Early Activation of the Inflammatory Response in the Liver of Brain-Dead Non-Human Primates

Danobeitia, Juan Sebastian; Sperger, Jamie M.; Hanson, Matthew S.; Park, Elisa E.; Chlebeck, Peter J.; Roenneburg, Drew A.; Sears, Mallory L.; Connor, Jolien X.; Schwarznau, Alice; Fernandez, Luis A.

doi:10.1016/j.jss.2011.10.042

« BackJournal of Surgical Research

Article in Press

Early Activation of the Inflammatory Response in the Liver of Brain-Dead Non-Human Primates

Juan Sebastian Danobeitia, M.D.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
- These authors contributed equally to this work.
Jamie M. Sperger, Ph.D.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
- These authors contributed equally to this work.
Matthew S. Hanson, Ph.D.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
Elisa E. Park, B.S.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
Peter J. Chlebeck, B.S.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
Drew A. Roenneburg, M.S.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
Mallory L. Sears, B.S.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
Jolien X. Connor, Ph.D.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
Alice Schwarznau, M.D.
- Department of Surgery, Campus Grosshadern, Ludwig-Maximilian University, Munich, Germany
Luis A. Fernandez, M.D.
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin
- To whom correspondence and reprint requests should be addressed at Department of Surgery, University of Wisconsin-Madison, UW Hospitals and Clinics, H5/301, 600 Highland Avenue, Madison, WI 53792-3236.

Received 25 July 2011; accepted 26 October 2011. published online 21 November 2011.
Corrected Proof

Background

Donor brain death (BD) triggers a systemic inflammatory response that reduces organ quality and increases immunogenicity of the graft. We characterized the early innate immune response induced by BD in the liver and peripheral blood of hemodinamically stable non-human primates (NHP).

Methods

Rhesus macaques were assigned to either brain death or control group. BD was induced by inflation of a subdurally placed catheter and confirmed clinically and by cerebral angiography. Animals were monitored for 6 h after BD and managed to maintain hemodynamic stability.

Results

Cortisol, epinephrine, nor-epinephrine, and IL-6 levels were elevated immediately after BD induction. Neutrophils and monocytes significantly increased in circulation following BD induction, while dendritic cells were decreased at 6 h post-induction. Flow cytometry revealed increased expression of chemokine receptors CxCR1, CxCR2, CCR2, and CCR5 in peripheral blood leukocytes from NHP subjected to BD. Microarray analysis demonstrated a significant up-regulation of genes related to innate inflammatory responses, toll-like receptor signaling, stress pathways, and apoptosis/cell death in BD subjects. Conversely, pathways related to glucose, lipid, and protein metabolism were down-regulated. In addition, increased expression of SOCS3, S100A8/A9, ICAM-1, MHC class II, neutrophil accumulation, and oxidative stress markers (carboxy-methyl-lysine and hydroxynonenal) were detected by immunoblot and immunohistochemistry.

Conclusions

Activation of the innate immune response after BD in association with a down-regulation of genes associated with cell metabolism pathways in the liver. These findings may provide a potential explanation for the reduced post-transplant function of organs from brain dead donors. In addition, this work suggests potential novel targets to improve donor management strategies.

Key Words: inflammation, innate immunity, brain-death, transplantation, organ donor, liver, toll-like receptors