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EGF-GH Axis in Rat Steatotic and Non-steatotic Liver Transplantation From Brain-dead Donors

Álvarez-Mercado, Ana I. PhD1; Negrete-Sánchez, Elsa MSc1; Gulfo, José PhD2; Ávalos de León, Cindy G. MSc1; Casillas-Ramírez, Araní PhD3; Cornide-Petronio, María Eugenia PhD1; Bujaldon, Esther MSc1; Rotondo, Floriana PhD1; Gracia-Sancho, Jordi PhD2,4; Jiménez-Castro, Mónica B. PhD5; Peralta, Carmen PhD1,2,6

doi: 10.1097/TP.0000000000002636
Original Basic Science—General
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Background. We evaluated the potential dysfunction caused by changes in growth hormone (GH) levels after brain death (BD), and the effects of modulating GH through exogenous epidermal growth factor (EGF) in steatotic and nonsteatotic grafts.

Methods. Steatotic and nonsteatotic grafts from non-BD and BD rat donors were cold stored for 6 hours and transplanted to live rats. Administration of GH and EGF and their underlying mechanisms were characterized in recipients of steatotic and nonsteatotic grafts from BD donors maintained normotensive during the 6 hours before donation. Circulating and hepatic GH and EGF levels, hepatic damage, and regeneration parameters were evaluated. Recipient survival was monitored for 14 days. Somatostatin, ghrelin, and GH-releasing hormones that regulate GH secretion from the anterior pituitary were determined. The survival signaling pathway phosphoinositide-3-kinase/protein kinase B that regulates inflammation (suppressors of cytokine signaling, high-mobility group protein B1, oxidative stress, and neutrophil accumulation) was evaluated.

Results. BD reduced circulating GH and increased GH levels only in steatotic livers. GH administration exacerbated adverse BD-associated effects in both types of graft. Exogenous EGF reduced GH in steatotic livers, thus activating cell proliferation and survival signaling pathways, ultimately reducing injury and inflammation. However, EGF increased GH in nonsteatotic grafts, which exacerbated damage. The benefits of EGF for steatotic grafts were associated with increased levels of somatostatin, a GH inhibitor, whereas the deleterious effect on nonsteatotic grafts was exerted through increased amounts of ghrelin, a GH stimulator.

Conclusions. GH treatment is not appropriate in rat liver transplant from BD donors, whereas EGF (throughout GH inhibition) protects only in steatotic grafts.

1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Barcelona, Spain.

3 Hospital Regional de Alta Especialidad de Ciudad Victoria, Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Tamaulipas, México.

4 Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain.

5 Transplant Biomedicals SL, Barcelona Advanced Industry Park, Barcelona, Spain.

6 Facultad de Medicina, Universidad Internacional de Cataluña, Barcelona, Spain.

Received 3 October 2018. Revision received 11 January 2019.

Accepted 13 January 2019.

A.I.Á.-M. and E.N.-S. contributed equally to this article.

M.B.J.C. and C.P. contributed equally to this article.

The authors declare no conflicts of interest.

This work was supported by the Ministerio de Economía y Competitividad (MINECO) (grant SAF2015-64857-R), Madrid, Spain;, by the European Union (Fondos FEDER, “una manera de hacer Europa”), by CERCA Program/Generalitat de Catalunya and by the Secretaria d’ Universitats i Recerca del Departament d’ Economia i Coneixement (grant 2017_SGR_551), Barcelona, Spain;, and the Consejo Nacional de Ciencia y Tecnología (CONACYT) (Fondo Sectorial de Investigación para la Educación [grant 257743]), México. M.B.J.-C. has a contract from the Programa de Promoción del talento y su empleabilidad—Ministerio de Economía y Competitividad (grant EMP-TU-2015-4167), Madrid, Spain. C.G.A.-L. is the recipient of a fellowship from CONACYT (grant 411424), México. M.E.C.-P. has a Sara Borrell contract from the Instituto de Salud Carlos III (grant CD15/00129), Madrid, Spain.

E.N.-S., J.G., and C.G.A.-L. performed experimental groups and participated in data collection. A.C.-R., M.E.C.-P., E.B., and F.R. all contributed in biochemical and histological analyses and data acquisition. J.G.-S. contributed to data analysis/interpretation and critical revision of this article. M.B.J.-C., C.P., and A.I.A.-M. contributed to the study concept/design, acquisition of experimental data, data analysis/interpretation, and drafting and critical revision of this article. All authors have approved the final article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Carmen Peralta, Institut d´Investigacions Biomèdiques August Pi I Sunyer, Esther Koplowitz Center, Roselló 149–153, 3rd Floor, Office 3.8, E-08036 Barcelona, Spain. (cperalta@clinic.ub.es)

Mónica B. Jiménez-Castro, Transplant Biomedicals SL, Barcelona Advanced Industry Park, Marie Curie 8–14, 08042 Barcelona, Spain. (monicabjimenez@hotmail.com).

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