Immune dysfunction following severe trauma: A systems failure from the central nervous system to mitochondria

Dobson, Geoffrey P., Morris, Jodie L., and Letson, Hayley L. (2022) Immune dysfunction following severe trauma: A systems failure from the central nervous system to mitochondria. Frontiers in Medicine, 9. 968453.

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Abstract

When a traumatic injury exceeds the body’s internal tolerances, the innate immune and inflammatory systems are rapidly activated, and if not contained early, increase morbidity and mortality. Early deaths after hospital admission are mostly from central nervous system (CNS) trauma, hemorrhage and circulatory collapse (30%), and later deaths from hyperinflammation, immunosuppression, infection, sepsis, acute respiratory distress, and multiple organ failure (20%). The molecular drivers of secondary injury include damage associated molecular patterns (DAMPs), pathogen associated molecular patterns (PAMPs) and other immune-modifying agents that activate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic stress response. Despite a number of drugs targeting specific anti-inflammatory and immune pathways showing promise in animal models, the majority have failed to translate. Reasons for failure include difficulty to replicate the heterogeneity of humans, poorly designed trials, inappropriate use of specific pathogen-free (SPF) animals, ignoring sex-specific differences, and the flawed practice of single-nodal targeting. Systems interconnectedness is a major overlooked factor. We argue that if the CNS is protected early after major trauma and control of cardiovascular function is maintained, the endothelial-glycocalyx will be protected, sufficient oxygen will be delivered, mitochondrial energetics will be maintained, inflammation will be resolved and immune dysfunction will be minimized. The current challenge is to develop new systems-based drugs that target the CNS coupling of whole-body function.

Item ID: 75920
Item Type: Article (Scholarly Work)
ISSN: 2296-858X
Keywords: trauma; hemorrhage; immune; inflammation; mitochondria; system; ALM; cytokines
Copyright Information: © 2022 Dobson, Morris and Letson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Date Deposited: 09 Sep 2022 00:49
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3208 Medical physiology > 320803 Systems physiology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320407 Innate immunity @ 40%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320207 Emergency medicine @ 10%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 10%
20 HEALTH > 2001 Clinical health > 200199 Clinical health not elsewhere classified @ 80%
20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 10%
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