Toll-like receptor activation as a biomarker in traumatically injured patients

Darrabie, Marcus D.; Cheeseman, Jennifer A.; Borawski, Joseph; Sullenger, Bruce A.; Elster, Eric A.; Kirk, Allan D.; Lee, Jae Woo

doi:10.1016/j.jss.2018.05.059

Cited by 8 publications

(6 citation statements)

References 34 publications

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“…Since the mRNA expression of the TLRs was upregulated, the protein expression of these receptors might be increased after Mdk treatment. This might lead to sensitization of the CMs for other systemic circulating DAMPs, such as HMGB1 and extracellular histones, which were elevated after polytrauma, leading to cardiomyocyte dysfunction (7, 24, 50). The P2X7 receptor was also shown to be involved in cardiac contractile dysfunction (51).…”

Section: Discussionmentioning

confidence: 99%

Midkine Is Elevated After Multiple Trauma and Acts Directly on Human Cardiomyocytes by Altering Their Functionality and Metabolism

et al. 2019

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Background and Purpose: Post-traumatic cardiac dysfunction often occurs in multiply injured patients (ISS ≥ 16). Next to direct cardiac injury, post-traumatic cardiac dysfunction is mostly induced by the release of inflammatory biomarkers. One of these is the heparin-binding factor Midkine, which is elevated in humans after fracture, burn injury and traumatic spinal cord injury. Midkine is associated with cardiac pathologies but the exact role of Midkine in the development of those diseases is ambiguous. The systemic profile of Midkine after multiple trauma, its effects on cardiomyocytes and the association with post-traumatic cardiac dysfunction, remain unknown.Experimental Approach: Midkine levels were investigated in blood plasma of multiply injured humans and pigs. Furthermore, human cardiomyocytes (iPS) were cultured in presence/absence of Midkine and analyzed regarding viability, apoptosis, calcium handling, metabolic alterations, and oxidative stress. Finally, the Midkine filtration capacity of the therapeutic blood absorption column CytoSorb ®300 was tested with recombinant Midkine or plasma from multiply injured patients.Key Results: Midkine levels were significantly increased in blood plasma of multiply injured humans and pigs. Midkine acts on human cardiomyocytes, altering their mitochondrial respiration and calcium handling in vitro. CytoSorb®300 filtration reduced Midkine concentration ex vivo and in vitro depending on the dosage.Conclusion and Implications: Midkine is elevated in human and porcine plasma after multiple trauma, affecting the functionality and metabolism of human cardiomyocytes in vitro. Further examinations are required to determine whether the application of CytoSorb®300 filtration in patients after multiple trauma is a promising therapeutic approach to prevent post-traumatic cardiac disfunction.

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Section: Discussionmentioning

confidence: 99%

Midkine Is Elevated After Multiple Trauma and Acts Directly on Human Cardiomyocytes by Altering Their Functionality and Metabolism

et al. 2019

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“…As intrinsic danger signals, DAMPs are sensitized and recognized via pattern recognition receptors (PRR) that mediated innate immune responses 46,47 . Toll‐like receptors (TLRs) are the main PRR for detection of DAMPs and TLR activation could predict the pathological conditions in trauma patients 48,49 . An important inflammatory signal TLR‐MyD88 was activated by DAPMs triggered a cascade signal response that increase the transcription activity of nuclear factor kappa‐B (NF‐κB) 44 …”

Section: Damps Inflammation Neutrophils and Macrophages In Surgicamentioning

confidence: 99%

Surgical trauma‐induced immunosuppression in cancer: Recent advances and the potential therapies

Tang

Tie

et al. 2020

Clinical & Translational Med

114

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Surgical resection remains the mainstay treatment for solid cancers, especially for localized disease. However, the postoperative immunosuppression provides a window for cancer cell proliferation and awakening dormant cancer cells, leading to rapid recurrences or metastases. This immunosuppressive status after surgery is associated with the severity of surgical trauma since immunosuppression induced by minimally invasive surgery is less than that of an extensive open surgery. The systemic response to tissue damages caused by surgical operations and the subsequent wound healing induced a cascade alteration in cellular immunity. After surgery, patients have a high level of circulating damage‐associated molecular patterns (DAMPs), triggering a local and systemic inflammation. The inflammatory metrics in the immediate postoperative period was associated with the prognosis of cancer patients. Neutrophils provide the first response to surgical trauma, and the production of neutrophil extracellular traps (NETs) promotes cancer progression. Activated macrophage during wound healing presents a tumor‐associated phenotype that cancers can exploit for their survival advantage. In addition, the amplification and activation of myeloid‐derived suppressor cells (MDSCs), regulatory T cells (Tregs) or the elevated programmed death ligand‐1 and vascular endothelial growth factor expression under surgical trauma, exacerbate the immunosuppression and favor of the formation of the premetastatic niche. Therapeutic strategies to reduce the cellular immunity impairment after surgery include anti‐DAMPs, anti‐postoperative inflammation or inflammatory/pyroptosis signal, combined immunotherapy with surgery, antiangiogenesis and targeted therapies for neutrophils, macrophages, MDSCs, and Tregs. Further, the application of enhanced recovery after surgery also has a feasible outcome for postoperative immunity restoration. Overall, current therapies to improve the cellular immunity under the special condition after surgery are relatively lacking. Further understanding the underlying mechanisms of surgical trauma‐related immunity dysfunction, phenotyping the immunosuppressive cells, and developing the related therapeutic intervention should be explored.

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“…To address this question, we determined the correlation between the levels of circulating immunostimulatory DAMPs and procoagulative particles and the MOF incidence and mortality in polytrauma patients (Table 1). Because most endogenous DAMPs are unknown, the levels of total innate immune stimulators in the patient's plasma were indirectly determined using TLR reporter cells, as described previously (10).…”

Section: Persistent Circulation Of Damps In the Bloodstream Induce Symentioning

confidence: 99%

“…The dysregulated immune response that leads to late complications in both sterile and septic insults has been well-studied, yet pathogenesis is still incompletely understood. There exists a complex pathophysiologic interplay of innate immune stimulators, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), in the development of MOF and mortality in trauma and sepsis patients (6)(7)(8)(9)(10). Both DAMPs and PAMPs trigger inflammatory responses through innate immune receptors, such as TLRs (11).…”

Section: Introductionmentioning

confidence: 99%

Damage- and pathogen-associated molecular patterns play differential roles in late mortality after critical illness

Eppensteiner¹,

Kwun²,

Scheuermann³

et al. 2019

JCI Insight

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Toll-like receptor activation as a biomarker in traumatically injured patients

Cited by 8 publications

References 34 publications

Midkine Is Elevated After Multiple Trauma and Acts Directly on Human Cardiomyocytes by Altering Their Functionality and Metabolism

Midkine Is Elevated After Multiple Trauma and Acts Directly on Human Cardiomyocytes by Altering Their Functionality and Metabolism

Surgical trauma‐induced immunosuppression in cancer: Recent advances and the potential therapies

Damage- and pathogen-associated molecular patterns play differential roles in late mortality after critical illness

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