Suppressive effects of sivelestat on interleukin 8 and TNF-α production from LPS-stimulated granulocytes in whole blood culture

Shibata, Shigehiro; Takahashi, Goro; Shioya, Nobuki; Inada, Katsuya; Endo, Shunsuke

doi:10.1007/s00540-010-1030-2

Cited by 8 publications

(10 citation statements)

References 20 publications

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“…As neutrophils express Toll-like receptor (TLR)4 [15, 16], the receptor for LPS [16], and produce a variety of inflammatory mediators including chemoattractants for eosinophils, such as leukotriene (LT)B 4 and platelet-activating factor (PAF), on LPS stimulation [17–19], we hypothesised that LPS-stimulated neutrophils would play some role in the pathogenesis of eosinophilic inflammation observed with some cases of severe asthma, especially in neutrophil-dependent eosinophil accumulation in the airway. In the present study, we examined whether neutrophils stimulated with LPS modify the TBM of eosinophils.…”

Section: Introductionmentioning

confidence: 99%

Trans-basement membrane migration of eosinophils induced by LPS-stimulated neutrophils from human peripheral bloodin vitro

et al. 2015

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In the airways of severe asthmatics, an increase of neutrophils and eosinophils is often observed despite high-dose corticosteroid therapy. We previously reported that interleukin-8-stimulated neutrophils induced trans-basement membrane migration (TBM) of eosinophils, suggesting the link between neutrophils and eosinophils. Concentrations of lipopolysaccharide (LPS) in the airway increase in severe asthma. As neutrophils express Toll-like receptor (TLR)4 and can release chemoattractants for eosinophils, we investigated whether LPS-stimulated neutrophils modify eosinophil TBM.Neutrophils and eosinophils were isolated from peripheral blood of healthy volunteers and severe asthmatics. Eosinophil TBM was examined using a modified Boyden's chamber technique. Eosinophils were added to the upper compartment, and neutrophils and LPS were added to the lower compartment. Migrated eosinophils were measured by eosinophil peroxidase assays.LPS-stimulated neutrophils induced eosinophil TBM (about 10-fold increase), although LPS or neutrophils alone did not. A leukotriene B4 receptor antagonist, a platelet-activating factor receptor antagonist or an anti-TLR4 antibody decreased eosinophil TBM enhanced by LPS-stimulated neutrophils by almost half. Neutrophils from severe asthmatics induced eosinophil TBM and lower concentrations of LPS augmented neutrophil-induced eosinophil TBM.These results suggest that the combination of neutrophils and LPS leads eosinophils to accumulate in the airways, possibly involved the pathogenesis of severe asthma.

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Section: Introductionmentioning

confidence: 99%

Trans-basement membrane migration of eosinophils induced by LPS-stimulated neutrophils from human peripheral bloodin vitro

et al. 2015

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“…Importantly, enzyme inhibition experiments revealed that NE must be catalytically active to induce mRNA expression of TNF-␣, MIP-2, and IL-6. In support of this observation, sivelestat, a selective synthetic neutrophil elastase inhibitor, has been reported to suppress the production of TNF-␣ and MIP-2 by LPS and/or NE-stimulated leukocytes in whole blood culture (27,28). We have purposely used the synthetic inhibitor AEBSF instead of physiologic inhibitors such as SLPI because these latter have been reported to down-regulate the expression of inflammatory mediators (29,30).…”

Section: Discussionmentioning

confidence: 88%

Neutrophil Elastase Modulates Cytokine Expression

Benabid

Wartelle

Malleret

et al. 2012

Journal of Biological Chemistry

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Background: Neutrophil elastase (NE) is a potent serine protease with bactericidal activity against Pseudomonas aeruginosa. Results: We now provide evidence that NE modulates inflammatory cytokine expression in response to this pathogen. Conclusion: In addition to its bactericidal action, NE promotes cytokine response that contributes to host antibacterial defense. Significance: This finding reveals that NE plays a multifaceted role in protecting against bacterial infections.

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“…1), a specific low-weight HNEI, has been approved in Japan for the treatment of ALI/ARDS with systemic inflammatory response syndrome (SIRS) [8]. ONO-5046 is not sensitive to active oxygen radicals and effectively penetrates to the lesion location to improve pulmonary function in patients through attenuating the influx and stiffness of neutrophils and the permeability of pulmonary vessels [9,10]; reducing the levels of some inflammatory mediators, such as NO, interleukin 6, interleukin 8, and TNF-␣, among others [11][12][13]. However, ONO-5046 does not improve the mortality outcome of ALI/ARDS patients [14].…”

Section: Introductionmentioning

confidence: 99%

Direct interaction of ONO-5046 with human neutrophil elastase through 1H NMR and molecular docking

Zhu

Huang

et al. 2012

International Journal of Biological Macromolecules

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Suppressive effects of sivelestat on interleukin 8 and TNF-α production from LPS-stimulated granulocytes in whole blood culture

Abstract: Suppression of granulocytic production of IL-8 and TNF-α by sivelestat suggests that this drug may be useful for treatment of morbid conditions involving IL-8 and TNF-α at onset.

Cited by 8 publications

References 20 publications

Trans-basement membrane migration of eosinophils induced by LPS-stimulated neutrophils from human peripheral bloodin vitro

Trans-basement membrane migration of eosinophils induced by LPS-stimulated neutrophils from human peripheral bloodin vitro

Neutrophil Elastase Modulates Cytokine Expression

Direct interaction of ONO-5046 with human neutrophil elastase through 1H NMR and molecular docking

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