title: Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation.
abstract: BACKGROUND.Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant.METHODS.We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n= 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion.RESULTS.Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq.CONCLUSION.These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment.FUNDING.Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Sosa
authors.affiliation: Department of Surgery.
authors.forename: Ali
authors.initials: A
authors.lastname: Zarrinpar
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Maura
authors.initials: M
authors.lastname: Rossetti
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Lassman
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Bita V
authors.initials: BV
authors.lastname: Naini
authors.affiliation: Department of Surgery.
authors.forename: Nakul
authors.initials: N
authors.lastname: Datta
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Ping
authors.initials: P
authors.lastname: Rao
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Harre
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, and.|Institute for Quantitative and Computational Biosciences, UCLA, California, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, and.|Institute for Quantitative and Computational Biosciences, UCLA, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Department of Surgery.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: David W
authors.initials: DW
authors.lastname: Gjertson
authors.affiliation: Department of Surgery.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Pathology and Laboratory Medicine.|Department of Surgery.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Reed
mesh_terms: D000368:Aged; D001663:Bilirubin / Q000097:blood; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood*; D005260:Female; D006085:Graft Survival; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008107:Liver Diseases / Q000601:surgery; D008111:Liver Function Tests; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D018121:Receptors, Cytokine / Q000378:metabolism; D015427:Reperfusion Injury / Q000097:blood / Q000175:diagnosis*; D000637:Transaminases / Q000097:blood
chemical_list: D018925:Chemokines; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D018121:Receptors, Cytokine; D000637:Transaminases; D001663:Bilirubin