Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eosinophils may play a critical role in asthma and bronchial hyperresponsiveness, yet the effect of theophylline on their function is not certain. We have examined the effects of theophylline on opsonized zymosan-induced superoxide anion (O2-) release from guinea pig eosinophils harvested from the peritoneal cavity and from human eosinophils obtained by differential centrifugation of blood from patients with peripheral eosinophilia. Theophylline at high concentration (10(-3) M) inhibited O2- release by 27.6 +/- 9.4% (mean +/- SEM, p less than 0.05), whereas at clinically relevant concentrations (10(-6) and 10(-5) M), it significantly potentiated this by 26.8 +/- 9.9% (p less than 0.05) and 36.9 +/- 6.3% (p less than 0.01), respectively. 8-phenyltheophylline (10(-7) to 10(-3) M), which like theophylline inhibits adenosine receptors but does not inhibit phosphodiesterase activity, produced potentiation at all concentrations. Preincubation of eosinophils with adenosine deaminase (0.1 U/ml) enhanced O2- release by 72.4 +/- 15.2% (p less than 0.01), whereas addition of adenosine (3 x 10(-8) to 10(-6) M) reversed the potentiation induced by theophylline (10(-5) M) in a concentration-dependent manner. Inhibition was greater with the A2-selective analog N-ethylcarboxamide adenosine than the A1-selective analog phenylisopropyladenosine, suggesting that A2-receptors are involved. In human eosinophils we have demonstrated a similar effect of theophylline and adenosine on O2- release. Our results indicate that therapeutic concentrations of theophylline may potentiate eosinophil activation in vivo by competing with circulating adenosine for eosinophil A2-receptors. This would be consistent with the lack of effect of theophylline on bronchial hyperresponsiveness, which may be related to eosinophilic inflammation.
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PMID:Effect of theophylline and adenosine on eosinophil function. 254 25

We report a 5-year-old girl with adenosine deaminase (ADA) deficiency who was asymptomatic during the first years of life. At 3 years of age, she developed chronic and recurrent sinopulmonary infections, and at 4 1/2 years of age she had one major infection with Streptococcus pneumoniae (bacteremia and septic arthritis of the hip). Immunologic evaluation at 5 years of age revealed persistent lymphopenia, decreased helper-suppressor T cell ratios, and low proliferative responses to mitogens. The IgG, IgM, and IgA levels were normal; the IgG2 level was low normal or below normal. The patient had specific antibodies against toxoids and viral antigens but failed to produce antibodies against Haemophilus influenzae type b and pneumococcal polysaccharides. Although no symptoms of allergy were present, she had persistent eosinophilia and elevated IgE levels. The patient had 0.6% of normal ADA activity in erythrocytes and approximately 1% of normal ADA activity in peripheral blood mononuclear cells. Beginning at 6 years of age, she was treated with weekly injections of polyethylene glycol-modified bovine ADA. This treatment was well tolerated and effectively reversed the biochemical consequence of ADA deficiency. Concomitantly, she improved clinically and her T lymphocyte numbers and blastogenic responses to mitogens in vitro became normal. The late onset of clinical symptoms and relatively benign clinical course in this patient emphasize the need to consider ADA deficiency in a broad spectrum of immunodeficient children.
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PMID:Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase. 326 Sep 44

Genetic deficiency of adenosine deaminase (ADA) results in varying degrees of immunodeficiency, including neonatal onset severe combined immunodeficiency (ADA- SCID) and milder, later onset immunodeficiency. We have determined the molecular basis of disease in a child from a consanguineous mating with ADA- SCID of clinically and biochemically reduced severity, diagnosed at 15 months of age and characterized by retention of more immunologic function than is typical of the fulminant neonatal onset type. The course was notable for an early predominance of bacterial infections and eosinophilia. In contrast to its absence in most ADA- SCIDs, residual ADA activity (1-2% of normal) could be detected in EBV-transformed B cells. Consistent with the increased residual ADA, excretion of the substrate deoxyadenosine and accumulation of the toxic metabolite deoxyATP were less than seen in ADA- SCID patients with fulminant disease. Sequence analysis of cDNA revealed a G853C transversion, predicting a substitution of proline for arginine at codon 253 (Arg253Pro). The parents were heterozygous and the child was homozygous for the mutation, as shown by sequence analysis of amplified genomic DNA. Transient expression of mutant cDNA in Cos cells revealed an electrophoretically abnormal, more negatively charged ADA with 1-2% of normal activity. These observations are consistent with replacement of positively charged arginine by proline, the lower accumulation of toxic metabolites, and the milder phenotype. By contrast, transient expression of a Gly216Arg mutant cDNA, associated, when homozygous, with neonatal onset ADA-SCID, did not reveal ADA activity. Mutations such as Arg253Pro, which retain residual activity of monomeric ADA, should be dominant for ameliorating the phenotype in patients carrying two different allelic mutations. Identification of additional similar mutations may be significant in evaluating the goals for and efficacy of current trials of gene and gene product replacement.
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PMID:Severe combined immunodeficiency of reduced severity due to homozygosity for an adenosine deaminase missense mutation (Arg253Pro). 825 46

Adenosine has been implicated as a modulator of inflammatory processes central to asthma. However, the molecular mechanisms involved are poorly understood. We used Atlas mouse cDNA arrays to analyze differential gene expression in association with lung inflammation resulting from elevated adenosine in adenosine deaminase (ADA)-deficient mice. We report that of the 1,176 genes on the array, the expression patterns of 280 genes were consistently altered. Of these genes, the steady-state levels of 93 genes were upregulated and 29 were downregulated. We also show that lowering adenosine levels with ADA enzyme therapy has striking effects on gene expression that may be associated with resolution of pulmonary eosinophilia. In addition, we confirmed the nucleic acid and protein expression of vascular endothelial growth factor and monocyte chemoattractant protein-3, two candidate genes that may be regulated by adenosine. In conclusion, high-throughput profiling of gene expression by cDNA array hybridization has provided an overview of critical regulatory genes involved in airway inflammation in ADA-deficient mice. These mice will serve as a useful in vivo model for characterizing molecular mechanisms of adenosine-mediated lung damage.
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PMID:Gene expression profiling in inflammatory airway disease associated with elevated adenosine. 1179 19

Mice rendered adenosine deaminase-deficient manifest an 'asthma' phenotype in the lungs that includes mast cell degranulation, eosinophilia, mucus hypersecretion and bronchial hyperresponsiveness. These changes can be reversed by enzyme therapy with adenosine deaminase, and attenuated by theophylline. Theophylline also blocks the pro-inflammatory effects of adenosine in allergen-challenged mice. Adenosine A(2A) receptors are an essential part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses. In recent clinical studies, increases in plasma adenosine have been shown to accompany exercise-induced asthma, and adenosine concentrations in exhaled breath condensate are increased in asthmatics. These new data provide support for a key role for adenosine in asthma, which has become increasingly persuasive in recent years. The evidence is now convincing, and the time has come for the asthma community to give its full support to the design and evaluation of molecules that mimic or block the biological effects of adenosine as potential novel therapeutics for this condition.
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PMID:The case for a role for adenosine in asthma: almost convincing? 1281 Jan 90

Adenosine signaling has been implicated in chronic lung diseases such as asthma and chronic obstructive pulmonary disease; however, the specific roles of the various adenosine receptors in processes central to these disorders are not well understood. In this study, we have investigated the role(s) of the A(3) adenosine receptor in adenosine-dependent pulmonary inflammation observed in adenosine deaminase (ADA)-deficient mice. The A(3) receptor (A(3)R) was found to be expressed in eosinophils and mucus-producing cells in the airways of ADA-deficient mice. Treatment of ADA-deficient mice with MRS 1523, a selective A(3)R antagonist, prevented airway eosinophilia and mucus production. Similar findings were seen in the lungs of ADA/A(3) double knockout mice. Although eosinophils were decreased in the airways of ADA-deficient mice following antagonism or removal of the A(3)R, elevations in circulating and lung interstitial eosinophils persisted, suggesting signaling through the A(3)R is needed for the migration of eosinophils into the airways. These findings identify an important role for the A(3)R in regulating lung eosinophilia and mucus production in an environment of elevated adenosine.
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PMID:A3 adenosine receptor signaling contributes to airway inflammation and mucus production in adenosine deaminase-deficient mice. 1524 Jul 34

It has been known for a long time that inhaled adenosine-monophosphate (AMP) induces airway obstruction in asthmatic patients, but not in healthy subjects. The mechanism of AMP is indirect and occurs via its decay product, adenosine. It stimulates mast cells through its low-affinity receptor A2B to release histamine, which ultimately leads to smooth muscle contraction. This feature of adenosine reveals its pro-inflammatory function, which may play important role in asthma. Indeed, mice lacking adenosine deaminase (ADA), an enzyme which decomposes adenosine, develop asthma-like disorder with elevated IgE, eosinophilia and airway hyperresponsiveness. Human studies showed elevated adenosine levels in bronchoalveolar lavage and exhaled breath condensate of asthmatics as compared to healthy people. Furthermore, certain human ADA phenotypes are associated with prevalence of asthma. These data suggest a protective role for ADA and a pro-inflammatory function for adenosine in asthma. The role of adenosine in inflammatory processes, however, is not unequivocal. Some in vitro studies showed that adenosine binding to its high-affinity receptor A2A results in inhibition of leukotriene synthesis or function of adhesion molecules. It is possible that the concentration of adenosine in lung tissues determines whether it promotes or reduces inflammation. Adenosine has also been associated with other respiratory diseases such as fibrosis, sarcoidosis, cystic fibrosis or tuberculosis. Identification of adenosine receptor subtypes and their role in the pathomechanism of respiratory diseases may provide new therapeutical targets. This review aims to summarize the role of adenosine and adenosine receptors in asthma and other pulmonary disorders.
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PMID:Adenosine and adenosine receptors in the pathomechanism and treatment of respiratory diseases. 1847 99

Omenn syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of severe combined immunodeficiency (SCID). Similar to other patients with SCID, patients with OS present early in infancy with viral or fungal pneumonitis, chronic diarrhea, and failure to thrive. Unlike typical SCID, patients with OS have enlarged lymphoid tissue, severe erythroderma, increased IgE levels, and eosinophilia. The inflammation observed in these patients is believed to be triggered by clonally expanded T cells, which are predominantly of the T(H)2 type. These abnormal T cells, in the absence of proper regulation by other components of the immune system, secrete a host of cytokines that promote autoimmune as well as allergic inflammation. The emergence of these T-cell clones occurs in patients with hypomorphic mutations in recombination activating gene 1 or 2, but not in patients with deleterious mutations in these enzymes which render them inactive. Recently, OS was also identified in a growing list of other leaky SCIDs with mutations in RNA component of mitochondrial RNA processing endoribonuclease, adenosine deaminase, IL-2 receptor gamma, IL-7 receptor alpha, ARTEMIS, and DNA ligase 4. This new information revealed OS is a distinct inflammatory process that can be associated with genetically diverse leaky SCIDS.
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PMID:Omenn syndrome: inflammation in leaky severe combined immunodeficiency. 1899 30

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