Inhalation Injury Is Associated With Endotheliopathy and Abnormal Fibrinolytic Phenotypes in Burn Patients: A Cohort Study

Keyloun, John W; Le, Tuan; Brummel‐Ziedins, Kathleen E.; McLawhorn, Melissa M; Bravo, Maria Cristina; Orfeo, Thomas; Johnson, Laura S.; Moffatt, Lauren T.; Shupp, Jeffrey W.

doi:10.1093/jbcr/irab102

Cited by 3 publications

(1 citation statement)

References 51 publications

(66 reference statements)

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“…This is called sepsis-induced endotheliopathy [ 83 ]. The glycocalyx is negatively charged and anchored to the single layer of endothelial cells that forms the nexus between the vasculature and the tissues [ 88 , 176 ]. It covers a vast surface area of over 55,000 m 2 [ 49 , 54 ].…”

Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

Revolution in sepsis: a symptoms-based to a systems-based approach?

Dobson,

Letson,

Morris

2024

J Biomed Sci

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Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems’ perspective and future opportunities. We argue that targeting the body’s early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O2 supply. Future research will investigate the potential translation to humans.

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Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

Revolution in sepsis: a symptoms-based to a systems-based approach?

Dobson,

Letson,

Morris

2024

J Biomed Sci

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Implications of the Regulation of Endothelial Glycocalyx Breakdown and Reconstitution in Severe Burn Injury

Basas¹,

Schutzman²,

Brown³

2023

Journal of Surgical Research

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Pathophysiology of Severe Burn Injuries: New Therapeutic Opportunities From a Systems Perspective

Dobson,

Morris,

Letson

2024

Journal of Burn Care &Amp; Research

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Severe burn injury elicits a profound stress response with the potential for high morbidity and mortality. If polytrauma is present, patient outcomes appear to be worse. Sex-based comparisons indicate females have worse outcomes than males. There are few effective drug therapies to treat burn shock and secondary injury progression. The lack of effective drugs appears to arise from the current treat-as-you-go approach rather than a more integrated systems approach. In this review, we present a brief history of burns research and discuss its pathophysiology from a systems’ perspective. The severe burn injury phenotype appears to develop from a rapid and relentless barrage of damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs) and neural afferent signals, which leads to a state of hyperinflammation, immune dysfunction, coagulopathy, hypermetabolism and intense pain. We propose that if the central nervous system (CNS) control of cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored early, these secondary injury processes may be minimized. The therapeutic goal is to switch the injury phenotype to a healing phenotype by reducing fluid leak and maintaining tissue O2 perfusion. Currently, no systems-based therapies exist to treat severe burns. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat hemorrhagic shock, traumatic brain injury and sepsis. Our early studies indicate that the ALM therapy holds some promise in supporting cardiovascular and pulmonary functions following severe burns. Future research will investigate the ability of ALM therapy to treat severe burns with polytrauma and sex disparities, and potential translation to humans.

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Inhalation Injury Is Associated With Endotheliopathy and Abnormal Fibrinolytic Phenotypes in Burn Patients: A Cohort Study

Cited by 3 publications

References 51 publications

Revolution in sepsis: a symptoms-based to a systems-based approach?

Revolution in sepsis: a symptoms-based to a systems-based approach?

Implications of the Regulation of Endothelial Glycocalyx Breakdown and Reconstitution in Severe Burn Injury

Pathophysiology of Severe Burn Injuries: New Therapeutic Opportunities From a Systems Perspective

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