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Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits
BACKGROUND: Liver injury caused by ischemia reperfusion (I/R) during surgical procedures, such as liver resection or liver transplantation, is a major cause of liver damage and graft failure. The current method of treatment is mostly preventative (i.e., ischemic preconditioning). While a number of p...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391051/ https://www.ncbi.nlm.nih.gov/pubmed/34485732 http://dx.doi.org/10.1016/j.heliyon.2021.e07845 |
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author | Jacob, Asha Wang, Zhimin Yen, Hao Ting Wang, Ping |
author_facet | Jacob, Asha Wang, Zhimin Yen, Hao Ting Wang, Ping |
author_sort | Jacob, Asha |
collection | PubMed |
description | BACKGROUND: Liver injury caused by ischemia reperfusion (I/R) during surgical procedures, such as liver resection or liver transplantation, is a major cause of liver damage and graft failure. The current method of treatment is mostly preventative (i.e., ischemic preconditioning). While a number of pharmacological modalities have been studied to reduce hepatic I/R injury, none have been entirely successful. It has been demonstrated that the administration of adrenomedullin (AM) in combination with AM-binding protein (AM/AMBP-1) exerts significant protective effects in various pathological conditions. In an effort to develop AM/AMBP-1 as a novel therapeutic for hepatic I/R injury, the present study examined the effect of a low dose of human AM, which does not induce hypotension, in combination with human AMBP-1 in a rabbit model of hepatic I/R (i.e., non-rodent species). METHODS: Ischemia of 70% of the liver was induced by placing a microvascular clip across the hilum of the left and median lobes for 60 min. The clip was then removed to commence reperfusion. At 15 min following clip removal (i.e., reperfusion), human AM/AMBP-1 was administered intravenously via the ear marginal vein continuously for 30 min. At 20 h, blood and tissue samples were collected for various measurements. RESULTS: The serum levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and lactate dehydrogenase, were elevated following hepatic I/R. The administration of AM/AMBP-1 significantly decreased these levels by 58, 44, 41%, respectively. Hepatic I/R increased the direct and total bilirubin levels, whereas treatment with human AM/AMBP-1 decreased these levels by 60% and 69%, respectively. Treatment with AM/AMBP-1 also inhibited interleukin-6 gene expression by 95%. There were no changes in tumor necrosis factor-α (TNF-α) gene expression and myeloperoxidase activity (MPO), lactate and Suzuki scores after treatment. The treatment, however, reduced apoptosis post-hepatic I/R in the ischemic portion of the liver. CONCLUSION: Additional experiments with AM and AMBP-1 alone are needed to completely interpret the experimental results in this non-rodent species of hepatic I/R injury. The present study suggests that human AM/AMBP-1 may be developed as a novel therapeutic to attenuate hepatic I/R associated inflammation and liver injury. |
format | Online Article Text |
id | pubmed-8391051 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-83910512021-09-02 Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits Jacob, Asha Wang, Zhimin Yen, Hao Ting Wang, Ping Heliyon Research Article BACKGROUND: Liver injury caused by ischemia reperfusion (I/R) during surgical procedures, such as liver resection or liver transplantation, is a major cause of liver damage and graft failure. The current method of treatment is mostly preventative (i.e., ischemic preconditioning). While a number of pharmacological modalities have been studied to reduce hepatic I/R injury, none have been entirely successful. It has been demonstrated that the administration of adrenomedullin (AM) in combination with AM-binding protein (AM/AMBP-1) exerts significant protective effects in various pathological conditions. In an effort to develop AM/AMBP-1 as a novel therapeutic for hepatic I/R injury, the present study examined the effect of a low dose of human AM, which does not induce hypotension, in combination with human AMBP-1 in a rabbit model of hepatic I/R (i.e., non-rodent species). METHODS: Ischemia of 70% of the liver was induced by placing a microvascular clip across the hilum of the left and median lobes for 60 min. The clip was then removed to commence reperfusion. At 15 min following clip removal (i.e., reperfusion), human AM/AMBP-1 was administered intravenously via the ear marginal vein continuously for 30 min. At 20 h, blood and tissue samples were collected for various measurements. RESULTS: The serum levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and lactate dehydrogenase, were elevated following hepatic I/R. The administration of AM/AMBP-1 significantly decreased these levels by 58, 44, 41%, respectively. Hepatic I/R increased the direct and total bilirubin levels, whereas treatment with human AM/AMBP-1 decreased these levels by 60% and 69%, respectively. Treatment with AM/AMBP-1 also inhibited interleukin-6 gene expression by 95%. There were no changes in tumor necrosis factor-α (TNF-α) gene expression and myeloperoxidase activity (MPO), lactate and Suzuki scores after treatment. The treatment, however, reduced apoptosis post-hepatic I/R in the ischemic portion of the liver. CONCLUSION: Additional experiments with AM and AMBP-1 alone are needed to completely interpret the experimental results in this non-rodent species of hepatic I/R injury. The present study suggests that human AM/AMBP-1 may be developed as a novel therapeutic to attenuate hepatic I/R associated inflammation and liver injury. Elsevier 2021-08-20 /pmc/articles/PMC8391051/ /pubmed/34485732 http://dx.doi.org/10.1016/j.heliyon.2021.e07845 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Jacob, Asha Wang, Zhimin Yen, Hao Ting Wang, Ping Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits |
title | Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits |
title_full | Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits |
title_fullStr | Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits |
title_full_unstemmed | Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits |
title_short | Human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits |
title_sort | human adrenomedullin and its binding protein attenuate tissue injury and inflammation following hepatic ischemia reperfusion in rabbits |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391051/ https://www.ncbi.nlm.nih.gov/pubmed/34485732 http://dx.doi.org/10.1016/j.heliyon.2021.e07845 |
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