Death to the neutrophil! A resolution for acute respiratory distress syndrome?

Scott, Brian; Kubes, Paul

doi:10.1183/13993003.01274-2018

Cited by 14 publications

(11 citation statements)

References 14 publications

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“…However, even before the emergence of COVID-19, ARDS was the most common cause of death in the ICU, with no effective pharmacological therapies available [34][35][36][37]. Importantly, it has been shown that disease severity and progression are directly associated with the accumulation of neutrophils into the alveolar space [38,39], and many aspects of the pathophysiology of ARDS, such as edema formation and surfactant dysfunction, are consequences of excessive inflammation in the lung [3]. This has provided a strong rationale for glucocorticoid-based treatments, as evident by numerous clinical trials for ARDS and an ongoing trial for COVID-19 patients [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Exogenous Surfactant as a Pulmonary Delivery Vehicle for Budesonide In Vivo

Baer

McCaig

Yamashita

et al. 2020

Lung

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Background Lung inflammation is associated with many respiratory conditions. Consequently, anti-inflammatory medications, like glucocorticoids, have become mainstay intrapulmonary therapeutics. However, their effectiveness for treating inflammation occurring in the alveolar regions of the lung is limited by suboptimal delivery. To improve the pulmonary distribution of glucocorticoids, such as budesonide to distal regions of the lung, exogenous surfactant has been proposed as an ideal delivery vehicle for such therapies. It was therefore hypothesized that fortifying an exogenous surfactant (BLES) with budesonide would enhance efficacy for treating pulmonary inflammation in vivo. Methods An intratracheal instillation of heat-killed bacteria was used to elicit an inflammatory response in the lungs of male and female rats. Thirty minutes after this initial instillation, either budesonide or BLES combined with budesonide was administered intratracheally. To evaluate the efficacy of surfactant delivery, various markers of inflammation were measured in the bronchoalveolar lavage and lung tissue. Results Although budesonide exhibited anti-inflammatory effects when administered alone, delivery with BLES enhanced those effects by lowering the lavage neutrophil counts and myeloperoxidase activity in lung tissue. Combining budesonide with BLES was also shown to reduce several other pro-inflammatory mediators. These results were shown across both sexes, with no observed sex differences. Conclusion Based on these findings, it was concluded that exogenous surfactant can enhance the delivery and efficacy of budesonide in vivo.

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Section: Discussionmentioning

confidence: 99%

Exogenous Surfactant as a Pulmonary Delivery Vehicle for Budesonide In Vivo

Baer

McCaig

Yamashita

et al. 2020

Lung

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“…It has been proposed that activation of the intravascular immune system, through an increase in circulating pro‐inflammatory mediators, results in neutrophil priming, adhesion and/or trapping in lung capillaries. Subsequent migration along a variety of chemotactic gradients into the lung parenchyma therefore results in secondary lung injury . The alternative hypothesis is that the release of pro‐inflammatory mediators by alveolar macrophages plays a vital role in the initiation of inflammation , triggering an inflammatory cascade by activating surrounding tissues and resulting in chemotaxis of inflammatory cells, such as neutrophils, to the airways .…”

Section: Neutrophil Recruitment and Functionmentioning

confidence: 99%

Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential

Potey

Rossi

Lucas

et al. 2019

The Journal of Pathology

175

145

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Acute respiratory distress syndrome (ARDS) is the often fatal sequelae of a broad range of precipitating conditions. Despite decades of intensive research and clinical trials there remain no therapies in routine clinical practice that target the dysregulated and overwhelming inflammatory response that characterises ARDS. Neutrophils play a central role in the initiation, propagation and resolution of this complex inflammatory environment by migrating into the lung and executing a variety of pro‐inflammatory functions. These include degranulation with liberation of bactericidal proteins, release of cytokines and reactive oxygen species as well as production of neutrophil extracellular traps. Although these functions are advantageous in clearing bacterial infection, the consequence of associated tissue damage, the contribution to worsening acute inflammation and prolonged neutrophil lifespan at sites of inflammation are deleterious. In this review, the importance of the neutrophil will be considered, together with discussion of recent advances in understanding neutrophil function and the factors that influence them throughout the phases of inflammation in ARDS. From a better understanding of neutrophils in this context, potential therapeutic targets are identified and discussed. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…The association between increased HGMB1 levels and accelerated NET production by neutrophils has been discussed. This cytokine also exerts a pathological effect in the development of ARDS by aiding in delayed NET clearance, which is a distinctive element driving the development and acceleration of the condition [ 197 , 198 ]. Ultimately, the decreased clearance of NETs is a consequence of delayed neutrophil apoptosis [ 197 , 198 ] which is discussed below.…”

Section: The Recruitment Of Activated Neutrophils Into Alveolae and Imentioning

confidence: 99%

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

Morris

Bortolasci

Puri³

et al. 2020

Life Sciences

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In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.

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Death to the neutrophil! A resolution for acute respiratory distress syndrome?

Cited by 14 publications

References 14 publications

Exogenous Surfactant as a Pulmonary Delivery Vehicle for Budesonide In Vivo

Exogenous Surfactant as a Pulmonary Delivery Vehicle for Budesonide In Vivo

Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

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