communications

JF - Nuclear Medicine Communications

SN - 0143-3636

IS - 4

ER -