Immunohematologic diseases.
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Anemia, Hemolytic↗
Biomedical subjects
B Z Joseph
Publications and source records attributed to B Z Joseph.
Neutrophils from asthmatics exhibit diminished responsiveness to 2-chloroadenosine which is reversed by theophylline. Evidence for a cyclic-AMP-independent pathway on human neutrophils.
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 x 10(-8) M FMLP (2.08 +/- 0.36 nmol/5 x 10(5) PMNs (minus theophylline) (P less than 0.01 compared to controls) vs. 2.16 +/- 0.44 (plus theophylline) (P less than 0.01) as compared to controls (1.05 +/- 0.17 nmol). In the presence of FMLP (2 x 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. 67.1 +/- 3.8%; (P less than 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 (0.1 microM) accentuated the suppression of the respiratory burst in normals (74.1 +/- 5.9%, 80.1 +/- 4.9% (P less than 0.02) and 84.7 +/- 3.8% (P less than 0.02) at 0, 10, and 100 microM, 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 less than 0.01), respectively. Resting PMNs from normal controls generated 0.97 +/- 0.20 pmol cAMP/10(7) cells compared to 2.83 +/- 0.75 pmol in the presence of 0.1 microM 2-CADO. The combination of 2-CADO and theophylline (10-100 microM) 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)M 3H-labeled 2-CADO (in delta cpm) was 10,358 +/- 1502 (P less than 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 microM theophylline for 30 min (6013 +/- 969) compared to unexposed PMNs (3768 +/- 656; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
2-Chloroadenosine↗
Inflammation and the allergic response.
The atopic diseases--allergic rhinitis, asthma, and atopic dermatitis--are chronic inflammatory diseases characterized by an exacerbating and remitting course and can only rarely be associated causally with allergen exposure. The challenge to ascribe an allergic basis to these diseases is derived from the apparent inability to reconcile these chronic inflammatory features with a process thought to be initiated by the rapid release of mediators after the interaction of allergen with IgE-coated mast cells. The traditional understanding has been that mast cell activation results in the release of a series of preformed and rapidly synthesized substances that mediate the immediate onset of vasodilatation, vascular leakage, smooth muscle contraction, and irritant nerve receptor stimulation. These mediators, however, are rapidly degraded and are not thought to be associated with a significant inflammatory component. Recent studies, however, have established that the interaction of allergen with the immune system is, in fact, far more complex (Fig. 4). In addition to mast cell activation, allergen can interact with and activate T-lymphocytes and mononuclear phagocytic cells, leading to the secretion of cytokines and other inflammatory substances. Furthermore, the interaction of allergen with the mast cell may be far more complex, with the potential to stimulate the delayed release of newly synthesized cytokines. The interaction of allergen with the immune system also promotes the secondary release of inflammatory neuropeptides. Thus, the known spectrum of mediators released after allergen exposure has vastly been expanded. These include numerous still uncharacterized chemotactic and activating peptides; eicosanoids such as 5-HETE, 12-HETE, and leukotriene B4; platelet-activating factor; several proteases; neuropeptides and, most importantly, the cytokines. These mediators recruit and activate neutrophils, monocytes, basophils, and eosinophils, attract additional lymphocytes and mononuclear phagocytic cells, and induce mast cell proliferation with further mast cell degranulation. A vicious cycle subsequently develops, with further inflammation and tissue destruction. Thus, the interaction of allergen with the immune system has become a complex cascade capable of producing the chronic inflammatory changes characteristic of allergic diseases.
Cytokines↗