Dissociation between systemic and pulmonary anti‐inflammatory effects of dexamethasone in humans

Bartko, Johann; Stiebellehner, Leopold; Derhaschnig, Ulla; Schoergenhofer, Christian; Schwameis, Michael; Prosch, Helmut; Jilma, Bernd

doi:10.1111/bcp.12857

Cited by 30 publications

(39 citation statements)

References 53 publications

(65 reference statements)

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“…As CD11b [ 40 ] and CD13 [ 41 ] are cell surface markers typically expressed upon neutrophil activation, these results suggest a distinct pro-inflammatory milieu for neutrophils in airways and blood, regardless of the disease status. These findings also support the previous report [ 42 ] stating that following the bronchial instillation of endotoxins, dexamethasone has a more potent anti-inflammatory effect in the blood than in the lungs, in healthy human volunteers.…”

Section: Discussionsupporting

confidence: 92%

Neutrophil extracellular traps are downregulated by glucocorticosteroids in lungs in an equine model of asthma

et al. 2017

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BackgroundSevere neutrophilic asthma is poorly responsive to glucocorticosteroids (GC). Neutrophil extracellular traps (NETs) within the lungs have been associated with the severity of airway obstruction and inflammation in asthma, and were found to be unaffected by GC in vitro. As IL-17 is overexpressed in neutrophilic asthma and contributes to steroid insensitivity in different cell types, we hypothesized that NETs formation in asthmatic airways would be resistant to GC through an IL-17 mediated pathway.MethodsSix neutrophilic severe asthmatic horses and six healthy controls were studied while being treated with dexamethasone. Lung function, bronchoalveolar lavage fluid (BALF) cytology and NETs formation, as well as the expression of CD11b and CD13 by blood and airway neutrophils were evaluated. The expression of IL-17 and its role in NETs formation were also studied.ResultsAirway neutrophils from asthmatic horses, as opposed to blood neutrophils, enhanced NETs formation, which was then decreased by GC. GC also tended to decrease the expression of CD11b in blood neutrophils, but not in airway neutrophils. IL-17 mRNA was increased in BALF cells of asthmatic horses and was unaffected by GC. However, both GC and IL-17 inhibited NETs formation in vitro.ConclusionGC decreased NETs formation in vitro and also in vivo in the lungs of asthmatic horses. However, airway neutrophil activation during asthmatic inflammation was otherwise relatively insensitive to GC. The contribution of IL-17 to these responses requires further study.Electronic supplementary materialThe online version of this article (10.1186/s12931-017-0689-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Neutrophil extracellular traps are downregulated by glucocorticosteroids in lungs in an equine model of asthma

et al. 2017

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“…Endotoxin instillation into the lung induced a mild systemic inflammatory response in placebo‐treated individuals, and was generally well tolerated, without the occurrence of any severe adverse events; this has been reported previously, because the trial was performed concurrently with an investigation on the anti‐inflammatory effects of dexamethasone . The most pronounced effect of dexamethasone was complete prevention of the endotoxin‐induced protein extravasation into the alveolar space.…”

Section: Resultssupporting

confidence: 59%

“…The trial was performed concurrently with an investigation on the anti‐inflammatory effects of dexamethasone published recently . This randomized, double‐blind and placebo‐controlled trial was conducted at the Department of Clinical Pharmacology, Medical University of Vienna, Austria between July 2011 and June 2012.…”

Section: Methodsmentioning

confidence: 99%

“…Statistical comparisons between groups were performed with the Mann–Whitney U ‐test, and comparisons between lung sites of subjects were performed with the Wilcoxon test. The median obtained lavage volumes were comparable between lung sites: endotoxin 45 mL (interquartile range [IQR] 35–50 mL) and saline 54 mL (IQR 39–59 mL) in the placebo group; endotoxin 49 mL (IQR 43–64 mL) and saline 53 mL (IQR 45–61 mL) in the dexamethasone group . We performed a sensitivity analysis adjusting for differences in the BALF recovered, although the value of this is debatable, because the dilution is probably always the same after instillation of 140 mL of saline.…”

Section: Methodsmentioning

confidence: 99%

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Dexamethasone inhibits endotoxin‐induced coagulopathy in human lungs

Bartko

Schoergenhofer

Schwameis

et al. 2016

Journal of Thrombosis and Haemostasis

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Essentials Glucocorticoids are associated with an increased risk of thrombosis.Healthy volunteers received dexamethasone or placebo in an endotoxin lung instillation model.Dexamethasone suppressed thrombin generation in bronchoalveolar lavage.Glucocorticoids inhibit endotoxin induced pulmonary coagulopathy. SummaryBackgroundActivation of local and systemic coagulation is a common finding in patients with pneumonia. There is evidence that glucocorticoids have procoagulant activity in the circulation, particularly in the context of inflammation. The effects of glucocorticoids on local pulmonary coagulation have not yet been investigated.ObjectiveTo use a human model of lung inflammation based on the local instillation of endotoxin in order to investigate whether glucocorticoids alter pulmonary coagulation.MethodsTwenty‐four healthy volunteers were randomized to receive either dexamethasone or placebo in a double‐blind trial. Endotoxin was instilled via bronchoscope into right or left lung segments, followed by saline into the contralateral site. Six hours later, a bilateral bronchoalveolar lavage (BAL) was performed and coagulation parameters were measured.ResultsEndotoxin induced activation of coagulation in the bronchoalveolar compartment: the level of prothrombin fragment 1 + 2 (F1 + 2) was increased three‐fold (248 pmol L−1, 95% confidence interval [CI] 43–454 versus 743 pmol L−1, 95% CI 437–1050) and the level of thrombin–antithrombin complex (TATc) was increased by ~ 50% (31 μg L−1, 95% CI 18–45 versus 49 μg L−1, 95% CI 36–61) as compared with saline‐challenged segments. Dexamethasone reduced F1 + 2 (284 pmol L−1, 95% CI 34–534) and TATc (9 μg L−1, 95% CI 0.7–17) levels almost to those measured in BAL fluid from the saline‐instilled segments in the placebo group. Dexamethasone even profoundly reduced F1 + 2 levels (80%) in saline‐instilled lung segments (50 pmol L−1, 95% CI 12–87). In contrast, dexamethasone had no effect on systemic F1 + 2 levels.ConclusionsDexamethasone inhibits endotoxin‐induced coagulopathy in lungs. This trial is the first to provide insights into the effects of glucocorticoids on pulmonary coagulation in response to endotoxin.

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“…Mice were administered with DSC (100 mg/kg) either half an hour before (prophylactic treatment) or 1 h after (therapeutic treatment) the first caerulein injection. DEX, a synthetic adrenocortical steroid used in clinical treatment of inflammatory diseases ( 18 ), was used for positive control. The pancreatic damage was notably attenuated by both prophylactic and therapeutic treatment with DSC (Figures 2A–C ).…”

Section: Resultsmentioning

confidence: 99%

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

et al. 2018

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Acute pancreatitis (AP), a common abdominal inflammatory disorder, is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. Although the mechanism remains to be fully understood, inflammation is the main cause of pancreatic damage in AP. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits anti-inflammatory and anti-apoptotic properties in vitro. However, its potential beneficial effect in AP has not been demonstrated. This study aimed to investigate the effects and underlying mechanisms of DSC in experimental AP in mice. We found that DSC suppressed inflammatory responses in AP by inhibiting the activation of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome. Furthermore, treatment with DSC modulated the infiltration of neutrophils and the phenotypes of macrophages in mice induced with AP. Interestingly, we found that the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and its regulated antioxidant enzyme heme oxygenase-1 (HO-1), which modulate inflammatory activities, was significantly increased in DSC-treated groups. Together, our findings demonstrate that DSC alleviates pancreatic inflammation and damage in AP by inhibiting the activation of NF-κB, STAT3, and NLRP3 inflammasome and modulating immune cell responses.

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Dissociation between systemic and pulmonary anti‐inflammatory effects of dexamethasone in humans

Cited by 30 publications

References 53 publications

Neutrophil extracellular traps are downregulated by glucocorticosteroids in lungs in an equine model of asthma

Neutrophil extracellular traps are downregulated by glucocorticosteroids in lungs in an equine model of asthma

Dexamethasone inhibits endotoxin‐induced coagulopathy in human lungs

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

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