Adrenergic Modulation of Erythropoiesis After Trauma

Munley, Jennifer A.; Kelly, Lauren; Mohr, Alicia M.

doi:10.3389/fphys.2022.859103

Cited by 4 publications

(8 citation statements)

References 101 publications

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“…Bone marrow dysfunction after trauma is characterized by decreased hematopoietic progenitor growth, increased hematopoietic progenitor cell (HPC) mobilization to the peripheral blood, altered myelopoiesis, and persistent anemia (4,5). Prior studies have implicated systemic inflammation, disruption of iron homeostasis, prolonged HPC mobilization, hypercatecholaminemia, and chronic stress as contributors to bone marrow dysfunction after injury (6)(7)(8). Systemic inflammation that inhibits erythropoiesis is characterized by the presence of cytokines such as IL-1α, TNF-α, and interferon gamma (IFN-γ) (9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells

Munley

Kelly

Gillies

et al. 2023

Shock

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Background: Severe trauma disrupts bone marrow function resulting in persistent anemia and immunosuppression. Exosomes are extracellular vesicles implicated in disease, cellular functions, and immunomodulation. The effects of trauma plasma-derived exosomes on bone marrow hematopoiesis are unstudied; we hypothesized that trauma plasma-derived exosomes suppress bone marrow hematopoietic progenitor cell (HPC) growth and contribute to increased inflammatory cytokines and HPC mobilization. Methods: Plasma was collected from a prospective, cohort study of trauma patients (n = 15) with hip and/or femur fractures and an ISS > 15 and elective total hip arthroplasty (THA) patients (n = 15). Exosomes were isolated from both groups using the Invitrogen Total Exosome Isolation Kit. Healthy bone marrow was cultured with 2% plasma, 50 μg, 100 μg, or 200 μg of exosomal protein and HPC (granulocyte, erythrocyte, monocyte, megakaryocyte colony-forming units [CFU-GEMM], erythroid burst-forming units [BFU-E], and macrophage colony-forming units [CFU-GM]) growth assessed. After culturing healthy bone marrow stroma with 100 μg of exosomal protein, expression of cytokines and factors influencing HPC mobilization were assessed by qPCR. Differences were compared using the ANOVA, with significance defined as P < 0.05. Results: The only demographic difference was age; trauma patients were significantly younger than THA (mean 44 vs. 63 years). In vitro exposure to trauma plasma significantly decreased growth of all HPCs. In vitro exposure to 100 μg or 200 μg of trauma exosomal protein significantly decreased growth of BFU-E and CFU-GM, whereas 50 μg had no effect. Culture of trauma exosomal protein with bone marrow stromal cells resulted in increased expression of IFN-γ, IL-1α, TNF-α, G-CSF, CXCR4, SDF-1, and VCAM-1 in bone marrow stroma. Conclusions: Both plasma and plasma-derived exosomes from trauma patients adversely affect bone marrow function. Plasma-derived exosomes may contribute to altered hematopoiesis after severe trauma; analysis of exosomal content may improve our understanding of altered bone marrow function.

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Section: Introductionmentioning

confidence: 99%

Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells

Munley

Kelly

Gillies

et al. 2023

Shock

Self Cite

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“…The autonomic nervous system certainly modulates erythropoiesis in some specific and critical conditions [42][43][44], and hence RDW is influenced by autonomic nervous dysfunction as a stress memory. Dysregulated erythropoie sis reflects somatic stress which induces clonal hemato poiesis of indeterminate potential (CHIP) in the elderly.…”

Section: Rdw In Heart Failurementioning

confidence: 99%

Red cell distribution width in cardiac diseases: Role of hemorheology and chronic inflammation

Maruyama,

Nakashima

2023

J Biorheol

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Red cell distribution width (RDW) is a simple, inexpensive, and unique laboratory parameter. This hemato logic parameter reflecting the heterogeneity of red cell size was used conventionally to differentiate anemic diseases but is used currently as a prognostic marker of common as well as cardiac diseases. Higher RDW is associated with lower therapeutic response in patients with acute myo cardial infarction undergoing percutaneous coronary inter vention, those with atrial fibrillation undergoing catheter ablation, and those with heart failure under drug therapy. RDW showing such wide usefulness is linked to the chronic inflammation, which dysregulates normal erythropoiesis and impairs deformability of red cells within the micro circulation. Disturbed microcirculation causes persistent and systemic tissue hypoxiareoxygenation insult impairing redox homeostasis, which induces chronic inflammation and clonal hematopoiesis of intermediate potential as a stress memory. Therefore, higher RDW is sustained in many cardiac diseases by hemorheological insult causing chronic inflammation under the clonal expansion of eryth roid cells leading to the reduced deformability and increased RDW of red cells by unknown mechanisms.

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“…S evere trauma results in a hyperadrenergic state and a cascade of inflammation, which can result in multiorgan failure, notably including altered bone marrow function. 1,2 Bone marrow dysfunction after trauma can manifest as persistent anemia despite appropriate resuscitation, which can last for months after injury. 3 Suppression of hematopoietic progenitor growth, increased hematopoietic progenitor cell mobilization, altered myelopoiesis, and persistent anemia are hallmarks of postinjury bone marrow dysfunction.…”

mentioning

confidence: 99%

“…Severe trauma results in a hyperadrenergic state and a cascade of inflammation, which can result in multiorgan failure, notably including altered bone marrow function 1,2 . Bone marrow dysfunction after trauma can manifest as persistent anemia despite appropriate resuscitation, which can last for months after injury 3 .…”

mentioning

confidence: 99%

“…Bone marrow dysfunction after trauma can manifest as persistent anemia despite appropriate resuscitation, which can last for months after injury 3 . Suppression of hematopoietic progenitor growth, increased hematopoietic progenitor cell mobilization, altered myelopoiesis, and persistent anemia are hallmarks of postinjury bone marrow dysfunction 2,4 . Despite this knowledge, the multifactorial nature of postinjury bone marrow dysfunction requires that underlying mechanisms remain to be fully studied.…”

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confidence: 99%

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Exosomal microRNA following severe trauma: Role in bone marrow dysfunction

Munley,

Willis,

Gillies

et al. 2023

J Trauma Acute Care Surg

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Introduction Severe trauma disrupts bone marrow function and is associated with persistent anemia and altered hematopoiesis. Previously, plasma-derived exosomes isolated after trauma have been shown to suppress in vitro bone marrow function. However, the cargo contained in these vesicles has not been examined. We hypothesized that trauma plasma-derived exosomes exhibit microRNA (miR) changes that impact bone marrow function after severe injury. Methods Plasma was collected from a prospective, cohort study of trauma patients (n = 15; 7 males, 8 females) with hip and/or femur fractures and an injury severity score (ISS) ≥ 15; elective total hip arthroplasty (THA) patients (n = 8; 4 males, 4 females) served as operative controls. Exosomes were isolated from plasma with the Invitrogen Total Exosome Isolation Kit and RNA was isolated using a miRNeasy Mini Kit. Direct quantification of miRNA was performed by NanoString Technologies on a human miRNA gene panel and analyzed with nSolver with significance defined as p < 0.05. Results There were no differences in age or sex distribution between trauma and THA groups; the average ISS was 23. Trauma plasma-derived exosomes had 60 miR identities that were significantly downregulated and 3 miR upregulated when compared to THA (p < 0.05). Twelve of the downregulated miR have a direct role in hematopoiesis regulation. Further, male trauma plasma-derived exosomes demonstrated downregulation of 150 miR compared to male THA (p < 0.05). Female trauma plasma-derived exosomes demonstrated downregulation of only four miR and upregulation of two miR compared to female THA (p < 0.05). Conclusions We observed downregulation of 12 miRNA linked to hematopoiesis along with sexual dimorphism in miR expression from plasma-derived exosomes following severe trauma. Understanding sexually dimorphic miR expression provides new insight into sex-based changes in postinjury systemic inflammation, immune system dysregulation, and bone marrow dysfunction and will aid us in more precise future potential therapeutic strategies. Level of Evidence II, Prognostic and Epidemiological

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Adrenergic Modulation of Erythropoiesis After Trauma

Cited by 4 publications

References 101 publications

Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells

Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells

Red cell distribution width in cardiac diseases: Role of hemorheology and chronic inflammation

Exosomal microRNA following severe trauma: Role in bone marrow dysfunction

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