Dr Gabrielle Briggs

Objective: To test the hypothesis that blood donor demographics are associated with transfused polytrauma patients' post-injury multiple organ failure (MOF) status. Summary of Background Data: Traumatic shock and MOF are preventable causes of death and post-traumatic hemorrhage is a frequent indication for transfusion. The role of blood donor demographics on transfusion recipients is not well known. Methods: A log-linear analysis accounting for the correlated structure of the data based on our prospective MOF database was utilized. Tests for trend and interaction were computed using a likelihood ratio procedure. Results: A total of 229 critically injured transfused trauma patients were included, with 68% of them being males and a mean age of 45 years. On average 10 units of blood components were transfused per patient. A total of 4379 units of blood components were donated by donors aged 46 years on average, 74% of whom were males. Blood components used were red blood cells (47%), cryoprecipitate (29%), fresh frozen plasma (24%), and platelets (less than 1%). Donor-recipient sex mismatched red blood cells transfusions were more likely to be associated with MOF (P = 0.0012); fresh frozen plasma and cryoprecipitate recipients were more likely to experience MOF when transfused with a male (vs female) component (P = 0.0014 and <0.0001, respectively). Donor age was not significantly associated with MOF for all blood components. Conclusions: Blood components donor sex, but not age, may be an important factor associated with post-injury MOF. Further validation of our findings will help guide future risk mitigation strategies specific to blood donor demographics.

The physiology of tissue healing and aging share common pathways. Both patient age and tissue healing are crucial factors predicting outcomes in trauma patients. The presented hypothesis focuses on the concept that transfused trauma patients have better outcomes when transfused with blood components from young donors. The age of the donor of a blood transfusion could affect recovery following a major traumatic insult and help avoid postinjury immune paralysis and its associated complications. The frequent transfusion of blood components to the severely injured trauma patient provides an opportunity for the recipient to benefit from the potentially favourable effect of blood originating from young donors. Different types of evidence support the presented hypothesis including work on soluble circulating factors, research on animal parabiontic models and epidemiological studies. Theories on the role of transfusion of cells, on bone marrow and on senolytics also represent grounds to elaborate pathways to test this hypothesis. The precise molecular mechanism underlying this hypothesis is uncertain. A beneficial effect on trauma patients following transfusion of blood could be due to a positive effect of blood donated from younger donors or instead to the lack of a negative effect possibly occurring when transfusing blood from older donors. Either way, identifying this mechanism would provide a powerful tool enhance long and short term recovery after trauma.

Mitochondria play a key role in the pathophysiology of post-injury inflammation. Cell-free mitochondrial DNA (cf-mtDNA) is now understood to catalyse sterile inflammation after trauma. Observations in trauma cohorts have identified high cf-mtDNA in patients with systemic inflammatory response syndrome and multiple organ failure as well as following major surgery. The source of cf-mtDNA can be various cells affected by mechanical and hypoxic injury (passive mechanism) or induced by inflammatory mechanisms (active mechanism). Multiple forms of cf-mtDNA exist; mtDNA fragments, mtDNA in microparticles/vesicles and cell-free mitochondria. Trauma to cells that are rich in mitochondria are believed to release more cf-mtDNA. This review describes the current understanding of the mechanisms of cf-mtDNA release, its systemic effects and the potential therapeutic implications related to its modification. Although current understanding is insufficient to change trauma management, focussed research goals have been identified to pave the way for monitoring and manipulation of cf-mtDNA release and effects in trauma.

Immune activation can alter the activity of adrenal chromaffin cells. The effect of immune activation by lipopolysaccharide (LPS) on the regulation of tyrosine hydroxylase (TH) in the adrenal medulla in vivo was determined between 1 day and 6 months after LPS injection. The plasma levels of eleven cytokines were reduced 1 day after LPS injection, whereas the level for interleukin-10 was increased. The levels of all cytokines remained at control levels until 6 months when the levels of interleukin-6 and -4 were increased. One day after LPS injection, there was a decrease in TH-specific activity that may be due to decreased phosphorylation of serine 31 and 40. This decreased phosphorylation of serine 31 and 40 may be due to an increased activation of the protein phosphatase PP2A. One week after LPS injection, there was increased TH protein and increased phosphorylation of serine 40 that this was not accompanied by an increase in TH-specific activity. All TH parameters measured returned to basal levels between 1 month and 3 months. Six months after injection there was an increase in TH protein. This was associated with increased levels of the extracellular regulated kinase isoforms 1 and 2. This work shows that a single inflammatory event has the capacity to generate both short-term and long-term changes in TH regulation in the adrenal medulla of the adult animal. J. Cell. Biochem. 118: 2096¿2107, 2017. © 2016 Wiley Periodicals, Inc.

Mitochondria are membrane-enclosed organelles, the energy-producing centers in almost all eukaryotic cells. The evolutionary emergence of mitochondria is a result of the endocytosis of a-proteobacteria. There are several characteristic features which refer to its prokaryotic ancestors including its independent sets of double-stranded mitochondrial DNA, which is uniquely circular in form and contains a significant amount of unmethylated DNA as CpG islands. Resent research has proven that free mitochondrial DNA found in blood was associated with innate immunomodulation in a broad-range of clinical conditions. Upon release, mitochondrial DNA acts as a danger-associated molecular pattern in the circulation, it is recognized by pattern recognition receptors and it facilitates inflammatory responses. Besides its high receptor activation potential, mitochondrial DNA is likely to perform direct crosstalk with activated leukocytes and to be contributed to other anti-microbial activities. Here we highlight the pathological conditions where cell free mtDNA is involved, describe the potential sources and mechanisms of extracellular mtDNA release and explore evidence for its mechanism of action after being excreted and potential therapeutic strategies.

Tyrosine hydroxylase (TH) is the first and rate-limiting enzyme in dopamine synthesis. Dopamine regulates TH as an end-product inhibitor through its binding to a high and low affinity site, the former being abolished by Ser40 phosphorylation only, and the latter able to bind and dissociate according to intracellular dopamine levels. Here, we have investigated TH inhibition by a dopamine metabolite found in dopaminergic brain regions, salsolinol (SAL). SAL is known to decrease dopamine in the nigrostriatal pathway and mediobasal hypothalamus, and to also decrease plasma catecholamines in rat stress models, however a target and mechanism for the effects of SAL have not been found. We found that SAL inhibits TH activity in the nanomolar range in vitro, by binding to both the high and low affinity dopamine binding sites. SAL produces the same level of inhibition as dopamine when TH is non-phosphorylated. However, it produces 3.7-fold greater inhibition of Ser40-phosphorylated TH compared to dopamine by competing more strongly with tetrahydrobiopterin, the cofactor of this enzymatic reaction. SAL's potent inhibition of phosphorylated TH would prevent TH from being fully activated to synthesise dopamine. Crown Copyright © 2013 Published by Elsevier Ltd. All rights reserved.