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Published on: May 7, 2020
Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft
Justin Pollara1, R Whitney Edwards1, Liwen Lin1
1Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Abstract:
Brain death that occurs in the setting of deceased organ donation for transplantation is associated with systemic inflammation of unknown origin. It has recently been recognized that mitochondria-derived damage-associated molecular patterns (mtDAMPs) released into the circulation in the setting of trauma and tissue injury are associated with a systemic inflammatory response. We examined the blood of deceased organ donors and found elevated levels of inflammatory cytokines and chemokines that correlated with levels of mtDAMPs. We also found that donor neutrophils are activated and that donor plasma contains a neutrophil-activating factor that is blocked by cyclosporin H, a formyl peptide receptor-1 antagonist. Examination of donor plasma by electron microscopy and flow cytometry revealed that free- and membrane-bound mitochondria are elevated in donor plasma. Interestingly, we demonstrated a correlation between donor plasma mitochondrial DNA levels and early allograft dysfunction in liver transplant recipients, suggesting a role for circulating mtDAMPs in allograft outcomes. Current approaches to prolong allograft survival focus on immune suppression in the transplant recipient; our data indicate that targeting inflammatory factors in deceased donors prior to organ procurement is another potential strategy for improving transplant outcomes.
Insights
Systemic inflammation in deceased organ donors involves mitochondria-derived damage-associated molecular patterns (mtDAMPs). Elevated mtDAMPs correlate with organ transplant dysfunction, suggesting pre-procurement donor inflammation targeting improves outcomes.
Area of Science:
- Immunology
- Transplantation Biology
- Cellular Biology
Background:
- Deceased organ donation for transplantation is linked to unexplained systemic inflammation.
- Mitochondria-derived damage-associated molecular patterns (mtDAMPs) are implicated in systemic inflammation following trauma.
Purpose of the Study:
- To investigate the role of mtDAMPs in systemic inflammation in deceased organ donors.
- To explore the correlation between donor mtDAMPs and early allograft dysfunction.
Main Methods:
- Analysis of inflammatory cytokines, chemokines, and mtDAMPs in donor blood.
- Neutrophil activation assays and identification of neutrophil-activating factors.
- Electron microscopy and flow cytometry to detect circulating mitochondria.
- Correlation analysis between donor mtDAMPs and liver transplant outcomes.
Main Results:
- Elevated inflammatory cytokines and chemokines in donor blood correlated with mtDAMP levels.
- Donor neutrophils were activated, with plasma containing a neutrophil-activating factor.
- Free and membrane-bound mitochondria were elevated in donor plasma.
- Donor plasma mitochondrial DNA levels correlated with early allograft dysfunction in liver transplant recipients.
Conclusions:
- Circulating mtDAMPs contribute to systemic inflammation in deceased organ donors.
- mtDAMPs may play a role in early allograft dysfunction after liver transplantation.
- Targeting donor inflammation prior to organ procurement is a potential strategy to improve transplant outcomes.
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