TY - JOUR
T1 - Rapid clearance of transplanted hepatocytes from pulmonary capillaries in rats indicates a wide safety margin of liver repopulation and the potential of using surrogate albumin particles for safety analysis
AU - Rajvanshi, Pankaj
AU - Fabrega, Alfredo
AU - Bhargava, Kuldeep K.
AU - Kerr, Andrew
AU - Pollak, Raymond
AU - Blanchard, Jacqueline
AU - Palestro, Christopher J.
AU - Gupta, Sanjeev
N1 - Funding Information:
We thank Drs. Srinivas Tetali and Rahul Gupta for assistance with some of the experiments performed at University of Illinois at Chicago and Long Island Jewish Medical Center, respectively. We have been unable to locate Dr. Tetali during manuscript preparation; however, had we been able to contact him, he would have been invited to share authorship. The work was supported in part by NIH grants RO1 DK46952 (to S. G.) and P30–41296 (Marion Bessin Liver Research Center grant, P. I., David A. Shafritz, MD) and by an award from the Irma T. Hirschl Trust (to S. G.).
PY - 1999/2
Y1 - 1999/2
N2 - Background/Aims: Applications of liver repopulation by hepatocyte transplantation require analysis of cell biodistributions, particularly when portasystemic shunting coexists. The aims of this study were to determine the fate of hepatocytes transplanted into the pulmonary vascular bed and to examine whether cell biodistributions could be approximated by convenient surrogates. Methods: Rat hepatocytes and macroaggregated serum albumin particles of similar sizes were injected into the portal and pulmonary vascular beds of rats, followed by biodistribution, survival and function analyses. Results: Although functionally intact, virtually all hepatocytes were cleared from the pulmonary capillaries within 24 h. Serum albumin levels increased minimally in Nagase analbuminemic rats with or without portacaval shunting to enhance delivery of portal factors to transplanted cells in lungs. Despite intravenous injection of hepatocytes approaching > 1 x 109 cells in humans, the hemodynamic changes were limited to transient increases in right atrial pressures. The hepatocyte distributions in specific vascular beds were largely reproduced by macroaggregated human serum albumin particles. Conclusions: Incidental intrapulmonary cell translocations during liver repopulation will have a wide safety margin. Use of macroaggregated serum albumin particles as surrogates for initial short-term biodistribution and safety analysis will advance hepatocyte transplantation, as the cost of GLP-certified laboratories and consumption of scarce donor livers will be avoided.
AB - Background/Aims: Applications of liver repopulation by hepatocyte transplantation require analysis of cell biodistributions, particularly when portasystemic shunting coexists. The aims of this study were to determine the fate of hepatocytes transplanted into the pulmonary vascular bed and to examine whether cell biodistributions could be approximated by convenient surrogates. Methods: Rat hepatocytes and macroaggregated serum albumin particles of similar sizes were injected into the portal and pulmonary vascular beds of rats, followed by biodistribution, survival and function analyses. Results: Although functionally intact, virtually all hepatocytes were cleared from the pulmonary capillaries within 24 h. Serum albumin levels increased minimally in Nagase analbuminemic rats with or without portacaval shunting to enhance delivery of portal factors to transplanted cells in lungs. Despite intravenous injection of hepatocytes approaching > 1 x 109 cells in humans, the hemodynamic changes were limited to transient increases in right atrial pressures. The hepatocyte distributions in specific vascular beds were largely reproduced by macroaggregated human serum albumin particles. Conclusions: Incidental intrapulmonary cell translocations during liver repopulation will have a wide safety margin. Use of macroaggregated serum albumin particles as surrogates for initial short-term biodistribution and safety analysis will advance hepatocyte transplantation, as the cost of GLP-certified laboratories and consumption of scarce donor livers will be avoided.
KW - Hepatocyte
KW - Liver
KW - Lungs
KW - Macroaggregated albumin
KW - Transplantation
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U2 - 10.1016/S0168-8278(99)80077-4
DO - 10.1016/S0168-8278(99)80077-4
M3 - Article
C2 - 10068111
AN - SCOPUS:0032909452
SN - 0168-8278
VL - 30
SP - 299
EP - 310
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -