ProfessorIanAdcock

Hisada T, Adcock IM, Nasuhara Y, Salmon M, Huang TJ, Barnes PJ, Chung KFet al., 1999, Inhibition of ozone-induced lung neutrophilia and nuclear factor-κB binding activity by vitamin A in rat, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 377, Pages: 63-68, ISSN: 0014-2999

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• Citations: 15

Nasuhara Y, Adcock IM, Catley M, Barnes PJ, Newton Ret al., 1999, Differential IκB kinase activation and IκBα degradation by Interleukin-1β and tumor necrosis factor-α in human U937 monocytic cells -: Evidence for additional regulatory steps in κB-dependent transcription, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 274, Pages: 19965-19972, ISSN: 0021-9258

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• Citations: 145

Adcock IM, Nasuhara Y, Stevens DA, Barnes PJet al., 1999, Ligand-induced differentiation of glucocorticoid receptor (GR) trans-repression and transactivation:: preferential targetting of NF-κB and lack of I-κB involvement, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 127, Pages: 1003-1011, ISSN: 0007-1188

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• Citations: 99

Hancox RJ, Stevens DA, Adcock IM, Barnes PJ, Taylor DRet al., 1999, Effects of inhaled β agonist and corticosteroid treatment on nuclear transcription factors in bronchial mucosa in asthma, THORAX, Vol: 54, Pages: 488-492, ISSN: 0040-6376

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• Citations: 33

Adcock IM, Matthews JG, 1999, New drugs for asthma, International Journal of Immunopharmacology, Vol: 21, Pages: 395-399, ISSN: 0192-0561

Overall the conference was a dynamic interface where academic clinicians and scientists from the pharmaceutical industry could meet. Each of the talks was followed by healthy discussion and in spite of the usual problems of disclosure of company information, the current position in asthma research was clearly expressed and perhaps the way forward more clearly defined.

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Caramori G, Lim S, Ciaccia A, Fabbri LM, Barnes PJ, Adcock IMet al., 1999, Gate transcription factors expression is T cells, monocytes and bronchial biopsies of normal and asthmatic subjects., AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 159, Pages: A908-A908, ISSN: 1073-449X

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• Citations: 5

Payne DNR, Adcock IM, Oates T, James A, Scallon M, Wilson NM, Barnes PJ, Bush Aet al., 1999, Airway inflammation in children with difficult asthma., AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 159, Pages: A122-A122, ISSN: 1073-449X

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• Citations: 1

Tomassoni F, Caramori G, Barnes PJ, Adcock IMet al., 1999, The role of src kinases in IL-1β-induced GM-CSF release in A549 cells., AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 159, Pages: A442-A442, ISSN: 1073-449X

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Matthews JG, Irusen E, Chung KF, Barnes PJ, Adcock IMet al., 1999, P38 mitogen activated protein kinase mediates IL-2 and 4 mediated changes in glucocorticoid receptor (GR) affinity., AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 159, Pages: A337-A337, ISSN: 1073-449X

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• Citations: 2

Ito K, Adcock I, Barnes PJ, 1999, Different histone acetylation induced by glucocorticoids and IL-1β in human epithelial cells (A549), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 159, Pages: A442-A442, ISSN: 1073-449X

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• Citations: 1

Nasuhara Y, Newton R, Barnes PJ, Adcock IMet al., 1999, Activation of NF-κB and κB-dependent transcription by IL-1β does not primarily involve IKK-dependent phosphorylation of IκBα in U937 monocytic cells., AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 159, Pages: A441-A441, ISSN: 1073-449X

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Finney PA, Belvisi MG, Barnes PJ, Donnelly LE, Adcock IM, Giembycz MAet al., 1999, <i>In vivo</i> heterologous desensitisation of pulmonary β₂-adrenoceptors in Sprague-Dawley rats after chronic treatment with salmeterol., Publisher: AMER LUNG ASSOC, Pages: A396-A396, ISSN: 1073-449X

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Matthews JG, Irusen E, Payne D, Adcock IM, Chung KF, Barnes PJet al., 1999, Affinity of dexamethasone for the glucocorticoid receptor (GR) in steroid-sensitive and steroid-insensitive asthmatics., Publisher: AMER LUNG ASSOC, Pages: A703-A703, ISSN: 1073-449X

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Caramori G, Tomassoni F, Lazzeri N, Staples K, Matthews J, Barnes PJ, Adcock IMet al., 1999, Effects of interleukin-1β and interleukin-17 on GATA transcription factors expression in human monocytes and A549 cells., AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 159, Pages: A442-A442, ISSN: 1073-449X

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Donnelly LE, Adcock IM, Lim S, Chung KF, Barnes PJet al., 1999, Effect of glucocorticosteroids on inducible nitric oxide synthase expression in human airway primary epithelial cells., Publisher: AMER LUNG ASSOC, Pages: A446-A446, ISSN: 1073-449X

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Lane SJ, Adcock IM, Richards D, Hawrylowicz C, Barnes PJ, Lee THet al., 1998, Corticosteroid-resistant bronchial asthma is associated with increased c-<i>fos</i> expression in monocytes and T lymphocytes, JOURNAL OF CLINICAL INVESTIGATION, Vol: 102, Pages: 2156-2164, ISSN: 0021-9738

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• Citations: 107

Kuitert LM, Newton R, Adcock IM, Barnes PJet al., 1998, Effect of cytokines and steroids on eicosanoid mediator expression in asthmatic and normal subjects, Thorax, Vol: 53, ISSN: 0040-6376

It is not known whether cytokines with anti-inflammatory potential can alter the expression of the eicosanoid mediators. We examined the release of PGE2, 15-HETE, LTB4 and the cysteinyl leukotrienes ('LTC4') in the presence of cytokines or corticosteroid. Mononuclear cells from asthmatic and normal subjects were incubated for 24hrs +/- IL-4, IL-10, IL-13, IL-1β (0.1-10ng/ml) or dexamethasone (10-6 - 10-9M) and the supernatant assayed for eicosanoids by RIA (PGE2, 15-HETE) or ELISA (LT). IL-1β increased PGE2 release (P<0.01) in asthmatics but not normal subjects. There was a trend to a reduction in LTB4 release with increasing concentrations of IL-4 in both asthmatic and normal subjects. IL-4 significantly reduced LTC4 release in asthmatic (p=0.01) but not in normal subjects. 15-HETE production was not altered by cytokines or steroids. Neither IL-10, IL-13, nor dexamethasone, affected eicosanoid release. The addition of arachidonic acid substrate had no effect except with IL-1ß pre-treatment, where PGE2 release was increased (p<0.01). This suggests that only IL-4 is able to down-regulate pro-inflammatory eicosanoid release in cultured mononuclear cells.

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Payne D, James A, Adcock I, Wilson N, McKenzie S, Bush Aet al., 1998, Glucocorticoid receptor function and airway inflammation in children with steroid unresponsive asthma, Thorax, Vol: 53, ISSN: 0040-6376

Evidence of abnormal glucocorticoid receptor (GR) function in peripheral blood mononuclear cells (PBMC) has been demonstrated in adults with asthma who respond poorly to treatment with steroids. The majority of patients have an acquired defect (type I steroid resistant asthma) resulting in reduced binding affinity of nuclear GR for glucocorticoid. This appears to develop secondary to persistent inflammation and is potentially reversible. We have investigated whether similar changes are seen in children and how these relate to measurements of airway inflammation. Nuclear GR binding affinity in PBMC and exhaled nitric oxide (NO), a marker of airway inflammation, were measured in 11 children (age 5-17) with poorly controlled asthma, following a two week course of prednisolone (dose 2mg/kg/day to a maximum of 40mg/day). Compared to data from adult controls, nuclear GR binding affinity was reduced hi 7/11 children, with dissociation constant values similar to, or higher than, those seen in adults with type I steroid resistant asthma. Exhaled NO was within normal limits in 5 of these 7 children following prednisolone, suggesting suppression of airway inflammation. These results demonstrate that abnormalities of GR function are present in children as young as 5 years old and that these changes may be present in the absence of persisting airway inflammation.

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Kuitert LM, Newton R, Adcock IM, Barnes PJet al., 1998, Eicosanoid mediator expression in mononuclear cells: Comparison between normal and asthmatic subjects, Thorax, Vol: 53, ISSN: 0040-6376

The eicosanoid mediators, leukotrienes (LT), prostaglandins, and 15-HETE, have diverse and sometimes opposing biological activities. We examined expression of all pathways simultaneously in normal and asthmatic subjects. Mononuclear cells were incubated for 24hrs and the supernatant assayed for PGE2and 15-HETE by RIA, LTB4 and cysteinyl LT ('LTC4') by ELISA. A 10min incubation with 3H-arachidonic acid (AA) was used to determine enzyme activity. Normal subjects released 76.9±18ng/ml PGE2 and 22.3±12ng/ml 15-HETE whereas LT release was much lower (LTB4 82±65pg/ml, LTC4 23.4±9.3pg/ml). Asthmatic subjects released 88±17.2ng/ml PGE2, 10±3.9ng/ml 15-HETE, 58±45pg/ml LTB4 and 50.5±48.7pg/ml LTC4. After AA stimulation, normal subjects released 8.0±5.2ng/ml PGE2, 7.6±3ng/ml 15-HETE, 85±36pg/ml LTB4 and 104±39pg/ml LTC4. Asthmatic subjects released 5.0±1.5ng/ml PGE2, 3.8±0.3ng/ml 15-HETE, 110±36pg/ml LTB4, 84±39pg/ml LTC4. There was no difference in eicosanoid release between asthmatic and normal subjects. Thus mononuclear cells from both asthmatic and normal subjects release predominantly PGE2 and 15-HETE, which may be bronchoprotective.

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Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KFet al., 1998, Activation and localization of transcription factor, nuclear Factor-κB, in asthma, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 158, Pages: 1585-1592, ISSN: 1073-449X

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• Citations: 362

Wright LC, Seybold J, Robichaud A, Adcock IM, Barnes PJet al., 1998, Phosphodiesterase expression in human epithelial cells, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 275, Pages: L694-L700, ISSN: 1040-0605

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• Citations: 64

Adcock IM, Matthews JG, 1998, New drugs for asthma, DRUG DISCOVERY TODAY, Vol: 3, Pages: 395-399, ISSN: 1359-6446

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• Citations: 7

Seybold J, Newton R, Wright L, Finney PA, Suttorp N, Barnes PJ, Adcock IM, Giembycz MAet al., 1998, Induction of phosphodiesterases 3B, 4A4, 4D1, 4D2, and 4D3 in jurkat T-cells and in human peripheral blood T-lymphocytes by 8-bromo-cAMP and G_s-coupled receptor agonists -: Potential role in β₂-adrenoreceptor desensitization, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 273, Pages: 20575-20588, ISSN: 0021-9258

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• Citations: 88

Adcock IM, Nasuhari Y, Barnes PJ, 1998, Role of CBP in glucocorticoid-induced gene repression., BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 26, Pages: S255-S255, ISSN: 0300-5127

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• Citations: 2

Barnes PJ, Adcock IM, 1998, Transcription factors and asthma, EUROPEAN RESPIRATORY JOURNAL, Vol: 12, Pages: 221-234, ISSN: 0903-1936

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• Citations: 227

Newton R, Hart LA, Stevens DA, Bergmann M, Donnelly LE, Adcock IM, Barnes PJet al., 1998, Effect of dexamethasone on interleukin-1β(IL-1β)-induced nuclear factor-κB (NF-κB) and κB-dependent transcription in epithelial cells, EUROPEAN JOURNAL OF BIOCHEMISTRY, Vol: 254, Pages: 81-89, ISSN: 0014-2956

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• Citations: 94

Blease K, Seybold J, Adcock IM, Hellewell PG, Burke-Gaffney Aet al., 1998, Interleukin-4 and lipopolysaccharide synergize to induce vascular cell adhesion molecule-1 expression in human lung microvascular endothelial cells, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 18, Pages: 620-630, ISSN: 1044-1549

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• Citations: 38

Seldon PM, Stevens DA, Adcock IM, O'Connor BJ, Barnes PJ, Giembycz MAet al., 1998, Albuterol does not antagonize the inhibitory effect of dexamethasone on monocyte cytokine release, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 157, Pages: 803-809, ISSN: 1073-449X

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• Citations: 16

Wright LG, Seybold J, Robichaud A, Adcock IM, Barnes PJet al., 1998, Phosphodiesterase expression in human epithelial cells, American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol: 275, ISSN: 1040-0605

Epithelial cells play a critical role in airway inflammation and have the capacity to produce many inflammatory mediators, including bioactive lipids and proinflammatory cytokines. Intracellular levels of cAMP and cGMP are important in the control of inflammatory cell function. These cyclic nucleotides are inactivated via a family of phosphodiesterase (PDE) enzymes, providing a possible site for drug intervention in chronic inflammatory conditions. We studied the expression of PDE activity in an epithelial cell line (A549) and in primary human airway epithelial cells (HAECs). We measured PDE function using specific inhibitors to identify the PDE families present and used RT-PCR to elucidate the expression of PDE isogenes. Both A549 cells and HAECs predominantly expressed PDE4 activity, with lesser PDE1, PDE3, and PDE5 activity. RT-PCR identified HSPDE4A5 and HSPDE4D3 together with HSPDE7. Inhibition of PDE4 and PDE3 reduced secretion by these cells. Epithelial PDE may be an important target for PDE4 inhibitors in the development of the control of asthmatic inflammation, particularly when delivered via the inhaled route.

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• Citations: 74

Seldon PM, Stevens DA, Adcock IM, O'Connor BJ, Barnes PJ, Giembycz MAet al., 1998, Albuterol does not antagonize the inhibitory effect of dexamethasone on monocyte cytokine release, American Journal of Respiratory and Critical Care Medicine, Vol: 157, Pages: 803-809, ISSN: 1073-449X

β2-Adrenoceptor agonists given by the inhaled route are the most effective bronchodilators known, yet high doses of these drugs may be associated with an increase in asthma mortality and morbidity. One theory for this paradox is that chronic use of β2-adrenoceptor agonists compromises the antiinflammatory action of glucocorticosteroids. This hypothesis derives from the ability of albuterol and fenoterol to inhibit the interaction of the glucocorticosteroid receptor (GR) with proinflammatory transcriptional activators acting on the promoter region of certain target genes that encode cytokines such as tumor necrosis factor-α (TNFα) and granulocyte/macrophage colony-stimulating factor (GM-CSF). However, the functional relevance of these results has not been formally investigated. We have tested the hypothesis that albuterol reduces the ability of dexamethasone to inhibit the generation of TNFα and GM-CSF from lipopolysaccharide (LPS)-stimulated human monocytes. Pretreatment of human monocytes with albuterol (1 and 100 μM) for 5 and for 180 min inhibited maximally TNFα generation by approximately 25%. However, regardless of the concentration of albuterol, or the time of preincubation, the inhibitory effect of dexamethasone was not significantly affected with respect to the EC50 or the maximal effect produced. Qualitatively identical data were obtained when GM-CSF release was used as an index of monocyte activation. We conclude that high concentrations of albuterol do not compromise the ability of dexamethasone to suppress the Generation of TNFα and GM-CSF from LPS-stimulated human monocytes.

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• Citations: 16