What drives neutrophils to the alveoli in ARDS?

Zemans, Rachel L.; Matthay, Michael A.

doi:10.1136/thoraxjnl-2016-209170

Cited by 102 publications

(90 citation statements)

References 32 publications

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“…As the values for the ELISA of nucleosomes reflect a logarithmic scale, the actual magnitude of NET formation will be inclined to be underestimated, as it is in the range of mean elevations to the power of two to even four when compared with healthy volunteers [13,15,17,18] and is considerably higher than that observed in autoimmune diseases such as rheumatoid arthritis with well-controlled activity [13]. While NETs are formed to fight infectious agents by entrapping and killing a wide variety of bacteria [21] and other microbes [22,23], excessive activation of neutrophils and consecutive production of NETs are associated with the pathology of a number of airway disorders [24], such as COPD [25][26][27], impairment of alveolar gas exchange, lung dysfunction [28][29][30][31], and ultimately increased risk of early and late death.…”

Section: Discussionmentioning

confidence: 97%

Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial

et al. 2018

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Neutrophil extracellular traps (NETs) are a hallmark of the immune response in inflammatory diseases. However, the role of NETs in community-acquired pneumonia (CAP) is unknown. This study aims to characterise the impact of NETs on clinical outcomes in pneumonia.This is a secondary analysis of a randomised controlled, multicentre trial. Patients with CAP were randomly assigned to either 50 mg prednisone or placebo for 7 days. The primary end-point was time to clinical stability; main secondary end-points were length of hospital stay and mortality.In total, 310 patients were included in the analysis. Levels of cell-free nucleosomes as surrogate markers of NETosis were significantly increased at admission and declined over 7 days. NETs were significantly associated with reduced hazards of clinical stability and hospital discharge in multivariate adjusted analyses. Moreover, NETs were associated with a 3.8-fold increased adjusted odds ratio of 30-day mortality. Prednisone treatment modified circulatory NET levels and was associated with beneficial outcome.CAP is accompanied by pronounced NET formation. Patients with elevated serum NET markers were at higher risk for clinical instability, prolonged length of hospital stay and 30-day all-cause mortality. NETs represent a novel marker for outcome and a possible target for adjunct treatments of pneumonia.

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Section: Discussionmentioning

confidence: 97%

Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial

et al. 2018

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“…IFN‐γ is required for the changes induced by all three stimuli in myeloid cells. At the peak of LPS‐induced injury (day 4 post‐injury), IFN‐γ is required for full recruitment of neutrophils; however, this difference was only observed in Ifng −/− mice and not following IFN‐γ antibody‐mediated neutralization, which was initiated on day 1 after the neutrophil influx is established (D'Alessio et al, ; Zemans & Matthay, ). During resolution of all three injuries (day 7, 6, or 15), the Ifng −/− mice have more alveolar macrophages and fewer interstitial and inflammatory macrophages.…”

Section: Discussionmentioning

confidence: 99%

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

et al. 2020

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The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury.

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“…Despite considerable progress in elucidating the mechanisms of sepsis and sepsis-associated ALI as well as the development of novel intervention therapies in ICUs, sepsis and sepsis-induced ALI remain leading causes of mortality in critically ill patients (Matthay et al, 2012). Recruitment and infiltration of neutrophils is considered as a critical process in ALI (Grommes & Soehnlein, 2011;Zemans & Matthay, 2017). Because FPR1 plays a vital role in the process of neutrophil migration during acute and chronic inflammation (Tsai et al, 2016), researchers have carefully investigated the importance of FPR1 in neutrophil recruitment during the development of LPS-induced ALI (Wenceslau et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Propofol inhibits endogenous formyl peptide-induced neutrophil activation and alleviates lung injury

Chen

Tsai

Huang

et al. 2018

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Critically ill patients have a high risk of sepsis. Various studies have demonstrated that propofol has anti-inflammatory effects that may benefit critically ill patients who require anesthesia. However, the mechanism and therapeutic effect remain incompletely understood. Our previous data suggest that propofol can act as a formyl peptide receptor 1 (FPR1) antagonist. Here, we hypothesize that propofol mitigates sepsis-induced acute lung injury (ALI) by inhibiting mitochondria-derived N-formyl peptide-mediated neutrophil activation. In human neutrophils, propofol competitively reduced the release of elastase, superoxide, and reactive oxygen species induced by fMMYALF, a human mitochondria-derived N-formyl peptide. In addition, propofol significantly inhibited fMMYALF-induced chemotaxis, calcium mobilization, and phosphorylation of protein kinase B and mitogen-activated protein kinases. These results indicate that propofol suppresses neutrophil activation by blocking the interaction between endogenous N-formyl peptide and its receptor, FPR1, thus inhibiting downstream signaling. Furthermore, propofol alleviated alveolar wall disruption, edematous changes, and neutrophil infiltration in lipopolysaccharide-induced ALI in mice. Noticeably, propofol improved the survival of sepsis mice. This study indicates that the anti-neutrophil effects of propofol may benefit critically ill septic patients. 106-2320-B-255-003-MY3 and MOST Problem: Sedative agents should be selected carefully for anesthetizing critically ill patients who are at high risk of secondary infection and sepsis. Propofol hasanti-inflammatory effects that benefit critically ill patients who require anesthesia.However, the mechanism and therapeutic effect of propofol on neutrophil-dominant acute lung injury remain incompletely understood.Results: Here we found that propofol competitively inhibited various neutrophil activities by blocking the interaction between endogenous N-formyl peptide and its receptor, FPR1, thus inhibiting downstream signaling. Propofol also alleviated the severity of sepsis-associated acute lung injury in mice and improved the survival.Impact: Our in vitro and septic mouse model experiments revealed that the anesthetic agent propofol, an FPR1 antagonist, may be beneficial for treating patients who are critically ill with sepsis and sepsis-associated ALI.

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What drives neutrophils to the alveoli in ARDS?

Cited by 102 publications

References 32 publications

Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial

Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

Propofol inhibits endogenous formyl peptide-induced neutrophil activation and alleviates lung injury

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