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Anti-TNF inhibits the airways neutrophilic inflammation induced by inhaled endotoxin in human.

ABSTRACT: Inhaled endotoxin induces airways'neutrophilia, in human. TNF-a being a key cytokine in the response to endotoxin, the effect of anti-TNF on the endotoxin-induced neutrophilic response was evaluated among healthy volunteers.Among a population of 30 healthy subjects, an induced-sputum was collected 2 weeks before, and 24 hours after an inhalation of 20 mcg endotoxin (E. coli 026:B6). Then, the subjects were randomized into 3 parallel groups treated with control, oral methylprednisolone 20 mg/day during 7 days or anti-TNF (adalimumab, Humira®, Abbott) 40 mg s.c.. One week later, an induced-sputum was sampled, 24 hours after an inhalation of endotoxin.After endotoxin inhalation, the number of total cells, neutrophils and macrophages was significantly increased (p <0.001). Compared to the response to endotoxin among the control group, anti-TNF inhibited the endotoxin-induced neutrophil influx, both in relative (51.3 (±6.4)% versus 26.2 (±5.3)%, p <0.002) and in absolute values (1321 (443-3935) cells/mcL versus 247 (68-906) cells/mcL, p <0.02). The endotoxin-induced neutrophilic response was not significantly modified among the control group and oral corticosteroid group.While oral corticosteroid had no effect, anti-TNF inhibited the neutrophil influx in sputum, induced by inhalation of endotoxin, in human subject. The endotoxin model could be an early predictor of clinical efficacy of novel therapeutics.ClinicalTrials.gov NCT02252809 (EudraCT2008-005526-37).

SUBMITTER: Michel O

PROVIDER: S-EPMC4236481 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Anti-TNF inhibits the airways neutrophilic inflammation induced by inhaled endotoxin in human.

Michel Olivier O Dinh Phong Huy Duc PH Doyen Virginie V Corazza Francis F

BMC pharmacology & toxicology 20141103

<h4>Background</h4>Inhaled endotoxin induces airways'neutrophilia, in human. TNF-a being a key cytokine in the response to endotoxin, the effect of anti-TNF on the endotoxin-induced neutrophilic response was evaluated among healthy volunteers.<h4>Methods</h4>Among a population of 30 healthy subjects, an induced-sputum was collected 2 weeks before, and 24 hours after an inhalation of 20 mcg endotoxin (E. coli 026:B6). Then, the subjects were randomized into 3 parallel groups treated with control, ...[more]

PMID: 25371053

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Project description: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.SummaryBackground Activation 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. Objective To use a human model of lung inflammation based on the local instillation of endotoxin in order to investigate whether glucocorticoids alter pulmonary coagulation. Methods Twenty-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. Results Endotoxin 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. Conclusions Dexamethasone 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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Anti-TNF inhibits the airways neutrophilic inflammation induced by inhaled endotoxin in human.

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Anti-TNF inhibits the airways neutrophilic inflammation induced by inhaled endotoxin in human.

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