Donor hepatic steatosis induce exacerbated ischemia-reperfusion injury through activation of innate immune response molecular pathways

Ricardo C. Gehrau, Valeria Mas, Catherine I. Dumur, Jihee L. Suh, Ashish K. Sharma, Helen P. Cathro, Daniel Maluf

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background. Severe liver steatosis is a known risk factor for increased ischemia-reperfusion injury (IRI) and poor outcomes after liver transplantation (LT). This study aimed to identify steatosis-related molecular mechanisms associated with IRI exacerbation af-Ter LT. Methods. Paired graft biopsies (n = 60) were collected before implantation (L1) and 90 minutes after reperfusion (L2). The LT recipients (n = 30) were classified by graft macrosteatosis: Without steatosis (WS) of 5% or less (n = 13) and with steatosis (S) of 25% or greater (n = 17). Plasma samples were collected at L1, L2, and 1 day after LT (postoperative [POD]1) for cytokines eval- uation. Tissue RNA was isolated for gene expression microarrays. Probeset summaries were obtained using robust multiarray av- erage algorithm. Pairwise comparisons were fit using 2-sample t test. P values 0.01 or less were significant (false discovery rate <5%). Molecular pathway analyses were conducted using Ingenuity Pathway Analysis tool. Results. Significantly differentially expressed genes were identified for WS and S grafts after reperfusion. Comprehensive comparison analysis of molecular profiles revealed significant association of S grafts molecular profile with innate immune response activation, macrophage production of nitric oxide and reactive oxygen species, IL-6, IL-8, IL-10 signaling activation, recruitment of granulocytes, and accumulation of myeloid cells. Postreperfusion histological patterns of S grafts revealed neutrophilic infiltration surrounding fat accumulation. Circu- lating proinflammatory cytokines after reperfusion and 24 hours after LT concurred with intragraft-deregulated molecular pathways. All tested cytokines were significantly increased in plasma of S grafts recipients after reperfusion when compared with WS group at same time. Conclusions. Increases of graft steatosis exacerbate IRI by exacerbation of innate immune response after LT. Pre- emptive strategies should consider it for safety usage of steatotic livers.

Original languageEnglish (US)
Pages (from-to)2523-2533
Number of pages11
JournalTransplantation
Volume99
Issue number12
DOIs
StatePublished - Jan 1 2015

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Reperfusion Injury
Innate Immunity
Liver Transplantation
Transplants
Liver
Reperfusion
Cytokines
Macrophage Activation
Myeloid Cells
Fatty Liver
Interleukin-8
Granulocytes
Interleukin-10
Interleukin-6
Reactive Oxygen Species
Nitric Oxide
Fats
RNA
Biopsy
Safety

All Science Journal Classification (ASJC) codes

  • Transplantation

Cite this

Donor hepatic steatosis induce exacerbated ischemia-reperfusion injury through activation of innate immune response molecular pathways. / Gehrau, Ricardo C.; Mas, Valeria; Dumur, Catherine I.; Suh, Jihee L.; Sharma, Ashish K.; Cathro, Helen P.; Maluf, Daniel.

In: Transplantation, Vol. 99, No. 12, 01.01.2015, p. 2523-2533.

Research output: Contribution to journalArticle

Gehrau, Ricardo C. ; Mas, Valeria ; Dumur, Catherine I. ; Suh, Jihee L. ; Sharma, Ashish K. ; Cathro, Helen P. ; Maluf, Daniel. / Donor hepatic steatosis induce exacerbated ischemia-reperfusion injury through activation of innate immune response molecular pathways. In: Transplantation. 2015 ; Vol. 99, No. 12. pp. 2523-2533.
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abstract = "Background. Severe liver steatosis is a known risk factor for increased ischemia-reperfusion injury (IRI) and poor outcomes after liver transplantation (LT). This study aimed to identify steatosis-related molecular mechanisms associated with IRI exacerbation af-Ter LT. Methods. Paired graft biopsies (n = 60) were collected before implantation (L1) and 90 minutes after reperfusion (L2). The LT recipients (n = 30) were classified by graft macrosteatosis: Without steatosis (WS) of 5{\%} or less (n = 13) and with steatosis (S) of 25{\%} or greater (n = 17). Plasma samples were collected at L1, L2, and 1 day after LT (postoperative [POD]1) for cytokines eval- uation. Tissue RNA was isolated for gene expression microarrays. Probeset summaries were obtained using robust multiarray av- erage algorithm. Pairwise comparisons were fit using 2-sample t test. P values 0.01 or less were significant (false discovery rate <5{\%}). Molecular pathway analyses were conducted using Ingenuity Pathway Analysis tool. Results. Significantly differentially expressed genes were identified for WS and S grafts after reperfusion. Comprehensive comparison analysis of molecular profiles revealed significant association of S grafts molecular profile with innate immune response activation, macrophage production of nitric oxide and reactive oxygen species, IL-6, IL-8, IL-10 signaling activation, recruitment of granulocytes, and accumulation of myeloid cells. Postreperfusion histological patterns of S grafts revealed neutrophilic infiltration surrounding fat accumulation. Circu- lating proinflammatory cytokines after reperfusion and 24 hours after LT concurred with intragraft-deregulated molecular pathways. All tested cytokines were significantly increased in plasma of S grafts recipients after reperfusion when compared with WS group at same time. Conclusions. Increases of graft steatosis exacerbate IRI by exacerbation of innate immune response after LT. Pre- emptive strategies should consider it for safety usage of steatotic livers.",
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T1 - Donor hepatic steatosis induce exacerbated ischemia-reperfusion injury through activation of innate immune response molecular pathways

AU - Gehrau, Ricardo C.

AU - Mas, Valeria

AU - Dumur, Catherine I.

AU - Suh, Jihee L.

AU - Sharma, Ashish K.

AU - Cathro, Helen P.

AU - Maluf, Daniel

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background. Severe liver steatosis is a known risk factor for increased ischemia-reperfusion injury (IRI) and poor outcomes after liver transplantation (LT). This study aimed to identify steatosis-related molecular mechanisms associated with IRI exacerbation af-Ter LT. Methods. Paired graft biopsies (n = 60) were collected before implantation (L1) and 90 minutes after reperfusion (L2). The LT recipients (n = 30) were classified by graft macrosteatosis: Without steatosis (WS) of 5% or less (n = 13) and with steatosis (S) of 25% or greater (n = 17). Plasma samples were collected at L1, L2, and 1 day after LT (postoperative [POD]1) for cytokines eval- uation. Tissue RNA was isolated for gene expression microarrays. Probeset summaries were obtained using robust multiarray av- erage algorithm. Pairwise comparisons were fit using 2-sample t test. P values 0.01 or less were significant (false discovery rate <5%). Molecular pathway analyses were conducted using Ingenuity Pathway Analysis tool. Results. Significantly differentially expressed genes were identified for WS and S grafts after reperfusion. Comprehensive comparison analysis of molecular profiles revealed significant association of S grafts molecular profile with innate immune response activation, macrophage production of nitric oxide and reactive oxygen species, IL-6, IL-8, IL-10 signaling activation, recruitment of granulocytes, and accumulation of myeloid cells. Postreperfusion histological patterns of S grafts revealed neutrophilic infiltration surrounding fat accumulation. Circu- lating proinflammatory cytokines after reperfusion and 24 hours after LT concurred with intragraft-deregulated molecular pathways. All tested cytokines were significantly increased in plasma of S grafts recipients after reperfusion when compared with WS group at same time. Conclusions. Increases of graft steatosis exacerbate IRI by exacerbation of innate immune response after LT. Pre- emptive strategies should consider it for safety usage of steatotic livers.

AB - Background. Severe liver steatosis is a known risk factor for increased ischemia-reperfusion injury (IRI) and poor outcomes after liver transplantation (LT). This study aimed to identify steatosis-related molecular mechanisms associated with IRI exacerbation af-Ter LT. Methods. Paired graft biopsies (n = 60) were collected before implantation (L1) and 90 minutes after reperfusion (L2). The LT recipients (n = 30) were classified by graft macrosteatosis: Without steatosis (WS) of 5% or less (n = 13) and with steatosis (S) of 25% or greater (n = 17). Plasma samples were collected at L1, L2, and 1 day after LT (postoperative [POD]1) for cytokines eval- uation. Tissue RNA was isolated for gene expression microarrays. Probeset summaries were obtained using robust multiarray av- erage algorithm. Pairwise comparisons were fit using 2-sample t test. P values 0.01 or less were significant (false discovery rate <5%). Molecular pathway analyses were conducted using Ingenuity Pathway Analysis tool. Results. Significantly differentially expressed genes were identified for WS and S grafts after reperfusion. Comprehensive comparison analysis of molecular profiles revealed significant association of S grafts molecular profile with innate immune response activation, macrophage production of nitric oxide and reactive oxygen species, IL-6, IL-8, IL-10 signaling activation, recruitment of granulocytes, and accumulation of myeloid cells. Postreperfusion histological patterns of S grafts revealed neutrophilic infiltration surrounding fat accumulation. Circu- lating proinflammatory cytokines after reperfusion and 24 hours after LT concurred with intragraft-deregulated molecular pathways. All tested cytokines were significantly increased in plasma of S grafts recipients after reperfusion when compared with WS group at same time. Conclusions. Increases of graft steatosis exacerbate IRI by exacerbation of innate immune response after LT. Pre- emptive strategies should consider it for safety usage of steatotic livers.

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