Publications
69 results found
Alexander LEC, Akong-Moore K, Feldstein S, et al., 2013, Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function, JOURNAL OF MOLECULAR MEDICINE-JMM, Vol: 91, Pages: 637-644, ISSN: 0946-2716
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- Citations: 40
Porter L, Farahi N, Cowburn AS, et al., 2013, Effects of hypoxia on neutrophil apoptosis, efferocytosis and sensitivity to glucocorticosteroids, Publisher: WILEY-BLACKWELL, Pages: 6-7, ISSN: 0014-2972
Fiddler CA, Murphy G, Cowburn AS, et al., 2012, THE AMINOPEPTIDASE CD13 REGULATES HOMOTYPIC AGGREGATION OF NEUTROPHILS, Winter Meeting of the British-Thoracic-Society 2012, Publisher: BMJ PUBLISHING GROUP, Pages: A28-A29, ISSN: 0040-6376
Reaves M, Storisteanu D, Wills M, et al., 2012, HUMAN CYTOMEGALOVIRUS BINDING TO NEUTROPHILS TRIGGERS A PRO-SURVIVAL SECRETOME THAT MODULATES MONOCYTE MIGRATION, ACTIVATION AND PHENOTYPE, Winter Meeting of the British-Thoracic-Society 2012, Publisher: BMJ PUBLISHING GROUP, Pages: A177-A177, ISSN: 0040-6376
Porter L, Cowburn AS, Farahi N, et al., 2012, EFFECTS OF HYPOXIA ON EOSINOPHIL APOPTOSIS, EFFEROCYTOSIS AND SENSITIVITY TO GLUCOCORTICOSTEROIDS, Winter Meeting of the British-Thoracic-Society 2012, Publisher: BMJ PUBLISHING GROUP, Pages: A57-A57, ISSN: 0040-6376
Juss JK, Hayhoe RP, Owen CE, et al., 2012, Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival, PLoS One, Vol: 7, Pages: 1-15, ISSN: 1932-6203
We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δKOγKO or p110γKO). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110δKOγKO mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway.
White JF, Cowburn AS, Summers C, et al., 2011, The influence of the spleen on neutrophil apoptosis in vivo, Journal of Cell Death, Vol: 2011, Pages: 1-5
In contrast to radiolabelled erythrocytes and platelets, radiolabelled neutrophils leave the circulating blood in an exponential manner, indicating random rather than age-dependent removal. Neutrophils transit the spleen with a range of residence times that are log normally distributed. We hypothesized that neutrophils are conditioned to undergo apoptosis to an extent that depends on their intrasplenic residence time and that this provides an explanation for the random removal of these cells from blood. Splenic venous and peripheral arterial blood was sampled simultaneously during abdominal surgery in four patients and age-dependent apoptosis assessed in whole blood using annexin V/PI staining. Apoptosis increased after 4 and 20h ex-vivo incubation and was invariably higher in splenic venous vs arterial neutrophils. Transit through the spleen appears to promote neutrophil apoptosis, with subsequent high efficiency clearance by the liver. This may explain the mechanism underlying the random removal of neutrophils from the blood. © the author(s).
Cowburn AS, Summers C, Dunmore BJ, et al., 2011, Granulocyte/Macrophage Colony-Stimulating Factor Causes a Paradoxical Increase in the BH3-Only Pro-Apoptotic Protein Bim in Human Neutrophils, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 44, Pages: 879-887, ISSN: 1044-1549
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- Citations: 31
Farahi N, Uller L, Juss JK, et al., 2011, Effects of the cyclin-dependent kinase inhibitor R-roscovitine on eosinophil survival and clearance, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 41, Pages: 673-687, ISSN: 0954-7894
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- Citations: 21
Roe MFE, Bloxham DM, Cowburn AS, et al., 2011, Changes in helper lymphocyte chemokine receptor expression and elevation of IP-10 during acute respiratory syncytial virus infection in infants, PEDIATRIC ALLERGY AND IMMUNOLOGY, Vol: 22, Pages: 229-234, ISSN: 0905-6157
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- Citations: 19
McGovern NN, Cowburn AS, Porter L, et al., 2011, Hypoxia Selectively Inhibits Respiratory Burst Activity and Killing of <i>Staphylococcus aureus</i> in Human Neutrophils, JOURNAL OF IMMUNOLOGY, Vol: 186, Pages: 453-463, ISSN: 0022-1767
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- Citations: 103
Farahi N, Uller L, Juss JK, et al., 2010, EFFECTS OF THE CYCLIN-DEPENDENT KINASE INHIBITOR R-ROSCOVITINE ON EOSINOPHIL SURVIVAL AND CLEARANCE, British-Thoracic-Society-Winter-Meeting 2010, Publisher: B M J PUBLISHING GROUP, Pages: A18-A18, ISSN: 0040-6376
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- Citations: 1
Brode S, Farahi N, Cowburn AS, et al., 2010, Interleukin-5 inhibits glucocorticoid-mediated apoptosis in human eosinophils, THORAX, Vol: 65, Pages: 1116-1117, ISSN: 0040-6376
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- Citations: 17
McKeon DJ, Cadwallader KA, Idris S, et al., 2010, Cystic fibrosis neutrophils have normal intrinsic reactive oxygen species generation, EUROPEAN RESPIRATORY JOURNAL, Vol: 35, Pages: 1264-1272, ISSN: 0903-1936
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- Citations: 33
Brode S, Farahi N, Cowburn AS, et al., 2009, INTERLEUKIN-5 INDUCES GLUCOCORTICOID RESISTANCE IN HUMAN EOSINOPHILS, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A42-A42, ISSN: 0040-6376
Condliffe AM, Cowburn AS, Chilvers ER, 2009, Neutrophils: Biological Properties and Role in Health and Allergic Diseases, Allergy and Allergic Diseases, Second Edition, Pages: 295-319, ISBN: 9781405157209
The polymorphonuclear leukocyte or neutrophil is the most abundant yet shortest lived of all myeloid cells. It develops and matures in the bone marrow under the influence of interleukin (IL)-3, granulocyte colony-stimulating factor (GCSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) and is released into the circulating pool to fulfil its normal and vital functions of bacterial and fungal surveillance and phagocytic removal. In recent years, molecular steps underlying bone marrow release, neutrophil migration, pathogen recognition, phagocytosis, degranulation, activation of NADPH oxidase, and the precise mechanisms underlying pathogen destruction have been elucidated. Neutrophils are remarkably well adapted to survive and function in highly acidic and hypoxic environments such as an abscess cavity or infected joint space, in part through their capacity for anaerobic glycolytic metabolism. The numerical dominance, migratory potential, and highly destructive capacity of these cells results in their frequent and pathogenic role in many inflammatory diseases, the most notable being acute respiratory distress syndrome (ARDS), inflammatory bowel disease, and rheumatoid arthritis. In addition, a more prominent role has recently been attributed to the neutrophil in allergic diseases, in particular in the development of asthma exacerbations and in steroid-resistant asthma. New studies have also highlighted additional functions for the neutrophil, including the production of neutrophil extracellular traps comprising granule proteins and chromatin designed to trap and neutralize extracellular bacteria, a role in early antigen processing and transfer to dendritic cells, and a role in facilitating the migration of other inflammatory cells such as the eosinophil. In vivo trafficking studies using 111In- and 99mTclabeled autologous neutrophils have now defined the major role of the spleen, liver, and bone marrow in human neutrophil margination, and complementary s
Print C, Cook SJ, Cowburn AS, et al., 2008, TRANSCRIPTIONAL REGULATION OF BCL-2 FAMILY MEMBERS IN HUMAN NEUTROPHILS BY GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR AND TUMOUR NECROSIS FACTOR ALPHA, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A46-A46, ISSN: 0040-6376
Cowburn AS, Condliffe AM, Farahi N, et al., 2008, Advances in neutrophil biology - Clinical implications, CHEST, Vol: 134, Pages: 606-612, ISSN: 0012-3692
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- Citations: 135
McKeon DJ, Condliffe AM, Cowburn AS, et al., 2008, Prolonged survival of neutrophils from patients with ΔF508 CFTR mutations, THORAX, Vol: 63, Pages: 660-661, ISSN: 0040-6376
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- Citations: 51
Farahi N, Cowburn AS, Upton PD, et al., 2007, Eotaxin-1/CC chemokine ligand 11: A novel eosinophil survival factor secreted by human pulmonary artery endothelial cells, JOURNAL OF IMMUNOLOGY, Vol: 179, Pages: 1264-1273, ISSN: 0022-1767
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- Citations: 28
Walmsley SR, Cowburn AS, Clatworthy MR, et al., 2006, Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis, BLOOD, Vol: 108, Pages: 3176-3178, ISSN: 0006-4971
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- Citations: 55
Cowburn AS, Sobolewski A, Reedo BJ, et al., 2006, Aminopeptidase N (CD13) regulates tumor necrosis factor-α-induced apoptosis in human neutrophils, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 281, Pages: 12458-12467, ISSN: 0021-9258
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- Citations: 29
Cowburn AS, White JF, Deighton J, et al., 2005, z-VAD-fmk augmentation of TNFα-stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species, BLOOD, Vol: 105, Pages: 2970-2972, ISSN: 0006-4971
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- Citations: 44
Walmsley SR, Print C, Farahi N, et al., 2005, Hypoxia-induced neutrophil survival is mediated by HIF-1 alpha-dependent NF-kappa B activity, Journal of Experimental Medicine, Vol: 201, Pages: 105-115, ISSN: 0022-1007
Neutrophils are key effector cells of the innate immune response and are required to migrate and function within adverse microenvironmental conditions. These inflammatory sites are characterized by low levels of oxygen and glucose and high levels of reductive metabolites. A major regulator of neutrophil functional longevity is the ability of these cells to undergo apoptosis. We examined the mechanism by which hypoxia causes an inhibition of neutrophil apoptosis in human and murine neutrophils. We show that neutrophils possess the hypoxia-inducible factor (HIF)-1α and factor inhibiting HIF (FIH) hydroxylase oxygen-sensing pathway and using HIF-1α–deficient myeloid cells demonstrate that HIF-1α is directly involved in regulating neutrophil survival in hypoxia. Gene array, TaqMan PCR, Western blotting, and oligonucleotide binding assays identify NF-κB as a novel hypoxia-regulated and HIF-dependent target, with inhibition of NF-κB by gliotoxin or parthenolide resulting in the abrogation of hypoxic survival. In addition, we identify macrophage inflammatory protein-1β as a novel hypoxia-induced neutrophil survival factor.
Walmsley SR, Eaton V, Paterson J, et al., 2005, Neutrophil expression of the HIF oxygen sensing pathway and regulation of constitutive neutrophil apoptosis, 38th Annual Meeting of the Society-for-Leukocyte-Biology, Publisher: FEDERATION AMER SOC EXP BIOL, Pages: 39-39, ISSN: 0741-5400
Farahi N, Cowburn AS, Rossi AG, et al., 2004, Eating their way out of trouble: selective uptake of apoptotic eosinophils by bronchial epithelial cells, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 34, Pages: 1503-1506, ISSN: 0954-7894
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- Citations: 3
Cadwallader KA, Uddin M, Condliffe AM, et al., 2004, Effect of priming on activation and localization of phospholipase D-1 in human neutrophils, EUROPEAN JOURNAL OF BIOCHEMISTRY, Vol: 271, Pages: 2755-2764, ISSN: 0014-2956
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- Citations: 21
Walmsley SR, Cowburn AS, Sobolewski A, et al., 2004, Characterization of the survival effect of tumour necrosis factor-α in human neutrophils, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 32, Pages: 456-460, ISSN: 0300-5127
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- Citations: 21
Cowburn AS, Deighton J, Walmsey SR, et al., 2004, The survival effect of TNF-α in human neutrophils is mediated via NF-κB-dependent IL-8 release, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 34, Pages: 1733-1743, ISSN: 0014-2980
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- Citations: 85
Walmsley SR, Cowburn AS, Johnson N, et al., 2003, Effects of hypoxia on transcriptional regulation in neutrophils, Winter Meeting of the British Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: 31-31, ISSN: 0040-6376
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