Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage

Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ...

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Published in:	Frontiers in immunology Vol. 9; p. 891
Main Authors:	Aswani, Andrew, Manson, Joanna, Itagaki, Kiyoshi, Chiazza, Fausto, Collino, Massimo, Wupeng, Winston Liao, Chan, Tze Khee, Wong, W S Fred, Hauser, Carl J, Thiemermann, Chris, Brohi, Karim
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 08-05-2018
Subjects:	Adult Aged Alarmins - immunology Alarmins - metabolism Animals Cohort Studies damage-associated molecular patterns Disease Models, Animal DNA, Bacterial - blood DNA, Bacterial - immunology DNA, Mitochondrial - blood DNA, Mitochondrial - immunology Female Hexadimethrine Bromide - pharmacology Hexadimethrine Bromide - therapeutic use Humans Immunology Male Middle Aged Mitochondria - drug effects Mitochondria - immunology Mitochondria - metabolism Mitochondria - pathology mitochondrial DNA multiple organ dysfunction syndrome Multiple Organ Failure - drug therapy Multiple Organ Failure - immunology Multiple Organ Failure - mortality Multiple Organ Failure - pathology Multiple Trauma - drug therapy Multiple Trauma - immunology Multiple Trauma - mortality Multiple Trauma - pathology nucleic acid scavenger Prospective Studies Rats, Wistar Shock, Hemorrhagic - drug therapy Shock, Hemorrhagic - immunology Shock, Hemorrhagic - mortality Shock, Hemorrhagic - pathology trauma trauma hemorrhage Trauma Severity Indices Treatment Outcome Young Adult sterile inflammation trauma damage-associated molecular patterns mitochondrial DNA trauma hemorrhage nucleic acid scavenger multiple organ dysfunction syndrome Toll-like receptor-9
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Summary:	Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ dysfunction syndrome (MODS). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MODS are also not fully elucidated. As a result, successful therapies for trauma-related MODS are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through toll-like receptor-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. We aimed to determine whether mtDNA released after clinical trauma hemorrhage is sufficient for the development of MODS. Secondly, we aimed to determine the extent of mtDNA release with varying degrees of tissue injury and hemorrhagic shock in a clinically relevant rodent model. Our final aim was to determine whether neutralizing mtDNA with the nucleic acid scavenging polymer, hexadimethrine bromide (HDMBr), at a clinically relevant time point would reduce the severity of organ injury in this model. We have shown that the release of mtDNA is sufficient for the development of multiple organ injury. MtDNA concentrations likely peak at different points in the early postinjury phase dependent on the degree of isolated trauma vs combined trauma and hemorrhagic shock. HDMBr scavenging of circulating mtDNA (and nuclear DNA, nDNA) is associated with rescue from severe multiple organ injury in the animal model. This suggests that HDMBr could have utility in rescue from human trauma-induced MODS.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology Reviewed by: Zsolt J. Balogh, University of Newcastle, Australia; Neil Blumberg, University of Rochester, United States Edited by: Fabrice Cognasse, Groupe Sur L’immunité Des Muqueuses Et Agents Pathogènes (GIMAP), France
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2018.00891