Figures
- FIGURE 1
RV568 reduces inflammation in monocytes, macrophages and epithelial cells. a) Inhibition of lipopolysaccharide (LPS)-induced CXCL8 release in healthy peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from whole blood of healthy volunteers (n=3) and treated with 0.1 μg·mL−1 LPS for 4 h. b) Inhibition of LPS-induced CXCL8 release in d-U937 cells. U937 cells were differentiated into a macrophage-like cell with phorbol 12-myristate 13-acetate (n=3) and treated with 0.1 μg·mL−1 LPS for 4 h. c) Inhibition of tumour necrosis factor (TNF)-α-induced interleukin (IL)-6 release in normal human bronchial epithelial cells (NHBEs). NHBEs (n=3) were stimulated with 50 ng·mL−1 TNF-α for 4 h. d) Inhibition of TNFα-induced CXCL8 release in NHBEs. NHBEs (n=3) were stimulated with 50 ng·mL−1 TNF-α for 4 h. Cytokine releases were measured in the cell-free supernatants by ELISA; the per cent inhibitions were calculated by comparison with vehicle controls. Data are presented as mean±sem; ANOVA with Dunn's test, p<0.05 to RV568.
- FIGURE 2
Inhibition of poly I:C-induced cytokine release in BEAS-2B cells. Cells were pre-incubated with dexamethasone alone, RV568 alone and both drugs combined at all indicated concentrations for 1 h prior to stimulation with poly I:C. a) Inhibition of poly I:C-induced CXCL8. b) Inhibition of poly I:C-induced interleukin (IL)-6. Cytokine release was measured in the cell-free supernatants by ELISA; the per cent inhibitions were calculated by comparison with vehicle control. Data are presented as mean±sem; n=8; ANOVA with Dunn's test, p<0.05 to RV568.
- FIGURE 3
RV568 inhibits lipopolysaccharide (LPS)-induced neutrophilia with a long duration of action in the mouse. a) Mice (n=8) were intratracheally administered a solution of vehicle or RV568 2 h prior to LPS exposure via inhalation. b) Mice (n=8) were intratracheally administered a solution of vehicle or RV568 at the indicated time points prior to LPS exposure. Bronchoalveolar lavage was collected 8 h after the LPS challenge and neutrophil influx measured. Data are presented as mean±sem; ANOVA with Dunnett's test, *: p<0.05 to vehicle control.
- FIGURE 4
Therapeutic administration of RV568 attenuates smoking-induced inflammation in the mouse. Mice (n=5–6 per group) were exposed to 30 min of cigarette smoke once daily for 11 days followed by 3 days of once-daily intranasal administration of vehicle, fluticasone propionate (FP), RV568 or indicated drug combinations (μg per mouse). Bronchoalveolar lavage (BAL) was collected 24 h after the last drug administration and the numbers of alveolar macrophages and neutrophils were determined by fluorescence-activated cell sorting (FACS) analysis. a) MOMA2+-macrophage accumulation in BAL. b) Neutrophil accumulation in BAL. Data are presented as mean±sem; ANOVA with Dunnett's test: ***: significant difference from cigarette smoke control at p<0.001. ###: significant difference versus air control at p<0.001 and +++: significant difference versus FP treatment at p<0.001, by t-test with Welch's correction.
- FIGURE 5
Clinical and sputum biomarker improvements after a 14-day administration of RV568 in chronic obstructive pulmonary disease patients. a) Pre-bronchodilator forced expiratory volume in 1 s (FEV1) change on day 14 after treatment with RV568. Data are presented as mean±sem; ANOVA with Bonferonni's multiple comparison to placebo, *: p<0.05. Placebo n=10; 50 μg n=9; 100 μg n=9. b) Sputum supernatant malondialdehyde (MDA) change on day 14 after treatment with RV568. Data are presented as mean±sem; ANOVA with Bonferonni's multiple comparison to placebo, *: p<0.05. Placebo n=6; 50 μg n=7; 100 μg n=4. ICS: inhaled corticosteroids.
Tables
- TABLE 1
COPD patient demographics
Treatment group Placebo# 50 µg RV568# 100 µg RV568# Age years 66±5 62±5 60±5 Sex Male 7 4 4 Female 4 6 6 Race White 10 10 9 Other 0 0 1 Weight kg 78.9±13.6 70.9±14.0 70.6±13.1 Height cm 173±12 164±12 164±10 BMI kg·m−2 26.3±2.8 26.7±5.5 26.4±4.3 Post-bronchodilator FEV1 % predicted 67±10 65±9 62±11 Post-bronchodilator FEV1/FVC ratio % 52.2±10.2 49.2±12.5 48.1±11.6 Smoking status Current 5 5 4 Former 5 5 6 COPD therapy Single (SABA, LABA or LAMA) 2 4 4 Dual (ICS/LABA or LABA/LAMA) 2 2 2 Triple (ICS/LABA/LAMA) 6 4 4 Data are presented as mean±sd or n. COPD: chronic obstructive pulmonary disease; BMI: body mass index; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; SABA: short-acting beta agonists; LABA: long-acting beta agonists; LAMA: long-acting muscarinic antagonists; ICS: inhaled corticosteroids. #: n=10.
Supplementary Material
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