Effect of CGS21680, an adenosine A2A receptor agonist, in murine models of asthma and chronic obstructive pulmonary disease

Alexandre Trifilieff, Olivier Bonneau, Daniel Wyss, Stephane Ferretti, Clare Blaydon, Christopher S. Stevenson. Novartis Institute for BioMedicale Research, Horsham, UK.

Activation of the adenosine A2A receptor has been postulated as a possible approach to the treatment of asthma and chronic obstructive pulmonary disease (COPD). In this report, we have studied the anti-inflammatory properties of the reference A2A receptor agonist, CGS21680, given intranasally, in murine models of asthma and COPD.

To model asthma, ovalbumin (OVA) sensitised mice were acutely (Trifilieff et al., 2000) or repeatedly ( Cieslewiczet al., 1999) challenged with an aerosol of OVA. Lung function changes (Penh) were measured using whole body plethysmography. The OVA-induced bronchoconstriction and airway reactivity to aerosolised methacholine were measured 4 and 24 h after the last OVA challenge, respectively. To model COPD, mice were either challenged intranasally with lipopolysaccharide (LPS) (Corteling et al., 2002) or exposed to cigarette smoke on 3 consecutive days (Stevenson et al., 2005). Inflammatory cell numbers, neutrophil elastase activity (Corteling et al., 2002) and mucin levels (Stevenson et al., 2005) were measured in the bronchoalveolar lavage fluids (BALF). Female BALB/c (20 g) mice were used. Data are expressed as means ± s.e. mean (n = 8) and statistical significance (P < 0.05) was determined using the Mann-Whitney test.

CGS21680, given 30 min before and 3 h after OVA challenge, had no effect on the airway hyperreactivity to methacholine but inhibited the increase in eosinophil, neutrophil and lymphocyte numbers in BALF with ED50 values of 21 ± 5, 16 ± 3 and 19 ± 2 m g kg-1, respectively. In the repeated OVA challenge model, when given twice daily starting 30 min before the last challenge, CGS21680 did not inhibit the OVA-induced bronchoconstriction or the airway hyperreactivity to methacholine. However, the mice treated with 100 μg kg-1 of CGS21680 had an increased baseline Penh value (678 ± 111 and 271 ± 22, respectively) and increased airway sensitivity to methacholine. CGS21680 inhibited the OVA-induced increase in inflammatory cells in BALF (ED50 in m g kg-1; eosinophils, 100 ± 22; neutrophils, 82 ± 2, macrophages, 31 ± 6; lymphocytes, 17 ± 5) but had no statistically significant effect on the increase in mucus levels (in u ml-1; OVA, 10 ± 2; 10 μg kg-1, 6 ± 1; 100 μg kg-1, 6 ± 2). When given 30 min before and 6 h after the LPS challenge, CGS21680 had no effect on the changes in neutrophil and macrophage numbers observed at 3 or 24 h post LPS challenge. Similarly, the increase in TNF-α , MIP-2 and KC levels observed 3 h post LPS challenge were not affected by the compound. In contrast, CGS21680 potently inhibited the neutrophil elastase levels, measured at 24 h post challenge (in ng 105 neutrophil-1; LPS, 85 ± 9; 10 μg kg-1, 10 ± 1; 100 μg kg-1, 2.3 ± 0.1). CGS21680 (100 μg kg-1), given intranasally 30 min before and 6 h after the two last cigarette smoke exposures significantly reverse the decrease in macrophage numbers observed one day after the last challenge (in 105 cell ml-1; air, 1.1 ± 0.2; smoke, 0.8 ± 0.1; CGS21680, 1.3 ± 0.2). Taken together, these results suggest that activation of the adenosine A 2areceptor could have beneficial effects by inhibiting inflammatory cell influx and down-regulating inflammatory cell activation in asthma and COPD.

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