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Neutrophils from asthmatics exhibit diminished responsiveness to 2-chloroadenosine which is reversed by theophylline

Evidence for a cyclic-AMP-independent pathway on human neutrophils

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Abstract

We have shown previously that neutrophils (PMNs) from patients with asthma have a more potent stimulated respiratory burst than normals and that their respiratory burst is significantly less suppressed with exposure to 2-chloroadenosine (2-CADO). The present studies investigated the basis of this defect in responsiveness to 2-CADO. PMNs obtained from asthmatics either not on theophylline (minus theophylline) or taking theophylline (plus theophylline) generated significantly more superoxide in response to 2×10−8 M FMLP (2.08±0.36 nmol/5×105 PMNs (minus theophylline) (P<0.01 compared to controls) vs. 2.16±0.44 (plus theophylline) (P<0.01) as compared to controls (1.05±0.17 nmol). In the presence of FMLP (2×10−8 M), PMNs from the minus theophylline cohort had less 2-CADO (10−6 M) -mediated suppression of superoxide generation as compared to controls (38.3±3.8% vs. 67±3.8%; (P<0.001). The plus theophylline group exhibited suppression values similar to controls (64.5±7.2%). Theophylline, in the presence of a physiological concentration of 2-CADO (0.1μM) accentuated the suppression of the respiratory burnt in normals (74.1±5.9%, 80.1±4.9% (P<0.02) and 84.7±3.8% (P<0.02) at 0, 10, and 100μM, respectively). PMNs from asthmatics not taking theophylline demonstrated suppression values of 46.2±6%, 53.8±6.6% (P=NS), and 63.2±7.1% (P<0.01), respectively. Resting PMNs from normal controls generated 0.97±0.20 pmol cAMP/107 cells compared to 2.83±0.75 pmol in the pressnce of 0.1μM 2-CADO. The combination of 2-CADO and theophylline (10–100μM) produced cAMP concentrations not significantly different from that observed with 2-CADO alone. These findings support the existence of a novel cAMP-independent adenosine receptor in PMNs. The specific binding of 10−8 M3H-labeled 2-CADO (in Δ cpm) was 10,358 ± 1502 (P < 0.001 compared to controls), 5468 ± 843 (NS compared to controls), and 3751 ± 477 in the plus theophylline group, minus theophylline group, and controls, respectively. Such up-regulation of specific binding may represent the effects of theophylline as shown by the specific binding of [3H]2-CADO in PMNs from normal controls exposed to 10 μM theophylline for 30 min (6013 ± 969) compared to unexposed PMNs (3768 ± 656; P < 0.05). These data support an antiinflammatory mechanism of action for theophylline in the therapy of asthma and suggest that this may occur through potentiation of the antiinflammatory mediator adenosine.

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Authors and Affiliations

  1. Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, University of Colorado Health Science Center, 1409 Jackson Street, 80206, Denver, Colorado

    Bobby Z. Joseph, Andrew M. Sustiel & Larry Borish

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This research was supported by NIH grants AI24843 and AI24848.

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Joseph, B.Z., Sustiel, A.M. & Borish, L. Neutrophils from asthmatics exhibit diminished responsiveness to 2-chloroadenosine which is reversed by theophylline. Inflammation 16, 101–116 (1992). https://doi.org/10.1007/BF00918951

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