Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

Sercundes, Michelle Klein; Ortolan, Luana dos Santos; Debone, Daniela; Soeiro-Pereira, Paulo Vítor; Gomes, E. A.; Aitken, Elizabeth H.; Condino‐Neto, Antônio; Russo, Marco; Lima, Maria Regina D'Império; Álvarez, José María; Portugal, Sílvia; Marinho, Cláudio R. F.; Epiphânio, Sabrina

doi:10.1371/journal.ppat.1006054

Cited by 92 publications

(129 citation statements)

References 65 publications

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“…We sought to utilize this advantage to identify neutrophils and NETs in whole blood samples from mice infected with Plasmodium parasites, the causative agent of malaria. Plasmodium falciparum is known to induce NETs in humans as indicated by blood smears , NETs have also been reported to be induced by the mouse malaria species Plasmodium berghei and in our case, we commonly observed NETs in blood smears from mice infected with Plasmodium yoelii NL (Supporting Information Fig. S6).…”

Section: Resultssupporting

confidence: 63%

Rapid Quantification of NETs In Vitro and in Whole Blood Samples by Imaging Flow Cytometry

et al. 2019

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Neutrophil extracellular trap (NET) formation involves the release of DNA outside the cell to neutralize pathogens. Techniques such as live microscopy, flow cytometry, and intravital imaging allow the characterization of NETs, but these either cannot be applied in vivo, lack specificity or require invasive procedures. We developed an automated analysis method to rapidly acquire and characterize cells as NETs or NET precursors, as opposed to cells undergoing other forms of cell death, using imaging flow cytometry. NETs were maintained in solution using a novel three‐dimensional cell culture system in which cells are suspended at the interface of two liquids of different density. Critically, we identify NETs using an image analysis algorithm based on morphological data showing the extrusion of DNA beyond the cell boundaries. In vitro, we used this technique to demonstrate different requirements for NET formation in human and mouse neutrophils. We also measured NETs in whole blood during infection of mice with the malaria parasite Plasmodium yoelii. We expect this technique will provide a valuable approach to better understand the process of NET formation and its importance in disease. © 2019 International Society for Advancement of Cytometry

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Section: Resultssupporting

confidence: 63%

Rapid Quantification of NETs In Vitro and in Whole Blood Samples by Imaging Flow Cytometry

et al. 2019

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“…In animal models of ARDS, enhanced neutrophil accumulation in the lung was found compared with mice without pulmonary complications. In addition, targeting neutrophils with a C‐X‐C chemokine receptor type 4 antagonist or neutrophil elastase inhibitor significantly inhibited the development of ARDS and increased the overall survival of ARDS mice (Sercundes et al., ), indicating that neutrophils are the potential target for ARDS treatment. Likewise, in the present study, we found that neutrophil accumulation (indicated indirectly by MPO activity) increased in ARDS mice and was decreased after MOR activation by EM‐1.…”

Section: Discussionmentioning

confidence: 99%

μ‐Opioid receptor signalling via PI3K/Akt pathway ameliorates lipopolysaccharide‐induced acute respiratory distress syndrome

Wang

2019

Experimental Physiology

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New Findings What is the central question of this study?The aim was to investigate the role of μ‐opioid receptors in acute respiratory distress syndrome and whether their protective effect is mediated via the PI3K/Akt signalling pathway. What is the main finding and its importance?Our findings show that activation of μ‐opioid receptors ameliorates lung injury, and the effects are reversed by the PI3K inhibitor, wortmannin. Abstract The main pathology of acute respiratory distress syndrome (ARDS) is the accumulation of inflammatory cells in the lung and increased permeability of vascular endothelial cells. The μ‐opioid receptor (MOR) is a G‐protein‐coupled receptor, which stimulates angiogenesis and vascular endothelial cell proliferation. In addition, the MOR inhibits cell apoptosis via the PI3K/Akt signalling pathway. In this study, we aimed to explore the contribution of the MOR in ARDS and whether its effects are mediated via PI3K/Akt signalling. An ARDS model was established by intratracheal instillation of 5 mg kg−1 lipopolysaccharide (LPS). Lung injury was confirmed by Haematoxylin and Eosin staining, lung wet/dry weight ratio, bronchoalveolar lavage fluid protein concentrations, myeloperoxidase activity and vascular cell adhesion molecule 1 expression. Lung inflammation was determined by assessment of interleukin‐1β and tumour necrosis factor‐α concentrations. The protein level of p‐Akt was detected by western blot. Endomorphin‐1‐activated MORs attenuated LPS‐induced lung injury, lung wet/dry weight ratio, bronchoalveolar lavage fluid protein concentrations, myeloperoxidase activity, interleukin‐1β and tumour necrosis factor‐α levels and vascular cell adhesion molecule 1 expression, and elevated LPS‐induced decreased p‐Akt expression. However, the protective effect of MOR activation on lung injury was reversed by the PI3K inhibitor, wortmannin. In conclusion, MOR involvement in LPS‐induced ARDS is via the PI3K/Akt pathway.

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“…Neutrophils, which secrete elastase, proteases, and MPO, can result in lung tissue damage [37]. Targeting neutrophils prevented malaria-associated lung injury in mice [38]. Our data show that SS-31 reduced MPO-positive cells, suggesting that SS-31 treatment suppresses neutrophil invasion to lung tissue following SCI.…”

Section: Discussionmentioning

confidence: 74%

Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

Zhu¹,

Li²,

He³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Spinal cord injury (SCI) is a common and devastating disease, which results in systemic inflammatory response syndrome and secondary lung injury. Mitochondrial dysfunction and inflammation are closely related to lung injury in diverse disease models. No studies have demonstrated the effects of mitochondrial targeted peptide SS-31 in a mouse model of SCI-induced lung injury. Methods: Immediately after injury, mice in the treatment groups received a daily, single-dose intraperitoneal injection of SS-31 and for the next 2 days. The sham and SCI groups also received a daily single dose of vehicle (DMSO and 0.9% NaCl, 1: 3). The lung tissue of mice was examined after SCI, and tissue damage, apoptosis, inflammation, and mitochondrial dysfunction were recorded. Results: SS-31 treatment attenuated lung edema and tissue damage. Furthermore, SS-31 treatment reduced apoptosis of alveolar type II cells, the number of total macrophages and M1 macrophages, and neutrophil infiltration. Moreover, SS-31 treatment attenuated reactive oxygen species levels, reversed mitochondrial dysfunction and inhibited NLRP3 inflammasome activation. Conclusions: Collectively, our results demonstrate that SS-31 attenuates mitochondrial dysfunction, controls inflammatory responses, and alleviates the severity of lung damage in a mouse model of SCI-induced lung injury.

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Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

Cited by 92 publications

References 65 publications

Rapid Quantification of NETs In Vitro and in Whole Blood Samples by Imaging Flow Cytometry

Rapid Quantification of NETs In Vitro and in Whole Blood Samples by Imaging Flow Cytometry

μ‐Opioid receptor signalling via PI3K/Akt pathway ameliorates lipopolysaccharide‐induced acute respiratory distress syndrome

Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

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