153 results found
Quinlan G, Phagomimetic action of antibiotics: revisited. How do antibiotics know where to go?, Biochemical and Biophysical Research Communications, ISSN: 0006-291X
Phagocytic cells know exactly where an infection is by following chemotactic signals. The phagocytosis of bacteria results in a 'respiratory burst' in which superoxide radicals are released. We have previously compared the release of reactive oxygen species (ROS) by antibiotics, during electron transfer reactions, to this event. Antibiotics in their normal bacterial environment, and ROS, are both increasingly implicated in purposeful signalling functions, rather than their more widely known roles in bacterial killing and molecular damage. Here, we extend our comparison between antibiotics and phagocytic cells to propose that antibiotics actively accumulate at a site of pathogen infection or tumour growth. A common link being virulent cellular growth. When this occurs, new proteins are secreted, aberrant iron acquisition takes place, and lipocalins are released. Each provide a mechanism by which antibiotics can bind, and be retained, at an active site of pathogen infection or tumour growth.
Nikolakopoulou Z, Hector LR, Creagh-Brown BC, et al., 2019, Plasma S100A8/A9 heterodimer is an early prognostic marker of acute kidney injury associated with cardiac surgery, Biomarkers in Medicine, Vol: 13, Pages: 205-218, ISSN: 1752-0363
We investigated whether plasma levels of the inflammation marker S100A8/A9, could predict acutekidney injury (AKI) onset in patients undergoing cardiac surgery necessitating cardiopulmonary bypass(CPB). Patients & methods: Plasma levels of S100A8/A9 and other neutrophil cytosolic proteins were measured in 39 patients pre- and immediately post-CPB. Results: All markers increased significantly post-CPBwith S100A8/A9, S100A12 and myeloperoxidase levels significantly higher in patients who developed AKIwithin 7 days. S100A8/A9 had good prognostic utility for AKI, with an area under the receiver operating characteristic curve of 0.81 (95% CI: 0.676–0.949) and a cut-off value of 10.6 μg/ml (85.7% sensitivityand 75% specificity) irrespective of age. Conclusion: Plasma S100A8/A9 levels immediately after cardiacsurgery, can predict onset of AKI, irrespective of age.
Pedersen S, Toe Q, Wort SJ, et al., 2018, Stabilised ferroportin activity affects pulmonary vascular cells responses: implications for pulmonary hypertension, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: European Respiratory Society, ISSN: 0903-1936
Ahmetaj-Shala B, Olanipekun M, Tesfai A, et al., 2018, Development of a novel UPLC-MS/MS-based platform to quantify amines, amino acids and methylarginines for applications in human disease phenotyping, Scientific Reports, Vol: 8, ISSN: 2045-2322
Amine quantification is an important strategy in patient stratification and personalised medicine. This is because amines, including amino acids and methylarginines impact on many homeostatic processes. One important pathway regulated by amine levels is nitric oxide synthase (NOS). NOS is regulated by levels of (i) the substrate, arginine, (ii) amino acids which cycle with arginine and (iii) methylarginine inhibitors of NOS. However, biomarker research in this area is hindered by the lack of a unified analytical platform. Thus, the development of a common metabolomics platform, where a wide range of amino acids and methylarginines can be measured constitutes an important unmet need. Here we report a novel high-throughput ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) platform where ≈40 amine analytes, including arginine and methylarginines can be detected and quantified on a molar basis, in a single sample of human plasma. To validate the platform and to generate biomarkers, human plasma from a well-defined cohort of patients before and after coronary artery bypass surgery, who developed systemic inflammatory response syndrome (SIRS), were analysed. Bypass surgery with SIRS significantly altered 26 amine analytes, including arginine and ADMA. Consequently, pathway analysis revealed significant changes in a range of pathways including those associated with NOS.
Ramakrishnan L, Pedersen SL, Toe QK, et al., 2018, The Hepcidin / Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells, Scientific Reports, Vol: 8, ISSN: 2045-2322
Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.
The interplay between iron and oxygen is longstanding and central to all aerobic life. Tight regulation of these interactions including homeostatic regulation of iron utilization ensures safe usage of this limited resource. However, when control is lost adverse events can ensue, which are known to contribute to an array of disease processes. Recently, associations between disrupted iron homeostasis and pulmonary artery hypertension (PAH) have been described with the suggestion that there is a contributory link with disease. This review provides a background for iron regulation in humans, describes PAH classifications, and discusses emerging literature, which suggests a role for disrupted iron homeostatic control in various sub-types of PAH, including a role for decompartmentalization of hemoglobin. Finally, the potential for therapeutic options to restore iron homeostatic balance in PAH are discussed.
Shackshaft T, Wort S, Quinlan G, et al., 2017, Conditioned media from human pulmonary arterial endothelial cells treated with hepcidin or haemoglobin cause proliferation and migration of human pulmonary artery smooth muscle cells, British Thoracic Society Annual Meeting, Publisher: BMJ Publishing Group, Pages: A68-A69, ISSN: 1468-3296
Tesfai A, MacCallum N, Kirkby NS, et al., 2017, Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways, PLoS ONE, Vol: 12, ISSN: 1932-6203
RationaleNitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known.ObjectiveOur objective was to apply a metabolomics approach to determine the influence of sepsis on a full array of amines and what consequence these changes may have on predicted iNOS activity.Methods and measurements34 amino acids were measured using ultra purification mass spectrometry in the plasma of septic patients (n = 38) taken at the time of diagnosis and 24–72 hours post diagnosis and of healthy volunteers (n = 21). L-arginine and methylarginines were measured using liquid-chromatography mass spectrometry and ELISA. A top down approach was also taken to examine the most changed metabolic pathways by Ingenuity Pathway Analysis. The iNOS supporting capacity of plasma was determined using a mouse macrophage cell-based bioassay.Main resultsOf all the amines measured 22, including L-arginine and ADMA, displayed significant differences in samples from patients with sepsis. The functional consequence of increased ADMA and decreased L-arginine in context of all cumulative metabolic changes in plasma resulted in reduced iNOS supporting activity associated with sepsis.ConclusionsIn early sepsis profound changes in amine levels were defined by dominant changes in the iNOS canonical pathway resulting in functionally meaningful changes in the ability of plasma to regulate iNOS activity ex vivo.
Cloonan SM, Mumby S, Adcock IM, et al., 2017, The IRONy of Iron-overload and Iron-deficiency in Chronic Obstructive Pulmonary Disease., American Journal of Respiratory and Critical Care Medicine, Vol: 196, ISSN: 1535-4970
Chronic obstructive pulmonary disease (COPD) is a debilitating inflammatory lung disease associated with cigarette smoking and is third leading cause of death worldwide. With the recent emergence of genome wide association studies (GWAS), the identification of multiple COPD susceptibility genes has enhanced and expanded our understanding of the pathogenic mechanisms associated with this debilitating lung disease. An example of such a pathogenic mechanism is the role of iron metabolism in the onset and progression of COPD. Historic observations of iron dysregulation in COPD can now be enlightened by the recent revelations that genetic polymorphisms in the gene iron regulatory protein-2 (IRP-2) associate with COPD susceptibility. A functional role for IRP-2 is supported by IRP-2 overexpression in murine models, that demonstrates cellular and mitochondrial iron accumulation in the lung linked with manifestations of experimental COPD. Increased IRP2 may explain the excessive iron deposition in alveolar macrophages and tissue in smokers and in patients with COPD. Changes in IRP2 expression may also associate with systemic iron mismanagement, which may explain the prevalence of systemic iron deficiency and iron-deficiency anemia in patients with COPD. It may also help to explain why patients with COPD and/or iron deficiency manifest altered responses to hypoxia including erythropoiesis and pulmonary hypertension. We provide a concise review of the role of iron in the pathogenesis, susceptibility and progression of COPD and highlight the prospective therapeutic interventions for treating both local and systemic iron dysregulation.
Ramakrishnan L, Anwar A, Wort S, et al., 2016, Haemoglobin mediated proliferation and IL-6 release in human pulmonary artery endothelial cells: a role for CD163 and implications for pulmonary vascular remodelling., Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A220-A220, ISSN: 1468-3296
Mumby S, Ramakrishnan L, Kempny A, et al., Dysregulation of iron homeostasis in Eisenmenger syndrome; comparison to idiopathic pulmonary arterial hypertension and healthy controls., ERS International Congress
Bastin AJ, Davies N, Lim E, et al., 2016, Systemic inflammation and oxidative stress post-lung resection: effect of pretreatment with N-acetylcysteine, Respirology, Vol: 21, Pages: 180-187, ISSN: 1440-1843
Background and objectiveN-acetylcysteine has been used to treat a variety of lung diseases, where is it thought to have an antioxidant effect. In a randomized placebo-controlled double-blind study, the effect of N-acetylcysteine on systemic inflammation and oxidative damage was examined in patients undergoing lung resection, a human model of acute lung injury.MethodsEligible adults were randomized to receive preoperative infusion of N-acetylcysteine (240 mg/kg over 12 h) or placebo. Plasma thiols, interleukin-6, 8-isoprostane, ischaemia-modified albumin, red blood cell glutathione and exhaled breath condensate pH were measured pre- and post-operatively as markers of local and systemic inflammation and oxidative stress.ResultsPatients undergoing lung resection and one-lung ventilation exhibited significant postoperative inflammation and oxidative damage. Postoperative plasma thiol concentration was significantly higher in the N-acetylcysteine-treated group. However, there was no significant difference in any of the measured biomarkers of inflammation or oxidative damage, or in clinical outcomes, between N-acetylcysteine and placebo groups.ConclusionPreoperative administration of N-acetylcysteine did not attenuate postoperative systemic or pulmonary inflammation or oxidative damage after lung resection.
Mumby S, Saito J, Adcock IM, et al., 2015, Decreased breath excretion of redox active iron in COPD: a protective failure?, European Respiratory Journal, Vol: 47, Pages: 1267-1270, ISSN: 1399-3003
Ramakrishnan L, Mumby S, Wort S, et al., CD163 is expressed and modulated in human pulmonary artery smooth muscle cells: Implications for Pulmonary Artery Hypertension., ERS Annual Congress
Ramakrishnan L, Mumby S, Wort JS, et al., 2014, Ferroportin is Expressed in Human Pulmonary Artery Smooth Muscle Cells: Implications for Pulmonary Arterial Hypertension., BTS Annual Winter Meeting, Publisher: BMJ Publishing Group, ISSN: 1468-3296
MacCallum NS, Finney SJ, Gordon SE, et al., 2014, Modified Criteria for the Systemic Inflammatory Response Syndrome Improves Their Utility Following Cardiac Surgery, CHEST, Vol: 145, Pages: 1197-1203, ISSN: 0012-3692
Mumby S, Ramakrishnan L, Evans TW, et al., 2014, Methemoglobin-induced signaling and chemokine responses in human alveolar epithelial cells, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 306, Pages: L88-L100, ISSN: 1040-0605
Nikolakopoulou Z, Smith M, Hector LR, et al., 2013, S100A12 AS A BIOMARKER FOR NEUTROPHIL MEDIATED INFLAMMATION IN PATIENTS UNDERGOING CARDIAC SURGERY NECESSITATING CARDIOPULMONARY BYPASS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A141-A141, ISSN: 0040-6376
Ramakrishnan L, Mumby S, Meng C, et al., 2013, IL-6 mediated proliferative responses in human pulmonary vascular cells are differentially modulated by Iron/Heme/Hemoglobin, ERS 2013 Annual Congress
Pulmonary Arterial Hypertension (PAH) is characterised by progressive pulmonary vascular remodelling culminating in heart failure. Disrupted iron metabolism and anaemia have been linked to development of PAH suggesting iron supplementation may be beneﬁ cial. However iron compounds are known proliferative agents. IL-6 which is both proinﬂ ammatory and central to iron homeostasis is elevated in PAH. With emerging evidence of minor hemolysis in PAH patients, the availability of heme and/or haemoglobin (Hb) to PVCs may further impact on cellular responses. We aim to address the above issues in this study.Human pulmonary arterial smooth muscle cells (PASMCs) & endothelial cells (PAECs) were exposed to iron (FAC)/Heme/Hb prior to treatment with IL6. Cell proliferation was quantiﬁed by Cyquant. RTPCR for expression of Hepcidin (regulatory hormone), Ferroportin (exporter), HO1, CD163(Hb scavenger) was also performed.IL-6 alone caused proliferation reversed by iron in PASMCs but not in PAECs. Heme restricted while Hb supported proliferation in both cell types. Basal CD163 mRNA was undetectable in PAECs but induced by IL-6. Hepcidin, Ferroportin and HO1 were also contrastingly regulated by IL6.[table1]Thus PVCs respond distinctly to the IL-6 stimulus which is further modulated by the availability of Iron/Heme/Hb. Besides IL-6 differentially regulated mRNA expression of genes involved in iron homeostasis. Further investigation of iron handling in PVCs seems warranted.
Nikolakopoulou Z, Creagh-Brown B, Burke-Gaffney A, et al., 2013, Decreased expression of receptor for advanced glycation end-products (RAGE) on neutrophils following surgery necessitating cardiopulmonary bypass (snCPB), 100th Annual Meeting of the American-Association-of-Immunologists, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Creagh-Brown BC, Quinlan GJ, Hector LR, et al., 2013, Association between Preoperative Plasma sRAGE Levels and Recovery from Cardiac Surgery, MEDIATORS OF INFLAMMATION, ISSN: 0962-9351
Conway FM, Gordon SE, Mumby SJ, et al., 2012, The relationship of biochemical indices to the systemic inflammatory response syndrome following cardiac surgery. Time for SIRS to bow out?, Am J Respir Crit Care Med, American Thoracic Society, Pages: A1656-A1656
Conway FM, Gordon SE, Quinlan GJ, et al., 2011, DOES MEETING THE CLINICAL CRITERIA FOR THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME EQUATE TO BIOCHEMICAL INFLAMMATION FOLLOWING CARDIAC SURGERY?, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A96-A97, ISSN: 0040-6376
Mumby S, Chung KF, McCreanor JE, et al., 2011, Pro-oxidant iron in exhaled breath condensate: A potential excretory mechanism, RESPIRATORY MEDICINE, Vol: 105, Pages: 1290-1295, ISSN: 0954-6111
Bastin AJ, Sato H, Davidson SJ, et al., 2011, Biomarkers of lung injury after one-lung ventilation for lung resection, RESPIROLOGY, Vol: 16, Pages: 138-145, ISSN: 1323-7799
Hector LR, Lagan AL, Melley DD, et al., 2011, Polymorphisms in the haptoglobin gene predispose patients to adverse outcome after surgery necessitating cardiopulmonary bypass, Am J Respir Crit Care Med, American Thoracic Society International Congress, Pages: A1161-A1161
Leaver SK, Quinlan GJ, Evans TW, et al., 2010, THIOREDOXIN MODIFIES MIF RELEASE FROM HUMAN MONOCYTES FOLLOWING STIMULATION WITH LTA AND LPS, British-Thoracic-Society-Winter-Meeting 2010, Publisher: B M J PUBLISHING GROUP, Pages: A25-A26, ISSN: 0040-6376
Zakeri N, Creagh-Brown B, Hector LR, et al., 2010, POLYMORPHISMS IN GENES ENCODING RAGE OR RAGE LIGANDS PREDISPOSE PATIENTS TO ADVERSE OUTCOMES FOLLOWING SURGERY NECESSITATING CARDIOPULMONARY BYPASS, British-Thoracic-Society-Winter-Meeting 2010, Publisher: B M J PUBLISHING GROUP, Pages: A49-A49, ISSN: 0040-6376
Creagh-Brown BC, Quinlan GJ, Evans TW, et al., 2010, The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target?, INTENSIVE CARE MEDICINE, Vol: 36, Pages: 1644-1656, ISSN: 0342-4642
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