Neutrophils in critical illness

McDonald, Braedon

doi:10.1007/s00441-017-2752-3

Cited by 25 publications

(23 citation statements)

References 84 publications

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“…Neutrophils are key executors of bacterial clearance in sepsis, and have been implicated in organ damage in both sepsis and trauma . HMGB1 aggravates sepsis‐induced organ dysfunction and mortality via inhibition of neutrophil ability to clear bacteria, and so induction of persistent inflammation.…”

Section: Location Location Location: the 3 Guiding Influences For Hmentioning

confidence: 99%

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Deng

Scott

Fan

et al. 2019

Journal of Leukocyte Biology

131

101

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High mobility group box 1 (HMGB1) is a multifunctional nuclear protein, probably known best as a prototypical alarmin or damage-associated molecular pattern (DAMP) molecule when released from cells. However, HMGB1 has multiple functions that depend on its location in the nucleus, in the cytosol, or extracellularly after either active release from cells, or passive release upon lytic cell death. Movement of HMGB1 between cellular compartments is a dynamic process induced by a variety of cell stresses and disease processes, including sepsis, trauma, and hemorrhagic shock.Location of HMGB1 is intricately linked with its function and is regulated by a series of posttranslational modifications. HMGB1 function is also regulated by the redox status of critical cysteine residues within the protein, and is cell-type dependent. This review highlights some of the mechanisms that contribute to location and functions of HMGB1, and focuses on some recent insights on important intracellular effects of HMGB1 during sepsis and trauma. K E Y W O R D S AIM2, autophagy, caspase-11, DAMPs, pyroptosis 2 NUCLEAR-TO-CYTOPLASM SHUTTLING OF HMGB1 HMGB1 consists of 215 aa residues, and contains 2 HMG DNAbinding domains, designated as A and B boxes, together with a negatively charged C-terminal acidic region. 14 Two nuclear localization sites (NLSs), one located in the A box (aa 28-44) and one in the B box (aa 179-185), control the nuclear localization of HMGB1 under homeostatic states. 14 Posttranslational modifications of NLS sites, including acetylation, phosphorylation, and methylation, regulate the ability of HMGB1 to translocate to the cytoplasm during cellular stress.Once in the cytoplasm HMGB1 can affect multiple inflammatory responses, and can be actively released into the extracellular space and circulation.

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Section: Location Location Location: the 3 Guiding Influences For Hmentioning

confidence: 99%

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Deng

Scott

Fan

et al. 2019

Journal of Leukocyte Biology

131

101

View full text Add to dashboard Cite

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“…These works span the spectrum, ranging from human critical care medicine (McDonald 2018) to bovine health and disease (Bassel and Caswell 2018), to the role of neutrophils in equine lung inflammation and ischemia reperfusion injury (Anderson and Singh 2018). These works bring our understanding of the neutrophil full circle, from mapping of specific effector functions and cell recruitment pathways to the role these cells play in the generation, and resolution, of disease.…”

mentioning

confidence: 99%

Neutrophils: multitasking first responders of immunity and tissue homeostasis

2018

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From an evolutionary perspective, neutrophils are one of oldest immune cell types and represent a key first responder to infection and tissue injury (Leiding 2017). These early immune components first appear in simple invertebrates, such as cnidarians, as cells called amebocytes. In higher invertebrates, these primordial neutrophils take the form of hemocytes, cells that possess many of the functions of both neutrophils (phagocytosis, degranulation) and platelets (ability to initiate clotting of hemolymph). In vertebrates, these frontline immune cells take the form of the classic neutrophil, a granular phagocyte that is rapidly recruited to sites of infection or injury. Diverging from its evolutionary roots, the vertebrate neutrophil has lost much of its hemostatic function and appears to be dedicated to the host response to infection/injury.In many ways, the rapid and robust response of neutrophils to infection has placed this leukocyte in the spotlight as the prototypical cell of the innate immune response. Upon infection or injury, neutrophils are recruited en masse, migrating from the bloodstream, crossing the endothelium, and entering the tissue interstitium where these cells then home to the specific site of challenge. Over the past century, these foot soldiers of the innate immune system have been studied in detail, providing great insight as to how the host recognizes pathogens, how cells are recruited to specific tissue beds, how immune cells are able to directly kill a variety of pathogens (lysosomes, proteases, reactive-oxygen species), and how immune cells inflict the collateral damage associated with inflammation. These studies began to define a clear role for the neutrophil as a short lived, non-discriminating killer that, while key to controlling infectious agents, often resulted in significant harm to self-tissues in an effort to ensure the clearance of the pathogen. For decades, this view of neutrophils as an unsophisticated Bthug^of the innate immune system predominated, and, for the most part, limited efforts to search for, and understand, other functions of the neutrophil.Despite the common view that we had already fully mapped the function of the neutrophil, research persisted and, with the advent of new techniques and technology (conditional genetic knock-out animals, blocking and depleting antibodies, multi-color flow cytometry, etc.), our understanding of these prototypical innate immune cells has changed dramatically over the last two decades. In particular, perhaps no single technique has advanced our understanding of neutrophils biology better than intravital imaging. What began with Julius Cohnheim nearly 150 years ago, using a simple white-light microscope to study blood flow and leukocyte behavior in a frog's tongue, has evolved to embrace cuttingedge technology allowing for the visualization multiple cell types, pathogens, and effector functions in real-time, in the living animal with resolution never believed to be possible. With this approach we have mapped cell recruitment, adhe...

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“…Even the phrase "neutropenic sepsis" is a misnomer, as the HSCT myelopreparative regimens also result in pancytopenia. Leukopenia, including neutropenia, lymphopenia, and monocytopenia, dramatically changes not only the acute response to infection, but the regulation of the adaptive immune response and the resolution and repair of injury [3,7,8,[84][85][86][87][88][89][90]. Platelets are increasingly recognized to play a vital role in the defense against bacterial, viral, and fungal infections, and like leukocytes, are integral to the development and resolution of organ failure [91][92][93][94][95].…”

Section: Biology Of Neutropenic Sepsis and Respiratory Failurementioning

confidence: 99%

ICU Complications of Hematopoietic Stem Cell Transplant, Including Graft vs Host Disease

Stephens

2020

Evidence-Based Critical Care

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A 44 year-old woman with a history of acute myeloid leukemia (AML) underwent a non-myeloablative haploidentical peripheral blood hematopoietic stem cell transplant (HSCT) 10 days ago. She was admitted to the hospital with fevers to 39 °C. On examination, she is anxious-appearing, with a temperature of 38.9 °C, a heart rate of 120 beats/min, a respiratory rate of 28 breaths/min, a blood pressure of 98/64 mmHg, and an oxygen saturation of 94% on 4 L/min oxygen via nasal cannula. A tunneled central venous catheter is in situ in her right internal jugular vein. Her total white blood cell (WBC) count is <0.5 cells/mm 3 and platelet count is 8000 cells/mm 3 . A chest CT scan shows diffuse patchy bilateral infiltrates (Figure). She is started on empiric antibiotic coverage with piperacillin/tazobactam, and 3 L of crystalloid are administered. Several hours later, she is more hypotensive, with nadir systolic pressures of 80-88 mmHg, and is more hypoxic, now saturating 85% on 6 L/min nasal cannula oxygen. QuestionHow should this patient be managed?Answer Broad spectrum antibiotics and lung-protective respiratory support.All patients after HSCT are immunosuppressed, profoundly so in the early post-transplant period before engraftment has occurred. This patient is likely to have a pneumonia with secondary septic shock, but a central line-associated infection from her tunneled central line is possible, as are non-infectious complications of HSCT. Respiratory failure is the most frequent cause of intensive care unit (ICU) admission after HSCT, most frequently from an infectious cause. The patient was placed on high-flow nasal cannula (HFNC) for oxygenation support and started on a norepinephrine infusion for hemodynamic support. Antibacterial coverage was changed to meropenem, levofloxacin, and vancomycin, and voriconazole was added for antifungal coverage. Her central line was removed. Her respiratory status continued to decline, and endotracheal intubation and mechanical ventilation were required 24 h after admission. She was placed on volume assist-control with a tidal volume of 6 mL/kg predicted body weight, and bronchoscopy with bronchoalveolar lavage (BAL) was performed. The BAL fluid was initially bloody, but cleared with sequential aliquots. Microbiologic studies of the BAL fluid were positive for respiratory syncytial virus and Pseudomonas aeruginosa. She was maintained on low tidal-volume ventilation and vasopressors were weaned off. Her white blood cell count slowly began to recover, and her respiratory status began to improve. She was extubated on hospital day 12 and was discharged from the ICU on hospital day 14. Principles of ManagementHematopoietic stem cell transplant (HSCT) has become an essential therapeutic modality in the treatment of malignant and non-malignant hematologic disease. In 2016, more than 23,000 HSCTs were performed in the United States, including approximately 15,000 autologous HSCTs and more than 8500 allogeneic transplants [1]. Allogeneic transplants are associated with more morbidity and m...

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Neutrophils in critical illness

Cited by 25 publications

References 84 publications

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Neutrophils: multitasking first responders of immunity and tissue homeostasis

ICU Complications of Hematopoietic Stem Cell Transplant, Including Graft vs Host Disease

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