WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Techniques to create aseptic inflammatory reactions provide information regarding acute inflammatory pathways and may be used to assess the anti-inflammatory properties of novel drugs. WHAT THIS STUDY ADDS• In this study, we have shown that the cantharidin-induced blister is a local inflammatory reaction, safe and well tolerated, with a good intra-subject inter-day reproducibility. This induced blister is inhibited by specific (anti-tumour necrosis factor (TNF)) and non specific (corticosteroids) systemic anti-inflammatory agents. This model could be of interest to evaluate anti-inflammatory agents in their early phase development. AIMPharmacological profiling techniques, such as the cantharidin-induced skin blister, may be used to assess the anti-inflammatory properties of novel drugs. However, no data are available on the reproducibility of this technique or on the blocking effect of anti-inflammatory drugs, such as anti-TNF and corticosteroids. METHODSA group of 30 healthy subjects were randomized into three parallel groups treated with placebo, oral methylprednisolone 20 mg day -1 for 7 days or anti-tumour necrosis factor (TNF) (adalimumab, Humira®, Abbott) 40 mg s.c. single dose. A first blister was induced at baseline and collected, immediately before the start of treatment and a second blister was obtained 7 days after the start of treatment. The total number of cells, the cell viability and the differential cell count were evaluated by two independent observers, who were blind to treatment. ANOVA was used to compare change from baseline among the three groups before pairwise comparisons. RESULTSAmong the placebo group, there was no significant difference in the total cell count, neutrophils, eosinophils and monocytes between day 1 and day 7. Methylprednisolone inhibited the eosinophil influx in mean % (95% CI) (-1.0 (-1.7, -0.3); P < 0.02) and absolute (P < 0.02) values, while anti-TNF inhibited the neutrophil influx in mean % (95% CI) (-19.3 (-29.5, -9.1); P < 0.01) and absolute (P < 0.05) values. CONCLUSIONSThe cantharidin-induced skin blister is a safe, well tolerated and reproducible procedure. Pre-treatment with anti-TNF or methylprednisolone inhibited the neutrophilic or eosinophilic trafficking, respectively. It could be useful in profiling anti-inflammatory drugs regarding their effects on the cellular inflammatory response.
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)
AIMSIn drug development, the anti-inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size. METHODSThree nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 μm), MB2 (3.2 μm) and Pari (7.9 μm)]. Participants inhaled three boluses of a 20 μg (technetium 99 m-labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gammascintigraphy, while blood and sputum biomarkers were evaluated before and after challenges. RESULTSMB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel -1 , respectively, vs. 67.9 (±20.6) counts pixel -1 ; P < 0.01]. MB2 and Pari caused higher levels of blood C-reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C-reactive protein levels correlated positively with lung deposition (P < 0.01). CONCLUSIONSInhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Inhaled lipopolysaccharide (LPS) challenge induces neutrophilic airway inflammation. The size of inhaled droplets is a physical parameter that affects total and regional deposition in the respiratory system. WHAT THIS STUDY ADDS• The current study demonstrates a link between inhaled LPS droplet size, lung deposition and the amplitude of the neutrophilic inflammatory response. The size of inhaled LPS droplets is a significant factor when investigating the mechanisms of inflammation and response to pharmacological inhibitors.
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