Septic Shock in Advanced Age: Transcriptome Analysis Reveals Altered Molecular Signatures in Neutrophil Granulocytes

Pellegrina, Diogo Vieira da Silva; Severino, Patrícia; Barbeiro, Hermes Vieira; Andreghetto, Flávia Maziero; Velasco, Irineu Tadeu; Souza, Heraldo Possolo de; Machado, Marcel Cerqueira César; Reis, Eduardo M.; Silva, Fabiano Pinheiro da

doi:10.1371/journal.pone.0128341

Cited by 29 publications

(26 citation statements)

References 91 publications

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“…However, exposing neutrophils from young adults to pooled plasma from older patients with CAP and sepsis replicates the functional deficits seen in sepsis,33 which suggests that the CAP environment can alter cellular function. In keeping with this, murine models of sepsis in older mice show transcriptomic changes in neutrophils which would contribute to cellular dysfunction, implicating cellular energetics and epigenetics 68…”

Section: Host Immune System At the Extremes Of Agementioning

confidence: 67%

Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age

Grudzinska

Brodlie

Scholefield

et al. 2019

Thorax

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"Science means constantly walking a tight rope" Heinrich Rohrer, physicist, 1933. Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore.

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Section: Host Immune System At the Extremes Of Agementioning

confidence: 67%

Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age

Grudzinska

Brodlie

Scholefield

et al. 2019

Thorax

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“…Studies of sepsis have shown an exponential increase in the population-based incidence of sepsis with age, followed closely by an increased mortality. In a small study of septic shock in advanced age, major molecular pathways were found to be deregulated following severe infection, indicating that the systemic inflammatory response differs according to age [15].…”

Section: Mortalitymentioning

confidence: 99%

The status of intensive care medicine research and a future agenda for very old patients in the ICU

Flaatten¹,

Lange²,

Artigas³

et al. 2017

Intensive Care Med

209

196

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The "very old intensive care patients" (abbreviated to VOPs; greater than 80 years old) are probably the fastest expanding subgroup of all intensive care unit (ICU) patients. Up until recently most ICU physicians have been reluctant to admit these VOPs. The general consensus was that there was little survival to gain and the incremental life expectancy of ICU admission was considered too small. Several publications have questioned this belief, but others have confirmed the poor long-term mortality rates in VOPs. More appropriate triage (resource limitation enforced decisions), admission decisions based on shared decision-making and improved prediction models are also needed for this particular patient group. Here, an expert panel proposes a research agenda for VOPs for the coming years.

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“…Recently, it has also been shown that diminished expression levels of Atg5 contributed to reduced capacity of neutrophils to form NETs upon TLR2 ligand stimulation in aged mice, suggesting an important role of autophagy in maintaining the mechanism of NETs ( Xu et al, 2017 ). Interesting, in vitro NET generation is impaired in older adults in response to LPS and IL-8 ( Hazeldine et al, 2014 ), and reduced ATG5 gene expression ( Vieira da Silva Pellegrina et al, 2015 ; Xu et al, 2017 ). Consistent with this, inhibition of autophagy by pharmacological inhibitors or by small interfering RNA against ATG7 attenuated LC3 autophagy formation and significantly decreased NET generation in promyelocytes ( Ma et al, 2016 ).…”

Section: Autophagy and Net Formationmentioning

confidence: 99%

Autophagy in Neutrophils: From Granulopoiesis to Neutrophil Extracellular Traps

Skendros

Mitroulis

Ritis

2018

Front. Cell Dev. Biol.

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Autophagy is an evolutionarily conserved intracellular degradation system aiming to maintain cell homeostasis in response to cellular stress. At physiological states, basal or constitutive level of autophagy activity is usually low; however, it is markedly up-regulated in response to oxidative stress, nutrient starvation, and various immunological stimuli including pathogens. Many studies over the last years have indicated the implication of autophagy in a plethora of cell populations and functions. In this review, we focus on the role of autophagy in the biology of neutrophils. Early studies provided a link between autophagy and neutrophil cell death, a process essential for resolution of inflammation. Since then, several lines of evidence both in the human system and in murine models propose a critical role for autophagy in neutrophil-driven inflammation and defense against pathogens. Autophagy is essential for major neutrophil functions, including degranulation, reactive oxygen species production, and release of neutrophil extracellular traps. Going back to neutrophil generation in the bone marrow, autophagy plays a critical role in myelopoiesis, driving the differentiation of progenitor cells of the myeloid lineage toward neutrophils. Taken together, in this review we discuss the functional role of autophagy in neutrophils throughout their life, from their production in the bone marrow to inflammatory responses and NETotic cell death.

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Septic Shock in Advanced Age: Transcriptome Analysis Reveals Altered Molecular Signatures in Neutrophil Granulocytes

Cited by 29 publications

References 91 publications

Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age

Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age

The status of intensive care medicine research and a future agenda for very old patients in the ICU

Autophagy in Neutrophils: From Granulopoiesis to Neutrophil Extracellular Traps

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