Abstract
BackgroundInhaled 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.MethodsAmong 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 SC. One week later, an induced-sputum was sampled, 24 hours after an inhalation of endotoxin.ResultsAfter 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.ConclusionsWhile 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.Trial registrationClinicalTrials.gov NCT02252809 (EudraCT2008-005526-37)
Highlights
Since Tumor necrosis factor (TNF)-a seems to be a key cytokine in endotoxininduced neutrophilic inflammation, the current study evaluated the inhibiting effect of anti-TNF on the neutrophilic response among healthy volunters exposed to inhaled endotoxin
Among the 30 subjects, during the screening phase, the endotoxin inhalation induced a significant rise of the geometric means of total viable cells (p
The arithmetic means of the percentage of neutrophils increased from 35.0 (26.9 – 43.1)% to 52.4 (44.6 – 60.3)%, (p
Summary
Airways’ neutrophilic inflammation is a risk factor of severity of several CRD. Neither oral corticosteroids (CS), nor a high dose inhaled CS has an effect on the airways’ neutrophilic inflammation in COPD [5,6], and neutrophilic exacerbations of asthma are refractory to increasing the dose of inhaled corticosteroids [7]. The lack of antiinflammatory effects of CS in COPD could be related to the reduction in recruitment of histone desacetylase-2 by CS, resulting in the absence of control of NFkB transcription, leading to expression of cytokines such as TNF-a and IL-8 [9]. TNF-a appears to participate to the mechanism of airways neutrophilic inflammation in COPD and severe asthma
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