Publications
415 results found
Kirkby NS, Lundberg MH, Chan MV, et al., 2013, Blockade of the purinergic P2Y<sub>12</sub> receptor greatly increases the platelet inhibitory actions of nitric oxide, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 15782-15787, ISSN: 0027-8424
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- Citations: 48
Reed DM, George PM, Francis CM, et al., 2013, A novel and translatable cell assay for the study of vascular signalling in pulmonary hypertension., Congress of the European Respiratory Society 2013
Kirkby NS, Zaiss AK, Wright WR, et al., 2013, Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies, Biochemical and Biophysical Research Communications, Vol: 438, Pages: 249-256, ISSN: 0006-291X
Cyclooxygenase 2 (COX)-2 is induced by bacterial and viral infections and has complex, poorly understood roles in anti-pathogen immunity. Here, we use a knock-in luciferase reporter model to image Cox2 expression across a range of tissues in mice following treatment with the either the prototypical bacterial pathogen-associated molecular pattern (PAMP), LPS, which activates Toll-like receptor (TLR)4, or with poly(I:C), a viral PAMP, which activates TLR3. LPS induced Cox2 expression in all tissues examined. In contrast, poly(I:C) elicited a milder response, limited to a subset of tissues. A panel of cytokines and interferons was measured in plasma of wild-type, Cox1−/− and Cox2−/− mice treated with LPS, poly(I:C), MALP2 (TLR2/6), Pam3CSK4 (TLR2/1), R-848 (TLR7/8) or CpG ODN (TLR9), to establish whether/how each COX isoform modulates specific PAMP/TLR responses. Only LPS induced notable loss of condition in mice (inactivity, hunching, piloerection). However, all TLR agonists produced cytokine responses, many of which were modulated in specific fashions by Cox1 or Cox2 gene deletion. Notably we observed opposing effects of Cox2 gene deletion on the responses to the bacterial PAMP, LPS, and the viral PAMP, poly(I:C), consistent with the differing abilities of the PAMPs to induce Cox2 expression. Cox2 gene deletion limited the plasma IL-1β and interferon-γ responses and hypothermia produced by LPS. In contrast, in response to poly(I:C), Cox2−/− mice exhibited enhanced plasma interferon (IFNα,β,γ,λ) and related cytokine responses (IP-10, IL-12). These observations suggest that a COX-2 selective inhibitor, given early in infection, may enhance and/or prolong endogenous interferon responses, and thereby increase anti-viral immunity.
George PM, Mitchell JA, 2013, Evidence that pulmonary vascular pathology explains the decline in lung function associated with interferon α based therapies for chronic hepatitis C virus., Journal of Viral Hepatitis, Vol: 20
Kirkby NS, Zaiss AK, Urquhart P, et al., 2013, LC-MS/MS confirms that COX-1 drives vascular prostacyclin whilst gene expression pattern reveals non-vascular sites of COX-2 expression, PLoS ONE, Vol: 8, ISSN: 1932-6203
Rauzi F, Kirkby NS, Edin M, et al., 2013, PLATELET COX-1 SUPPORTS THE PRODUCTION OF BOTH PROSTANOIDS AND HETES, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A114-A114, ISSN: 1355-6037
Lundberg MH, Kirkby NS, Mitchell JA, et al., 2013, P2Y12 INHIBITION GREATLY POTENTIATES THE ANTI-PLATELET EFFECTS OF PROSTACYCLIN AND NITRIC OXIDE, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A137-U630, ISSN: 1355-6037
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- Citations: 1
Reed DM, Foldes G, Gashaw HH, et al., 2013, Conditioning of human embryonic stem cell-derived endothelial cells with PBMCs confers TLR4 sensing in co-culture conditions, Experimental Biology 2013
Reed DM, Kirkby NS, Foldes G, et al., 2013, Prostacyclin release pathways in stem cell derived endothelial cells, Experimental Biology 2013
Kirkby NS, Zaiss AK, Urquhart P, et al., 2013, <i>Cox2</i> reporter gene expression and prostacylin mass spectrometry confirm vascular COX-1 dominance for prostacyclin production, Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB), Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638
Wright W, Mackenzie L, Kirkby NS, et al., 2013, Nitric oxide-dependent vasodilation is compromised in isolated pulmonary arteries from COX knockout mice, Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB), Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638
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- Citations: 1
Willeit P, Zampetaki A, Dudek K, et al., 2013, Circulating MicroRNAs as Novel Biomarkers for Platelet Activation, CIRCULATION RESEARCH, Vol: 112, Pages: 595-+, ISSN: 0009-7330
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- Citations: 316
Kirkby NS, Lundberg MH, Harrington LS, et al., 2013, Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system (vol 109, pg 17597, 2012), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 1561-1561, ISSN: 0027-8424
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- Citations: 1
Mitchell JA, Warner TD, 2013, Reply to Ricciotti et al.: Evidence for vascular COX isoforms, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: E184-E184, ISSN: 0027-8424
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- Citations: 4
Kojonazarov B, Luitel H, Sydykov A, et al., 2013, The Effects Pparβ/δ Agonist Gw0742 On Right Heart Hypertrophy And Function, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
Bailey L, Moreno L, Manigold T, et al., 2012, A simple whole blood bioassay detects cytokine responses to anti-CD28<sub>SA</sub> and anti-CD52 antibodies, JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, Vol: 68, Pages: 231-239, ISSN: 1056-8719
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- Citations: 11
Badiger R, Mitchell JA, Gashaw H, et al., 2012, Effect of Different Interferonα2 Preparations on IP10 and ET-1 Release from Human Lung Cells, PLOS ONE, Vol: 7, ISSN: 1932-6203
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- Citations: 10
Kirkby NS, Lundberg MH, Harrington LS, et al., 2012, Cyclooxygenase-1, not cyclooxygenase-2, is responsiblefor physiological production of prostacyclin in thecardiovascular system, Proceedings of the National Academy of Sciences of the United States of America
George PM, Cunningham ME, Galloway-Phillipps N, et al., 2012, Endothelin-1 as a mediator and potential biomarker for interferon induced pulmonary toxicity, Pulm Circ., Vol: 4, Pages: 501-504
Wojciak-Stothard B, Zhao L, Oliver E, et al., 2012, Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia (vol 110, pg 1423, 2012), CIRCULATION RESEARCH, Vol: 111, Pages: E163-E163, ISSN: 0009-7330
Gatheral T, Reed DM, Moreno L, et al., 2012, A Key Role for the Endothelium in NOD1 Mediated Vascular Inflammation: Comparison to TLR4 Responses, PLOS ONE, Vol: 7, ISSN: 1932-6203
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- Citations: 37
George PM, Badiger R, Shao D, et al., 2012, Viral Toll Like Receptor activation of pulmonary vascular smooth muscle cells results in endothelin-1 generation; relevance to pathogenesis of pulmonary arterial hypertension, Biochem Biophys Res Commun, Vol: 426, Pages: 486-491, ISSN: 1090-2104
Pulmonary arterial hypertension (PAH) is a rare but fatal condition in which raised pulmonary vascular resistance leads to right heart failure and death. Endothelin-1 is a potent endogenous vasoconstrictor, which is considered to be central to many of the events that lead to PAH, and is an important therapeutic target in the treatment of the condition. In many cases of PAH, the aetiology is unknown but inflammation is increasingly thought to play an important role and viruses have been implicated in the development of disease. The Toll Like Receptors (TLRs) play a key role in innate immune responses by initiating specific anti-bacterial and anti-viral defences in recognition of signature molecular motifs on the surface of invading pathogens. In this study, we set out to examine the expression of bacterial and viral TLRs in human pulmonary artery smooth muscle cells and to establish whether their activation could be relevant to PAH. We found that the viral TLR3 and bacterial TLRs 4 and 6 were most abundantly expressed in human pulmonary artery smooth muscle cells. Using specific TLR ligands, we found that activation of TLRs 3 and 4 resulted in IL-8 release by human pulmonary artery smooth muscle cells but that only TLR3 stimulation resulted in IP10 and endothelin-1 release. These data suggest that human pulmonary artery smooth muscle cells express significant levels of viral TLR3 and respond to its activation by releasing endothelin-1. This may have importance in understanding the association between viruses and the development of PAH.
Paul-Clark MJ, George PM, Gatheral T, et al., 2012, Pharmacology and therapeutic potential of pattern recognition receptors, Pharmacol Ther. 2012 Aug;135(2):200-15
Warner TD, Paul-Clark M, Mitchell JA, 2012, Smoking, atherothrombosis and clopidogrel, HEART, Vol: 98, Pages: 963-964, ISSN: 1355-6037
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- Citations: 4
Reed DM, Foldes G, Harding SE, et al., 2012, Stem cell derived endothelial cells for cardiovascular disease; a therapeutic perspective., British Journal of Clinical Pharmacology
Wojciak-Stothard B, Zhao L, Oliver E, et al., 2012, Role of RhoB in the Regulation of Pulmonary Endothelial and Smooth Muscle Cell Responses to Hypoxia, CIRCULATION RESEARCH, Vol: 110, Pages: 1423-+, ISSN: 0009-7330
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- Citations: 67
Warner TD, Mitchell JA, Kirkby NS, 2012, Short thromboelastography and the identification of high platelet reactivity while on and off therapy, HEART, Vol: 98, Pages: 679-680, ISSN: 1355-6037
George PM, Badiger R, Alazawi W, et al., 2012, Pharmacology and therapeutic potential of interferons., Pharmacol Ther. 2012 Jul;135(1):44-53
Wright WR, Parzych K, Crawford D, et al., 2012, Inflammatory Transcriptome Profiling of Human Monocytes Exposed Acutely to Cigarette Smoke, PLOS ONE, Vol: 7, ISSN: 1932-6203
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- Citations: 40
Potter CMF, Schobesberger S, Lundberg MH, et al., 2012, Shape and Compliance of Endothelial Cells after Shear Stress In Vitro or from Different Aortic Regions: Scanning Ion Conductance Microscopy Study, PLOS ONE, Vol: 7, ISSN: 1932-6203
ObjectiveTo measure the elongation and compliance of endothelial cells subjected to different patterns of shear stress in vitro, and to compare these parameters with the elongation and compliance of endothelial cells from different regions of the intact aorta.Materials and MethodsPorcine aortic endothelial cells were cultured for 6 days under static conditions or on an orbital shaker. The shaker generated a wave of medium, inducing pulsatile shear stress with a preferred orientation at the edge of the well or steadier shear stress with changing orientation at its centre. The topography and compliance of these cells and cells from the inner and outer curvature of ex vivo porcine aortic arches were measured by scanning ion conductance microscopy (SICM).ResultsCells cultured under oriented shear stress were more elongated and less compliant than cells grown under static conditions or under shear stress with no preferred orientation. Cells from the outer curvature of the aorta were more elongated and less compliant than cells from the inner curvature.ConclusionThe elongation and compliance of cultured endothelial cells vary according to the pattern of applied shear stress, and are inversely correlated. A similar inverse correlation occurs in the aortic arch, with variation between regions thought to experience different haemodynamic stresses.
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