Extracellular Histones Play an Inflammatory Role in Acid Aspiration-induced Acute Respiratory Distress Syndrome

Zhang, Yanlin; Wen, Zongmei; Guan, Li; Jiang, Ping; Gu, Tao; Jin-yuan, Zhao; Lv, Xin; Wen, Tao

doi:10.1097/aln.0000000000000429

Cited by 56 publications

(42 citation statements)

References 40 publications

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“…The content of the aspirate includes gastric contents, blood, bacteria, liquids and secretions. Gastric aspiration is a major direct cause of acute lung injury (ALI) and the more severe acute respiratory distress syndrome [1,2]. Gastric aspiration may result in a variety of clinical lung injuries, ranging from mild, subclinical pneumonitis to a more severe, progressive disease with associated high mortality.…”

Section: Introductionmentioning

confidence: 99%

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Bone‐marrow‐derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats

Zhou

Jiang

Long

et al. 2016

J Cellular Molecular Medi

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Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP + ) or EGFP À BMSCs or 15d-PGJ 2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-a and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of pp65 and increased the levels of interleukin-10 and 15d-PGJ 2 and the expression of peroxisome proliferator-activated receptor (PPAR)-c in the lung tissue in CASP-induced rats. Tumour necrosis factor-a stimulated BMSCs to secrete 15d-PGJ 2 . A tracking experiment showed that EGFP + BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ 2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ 2 activation of the PPAR-c receptor, reducing the production of proinflammatory cytokines.Keywords: bone marrow mesenchymal stem cell gastric aspiration acute respiratory distress syndrome 15-deoxy-D12 14 prostaglandin J 2 peroxisome proliferator-activated receptor-c

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Section: Introductionmentioning

confidence: 99%

“…Many studies have demonstrated that the activation of PPARc by 15d-PGJ 2 or other agonists has anti-inflammatory effects and leads to a substantial reduction in experimental ALI [9][10][11]. However, the roles of 15d-PGJ 2 and PPARc in gastric aspiration-induced lung injury are unknown.…”

Section: Introductionmentioning

confidence: 99%

Bone‐marrow‐derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats

Zhou

Jiang

Long

et al. 2016

J Cellular Molecular Medi

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“…Intravenous infusion of exogenous, full-length glycosaminoglycans (including heparin (a highly-sulfated HS (2, 6)) or the chondroitin sulfate-rich Inter-alpha inhibitor (17)) attenuated histone-induced organ injury. Whether circulating (endothelial glycocalyx-derived) HS fragments would provide similar protective benefit is uncertain, however, particularly given reports that fragmented HS can propagate inflammation via activation of toll-like receptor signaling (18).…”

Section: Discussionmentioning

confidence: 99%

“…In accordance with the charge-mediated nature of histone cytotoxicity, the direct injurious effects of extracellular histones can be negated by the exogenous administration of highly-sulfated (and accordingly highly negatively-charged) glycans, such as polysialic acid (5) or heparin (2, 6). Critical illnesses such as sepsis are similarly characterized by the endogenous release of heparan sulfate (HS, a highly negatively-charged glycosaminoglycan) into the plasma during endothelial glycocalyx degradation (7).…”

Section: Introductionmentioning

confidence: 99%

Circulating Heparan Sulfate Fragments Attenuate Histone-Induced Lung Injury Independently of Histone Binding

Zhang

Haeger

Yang

et al. 2017

Shock

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Extracellular histones are cationic damage-associated molecular pattern molecules capable of directly inducing cellular injury via charge-mediated interactions with plasma membranes. Accordingly, histones released into the plasma during critical illness are known to contribute to the onset and propagation of lung injury. Vascular injury (with consequent degradation of the endothelial glycocalyx) simultaneously releases anionic heparan sulfate fragments (hexa- to octasaccharides in size) into the plasma. It is unknown whether this endogenous release of heparan sulfate fragments modulates charge-dependent histone cytotoxicity, or if exogenous heparan sulfate fragments could therapeutically attenuate histone-induced lung injury. Using isothermic calorimetry, we found that extracellular histones only bind to heparan sulfate fragments ≥ 10 saccharides in size, suggesting that glycocalyx-derived heparan sulfate hexa/octasaccharides are incapable of intercepting/neutralizing circulating histones. However, we found that even heparan sulfate fragments incapable of histone binding (e.g. tetrasaccharides) attenuated histone-induced lung injury in vivo, suggesting a direct, size-independent protective effect of heparan sulfate. We found that histones had no effect on human neutrophils ex vivo but exerted toll-like receptor-independent cytotoxicity on human pulmonary microvascular endothelial cells in vitro. This cytotoxicity could be prevented by either the addition of negatively-charged (i.e. highly-sulfated) heparan sulfate tetrasaccharides (incapable of binding histones) or decasaccharides (capable of binding histones). Taken together, our findings suggest that heparan sulfate oligosaccharides may directly exert pulmonary endothelial-protective effects that attenuate histone-mediated lung injury.

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“…This concurs with the results of Yildiz et al [42] who found that mechanical ventilation induced netosis in an animal model of sepsis, but that netosis had no major pathogenic effect. However, netosis intensity has been linked to severity in two models of sterile ARDS: acid-aspiration-induced ARDS [43] and transfusion-related acute lung injury [44]. Gilz expression might thus be a more specific marker of ARDS severity than other markers such as CRP and NETs.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil expression of glucocorticoid-induced leucine zipper (GILZ) anti-inflammatory protein is associated with acute respiratory distress syndrome severity

Espinasse

Hajage

Montravers

et al. 2016

Ann. Intensive Care

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Background Glucocorticoid-induced leucine zipper (GILZ) is a potent anti-inflammatory protein involved in neutrophil apoptosis and the resolution of inflammation. Given the numerous pathophysiologic roles of neutrophils in the acute respiratory distress syndrome (ARDS), we postulated that neutrophil GILZ expression might be induced during ARDS, to modulate the inflammatory process and participate in lung repair.Methods This single-center, prospective, observational cohort study took place in the surgical intensive care unit of Bichat Hospital (Paris, France) and involved 17 ARDS patients meeting the Berlin criteria at inclusion, and 14 ventilated controls without ARDS. Serial blood samples were obtained every 2 days until extubation or death (from 1 to 9 samples per patient). GILZ protein and gene expression was quantified in blood neutrophils, along with markers of inflammation (CRP, extracellular DNA) or its resolution (Annexin A1).ResultsNeutrophil GILZ expression was detected at the transcriptional and/or translational level in 9/17 ARDS patients (in particular 7/10 severe ARDS) and in 2/14 ventilated controls. The highest mRNA levels were observed in the most severely ill patients (p < 0.028). GILZ was expressed in about ¾ of the corticosteroid-treated patients and its expression could also occur independently of corticosteroids, suggesting that inflammatory signals may also induce neutrophil GILZ expression in vivo.Conclusions In this pilot study, we show for the first time that blood neutrophils from patients with ARDS can express GILZ, in keeping with an anti-inflammatory and regulatory endogenous role of GILZ in humans. Contrary to some markers of inflammation or its resolution, the levels of gilz gene expression were related to ARDS severity.

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Extracellular Histones Play an Inflammatory Role in Acid Aspiration-induced Acute Respiratory Distress Syndrome

Cited by 56 publications

References 40 publications

Bone‐marrow‐derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats

Bone‐marrow‐derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats

Circulating Heparan Sulfate Fragments Attenuate Histone-Induced Lung Injury Independently of Histone Binding

Neutrophil expression of glucocorticoid-induced leucine zipper (GILZ) anti-inflammatory protein is associated with acute respiratory distress syndrome severity

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