The intratracheal administration of endotoxin: X. Dexamethasone downregulates neutrophil emigration and cytokine expression in vivo

Yi, Eunhee S.; Remick, Daniel G.; Lim, Young Hee; Tang, Winson W.; Nadzienko, Christine E.; Bedoya, Adriana; Su, Yin; Ulich, Thomas R.

doi:10.1007/bf01487403

Cited by 42 publications

(32 citation statements)

References 14 publications

(9 reference statements)

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“…In rats, modest glucocorticoid effects on LPS-induced lung expression of CINC and MIP-2 have been reported (42,43). The observed effect of dexamethasone on CXC chemokine BAL fluid protein level expression is largely in agreement with published data in which airway CINC-1 and/or MIP-2 expression were unaffected by glucocorticoids (36,44,45).…”

Section: Discussionsupporting

confidence: 88%

Differential Effects of Ebselen on Neutrophil Recruitment, Chemokine, and Inflammatory Mediator Expression in a Rat Model of Lipopolysaccharide-Induced Pulmonary Inflammation

Haddad

McCluskie

Birrell

et al. 2002

The Journal of Immunology

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We postulated that the seleno-organic compound ebselen would attenuate neutrophil recruitment and activation after aerosolized challenge with endotoxin (LPS) through its effect as an antioxidant and inhibitor of gene activation. Rats were given ebselen (1–100 mg/kg i.p.) followed by aerosolized LPS exposure (0.3 mg/ml for 30 min). Airway inflammatory indices were measured 4 h postchallenge. Bronchoalveolar lavage (BAL) fluid cellularity and myeloperoxidase activity were used as a measure of neutrophil recruitment and activation. RT-PCR analysis was performed in lung tissue to assess gene expression of TNF-α, cytokine-induced neutrophil chemoattractant-1 (CINC-1), macrophage-inflammatory protein-2 (MIP-2), ICAM-1, IL-10, and inducible NO synthase. Protein levels in lung and BAL were also determined by ELISA. Ebselen pretreatment inhibited neutrophil influx and activation as assessed by BAL fluid cellularity and myeloperoxidase activity in cell-free BAL and BAL cell homogenates. This protective effect was accompanied by a significant reduction in lung and BAL fluid TNF-α and IL-1β protein and/or mRNA levels. Ebselen pretreatment also prevented lung ICAM-1 mRNA up-regulation in response to airway challenge with LPS. This was not a global effect of ebselen on LPS-induced gene expression, because the rise in lung and BAL CINC-1 and MIP-2 protein levels were unaffected as were lung mRNA expressions for CINC-1, MIP-2, IL-10, and inducible NO synthase. These data suggest that the anti-inflammatory properties of ebselen are achieved through an inhibition of lung ICAM-1 expression possibly through an inhibition of TNF-α and IL-1β, which are potent neutrophil recruiting mediators and effective inducers of ICAM-1 expression.

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Section: Discussionsupporting

confidence: 88%

Differential Effects of Ebselen on Neutrophil Recruitment, Chemokine, and Inflammatory Mediator Expression in a Rat Model of Lipopolysaccharide-Induced Pulmonary Inflammation

Haddad

McCluskie

Birrell

et al. 2002

The Journal of Immunology

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“…This model has been widely applied to the study of the pathophysiology of human ARDS. In addition to a large number of neutrophils that are recruited to the lung parenchyma and into the bronchoalveolar space, pulmonary oedema develops [24]. In the current study a very early and fulminate neutrophilic cellular response in BALF and in the lung tissue was observed after IT LPS instillation.…”

Section: Discussionsupporting

confidence: 51%

Endothelin-1 production is associated with eosinophilic rather than neutrophilic airway inflammation

et al. 2000

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Endothelin‐1 (ET‐1) is a strong bronchoconstrictor which possesses pro‐inflammatory properties and is claimed to be an important mediator in bronchial asthma. The present study was undertaken to investigate whether ET‐1 synthesis, in an inflammation dominated by neutrophilic granulocytes, is as pronounced as previously demonstrated in an airway inflammation dominated by eosinophils. Moreover, the authors compared the production of ET‐1 and tumour necrosis factor (TNF)‐α in rat lungs following intratracheal instillation of either lipopolysaccharide (LPS) (neutrophilic inflammation) or Sephadex (SDX) (eosinophilic). The lung tissue ET‐1 messenger ribonucleic acid (mRNA) expression was not increased in LPS treated animals whereas a six‐fold increase was measured after 30 min in the SDX group (p<0.05). TNF‐α mRNA signals increased early following LPS instillation, peaking at 2 h, whereas elevated TNF‐α mRNA in the SDX model was observed at 24 h. The ET‐1 concentrations in bronchoalveolar lavage fluid (BALF) rose slightly, but significantly, 3 h after both LPS and SDX exposure. At 24 h no further rise in ET‐1 levels was observed in the LPS model, while a substantial increase in the ET‐1 concentration was measured in the SDX group (p<0.05). The TNF‐α concentrations in BALF rose considerably at 3 h in the LPS group, but was nearly abolished at 24 h. In SDX challenged animals however, an increase in BALF‐TNF‐α did not occur until 24 h postchallenge. In conclusion, intratracheal instillation of lipopolysaccharide, leading to a purely neutrophilic lung inflammation, does not induce synthesis of endothelin‐1. This is in contrast to observations during an eosinophilic airway inflammation, indicating a specific role of endothelin‐1 in lung inflammations dominated by eosinophils. In contrast to in vitro experiments, no evidence for induction of endothelin‐1 synthesis was observed by high levels of tumour necrosis factor‐αin vivo.

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“…Numerous studies have demonstrated that glucocorticoids are powerful tools for attenuating gram-negative bacterial toxin-induced mediator expression, leukocyte recruitment, and associated tissue injury during endotoxemia (1,22,41). In contrast, potential beneficial effects of corticoids on leukocyte recruitment in gram-positive bacterial toxin-induced inflammation have largely been neglected previously.…”

Section: Fig 4 Time-dependent Leukocyte Response To Seb Animals Rementioning

confidence: 99%

“…Due to structural differences in their amino acid sequences, the chemoattractive cytokines are classified into two main families (28). In mice, the bestknown CXC chemokines are macrophage inflammatory protein 2 (MIP-2) (CXCL2) (35) and cytokine-induced neutrophil chemoattractant (KC) (CXCL1) (25,28), both of which are potent stimulators of neutrophil activation and tissue infiltration (10,28,41). However, the detailed role of chemokines in the leukocyte response triggered by SEB remains to be clarified.…”

mentioning

confidence: 99%

“…We and other workers have previously demonstrated that treatment with dexamethasone reduces the expression and function of chemokines in response to pro-inflammatory cytokines and thus attenuates leukocyte adhesion and recruitment (16,32,34,42). On the one hand, production of inflammatory mediators and recruitment of leukocytes in response to a gram-negative bacterial toxin, such as lipopolysaccharide, have been extensively studied and, in most reports, have been shown to be sensitive to glucocorticoid treatment (30,40,41). On the other hand, the anti-inflammatory mechanisms of action of glucocorticoids in SEB-induced acute inflammation remain to be defined.…”

mentioning

confidence: 99%

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Staphylococcal Enterotoxin B-Induced Acute Inflammation Is Inhibited by Dexamethasone: Important Role of CXC Chemokines KC and Macrophage Inflammatory Protein 2

Schramm

Thorlacius

2003

Infect Immun

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This study was conducted to examine the anti-inflammatory mechanisms of dexamethasone during leukocyte recruitment and expression of the CXC chemokines macrophage inflammatory protein 2 (MIP-2) (CXCL2) and cytokine-induced neutrophil chemoattractant (KC) (CXCL1) in staphylococcal enterotoxin B (SEB)-induced acute inflammation. To do this, SEB was injected into murine air pouches with or without dexamethasone pretreatment for 2 h. SEB induced infiltration of leukocytes in a dose-and time-dependent manner, with the maximal response observed after 4 h of treatment with 10 g of SEB. The recruited leukocytes comprised more than 77% neutrophils. Moreover, SEB challenge (10 g) provoked time-dependent secretion of CXC chemokines, which peaked after 1 h. Local administration of antibodies against MIP-2 and KC significantly reduced SEB-triggered neutrophil accumulation by 38 and 59%, respectively. Dexamethasone (10 mg kg ؊1 ) significantly decreased neutrophil recruitment by 82% and reduced secretion of MIP-2 and KC by 89 and 85%, respectively, in response to SEB challenge. Our data demonstrate that dexamethasone potently inhibits neutrophil recruitment in SEB-induced inflammation. Moreover, we provide evidence that MIP-2 and KC are key mediators in the neutrophil response to SEB. Furthermore, our findings demonstrate that dexamethasone attenuates SEB-induced expression of MIP-2 and KC. Thus, this study elucidates important signaling pathways of SEB-induced neutrophil recruitment and anti-inflammatory mechanisms of action of dexamethasone.

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The intratracheal administration of endotoxin: X. Dexamethasone downregulates neutrophil emigration and cytokine expression in vivo

Cited by 42 publications

References 14 publications

Differential Effects of Ebselen on Neutrophil Recruitment, Chemokine, and Inflammatory Mediator Expression in a Rat Model of Lipopolysaccharide-Induced Pulmonary Inflammation

Differential Effects of Ebselen on Neutrophil Recruitment, Chemokine, and Inflammatory Mediator Expression in a Rat Model of Lipopolysaccharide-Induced Pulmonary Inflammation

Endothelin-1 production is associated with eosinophilic rather than neutrophilic airway inflammation

Staphylococcal Enterotoxin B-Induced Acute Inflammation Is Inhibited by Dexamethasone: Important Role of CXC Chemokines KC and Macrophage Inflammatory Protein 2

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