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Bangash M.N.,The William Harvey Research Institute | Patel N.S.A.,The William Harvey Research Institute | Benetti E.,University of Turin | Collino M.,University of Turin | And 4 more authors.
Critical Care | Year: 2013

Introduction: The effects of dopexamine, a β2-agonist, on perioperative and sepsis-related hemodynamic, microvascular, immune, and organ dysfunction are controversial and poorly understood. We investigated these effects in a rodent model of laparotomy and endotoxemia.Methods: In two experiments, 80 male Wistar rats underwent laparotomy. In 64 rats, this was followed by administration of endotoxin; the remainder (16) underwent sham endotoxemia. Endotoxemic animals received either dopexamine at 0.5, 1, or 2 μg/kg/min or 0.9% saline vehicle (controls) as resuscitation fluid. The effects of dopexamine on global hemodynamics, mesenteric regional microvascular flow, renal and hepatic function and immune activation were evaluated.Results: Endotoxin administration was associated with a systemic inflammatory response (increased plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, as well as cell-adhesion molecules CD11a and CD11b), and increased pulmonary myeloperoxidase (MPO) activity (indicating pulmonary leukocyte infiltration), whereas biochemical changes demonstrated lactic acidosis with significant renal and hepatic injury. Dopexamine administration was associated with less-severe lactic acidosis (pooled dopexamine versus controls, (lactate, 2.2 mM ± 0.2 mM versus 4.0 mM ± 0.5 mM; P < 0.001) and reductions in the systemic inflammatory response (pooled dopexamine versus control, 4 hour (TNF-α): 324 pg/ml ± 93 pg/ml versus 97 pg/ml ± 14 pg/ml, p < 0.01), pulmonary myeloperoxidase (MPO) activity, and hepatic and renal injury (pooled dopexamine versus control (ALT): 81 IU/L ± 4 IU/L versus 138 IU/L ± 25 IU/L; P < 0.05; (creatinine): 49.4 μM ± 3.9 μM versus 76.2 μM ± 9.8 μM; P < 0.005). However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow.Conclusions: In this model, dopexamine can attenuate the systemic inflammatory response, reduce tissue leukocyte infiltration, and protect against organ injury at doses that do not alter global hemodynamics or regional microvascular flow. These findings suggest that immunomodulatory effects of catecholamines may be clinically significant when used in critically ill surgical patients and are independent of their hemodynamic actions. © 2013 Bangash et al.; licensee BioMed Central Ltd.


Al-Kashi A.,The William Harvey Research Institute | Montero-Melendez T.,The William Harvey Research Institute | Moradi-Bidhendi N.,The William Harvey Research Institute | Gilligan J.P.,Tarsa Therapeutics | And 2 more authors.
PLoS ONE | Year: 2013

Introduction: Previous work reported the anti-arthritic synergy afforded by combining calcitonin (CT) and glucocorticoids (GC). Here we focus on the pairing of elcatonin (eCT) and dexamethasone (Dex), querying whether: i) this was a class-effect action; ii) mechanistic insights could be unveiled; iii) the synergy affected canonical GC adverse effects. Methods: Using the rat collagen-induced arthritis model, different combinations of eCT and Dex, were administered from disease onset to peak (day 11 to 18). Macroscopic disease score was monitored throughout, with biochemical and histological analyses conducted on plasma and tissues at day 18. The effect on acute hyperglycaemia and liver enzyme message were also assessed. Results: Whilst eCT alone was inactive, it synergised at 1 μg/kg with low doses of Dex (7.5 or 15 μg/kg) to yield an anti-arthritic efficacy equivalent to a 4- to 7-fold higher Dex dose. Mechanistically, the anti-arthritic synergy corresponded to a marked attenuation in RA-relevant analytes. CXCL5 expression, in both plasma and joint, was markedly inhibited by the co-therapy. Finally, co-administration of eCT did not exacerbate metrics of GC adverse effects, and rescued some of them. Conclusions: We present evidence of a class-effect action for the anti-arthritic synergy of CT/GC combination, underpinned by the powerful inhibition of joint destruction markers. Furthermore, we identify CXCL5 as a marker for the combination therapy with potential diagnostic and prognostic utility. Substantial GC dose reduction, together with the absence of exacerbated adverse effects, indicated a significant clinical potential for this co-therapy in RA and beyond. © 2013 Al-Kashi et al.


Iqbal A.,Moore Research | Barnes N.C.,Respiratory Medical Franchise | Barnes N.C.,The William Harvey Research Institute | Brooks J.,Respiratory Medicines Development Center
Clinical Drug Investigation | Year: 2015

Background: Chronic obstructive pulmonary disease (COPD) patients with blood eosinophil (EOS) count ≥2 % benefit from exacerbation reductions with inhaled corticosteroids (ICSs). We conducted post hoc analyses to determine if EOS count ≥2 % is a marker for greater responsiveness to the bronchodilators umeclidinium (UMEC; long-acting muscarinic antagonist), vilanterol (VI; long-acting β2-agonist) or UMEC/VI combination. Methods: Effects of once-daily UMEC/VI 62.5/25, UMEC 62.5 and VI 25 µg versus placebo on trough forced expiratory volume in one second (FEV1), Transition Dyspnoea Index (TDI), St George’s Respiratory Questionnaire (SGRQ) scores and adverse event (AE) incidences in four completed, 6-month studies were assessed by EOS subgroup. Trough FEV1 was also evaluated by ICS use and EOS subgroup. Analyses were performed using a repeated measures model. Results: At baseline, 2437 of 4647 (52 %) patients had EOS count ≥2 %. Overall, ≈50 % of patients used ICSs. At day 169, no notable variations were observed in trough FEV1 least squares mean differences between EOS subgroups versus placebo for UMEC/VI, UMEC and VI; results according to ICS use were similar. No differences were reported between EOS subgroups in TDI and SGRQ scores on day 168, or for incidences of AEs, serious AEs and AEs leading to withdrawal. Conclusions: Response to UMEC/VI, UMEC and VI in terms of trough FEV1, dyspnoea and health-related quality of life was similar for COPD patients with baseline EOS counts ≥2 or <2 %. EOS count did not appear to predict bronchodilator response in either ICS users or non-users. © 2015, The Author(s).


de Lima C.B.,University of Sao Paulo | Tamura E.K.,University of Sao Paulo | Montero-Melendez T.,The William Harvey Research Institute | Palermo-Neto J.,University of Sao Paulo | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

The 18kDa translocator protein (TSPO) also known as the peripheral benzodiazepine receptor (PBR), mediates the transportation of cholesterol and anions from the outer to the inner mitochondrial membrane in different cells types. Although recent evidences indicate a potential role for TSPO in the development of inflammatory processes, the mechanisms involved have not been elucidated. The present study investigated the ability of the specific TSPO ligands, the isoquinoline carboxamide PK11195 and benzodiazepine Ro5-4864, on neutrophil recruitment promoted by the N-formylmethionyl-leucyl-phenylalanine peptide (fMLP), an agonist of G-protein coupled receptor (GPCR). Pre-treatment with Ro5-4864 abrograted fMLP-induced leukocyte-endothelial interactions in mesenteric postcapillary venules in vivo. Moreover, in vitro Ro5-4864 treatment prevented fMLP-induced: (i) l-selectin shedding and overexpression of PECAM-1 on the neutrophil cell surface; (ii) neutrophil chemotaxis and (iii) enhancement of intracellular calcium cations (iCa+2). Intriguingly, the two latter effects were augmented by cell treatment with PK11195. An allosteric agonist/antagonist relation may be suggested, as the effects of Ro5-4864 on fMLP-stimulated neutrophils were reverted by simultaneous treatment with PK11195. Taken together, these data highlight TSPO as a modulator of pathways of neutrophil adhesion and locomotion induced by GPCR, connecting TSPO actions and the onset of an innate inflammatory response. © 2011 Elsevier Inc.


Whittle B.J.R.,The William Harvey Research Institute | Varga C.,University of Szeged
Pharmacological Reports | Year: 2010

Although a variety of pharmaceutical preparations of aminosalicylate are commonly used in the clinic for the control of inflammatory bowel disease, the mechanisms underlying their therapeutic actions remain unclear. Recent in vivo and in vitro studies have demonstrated that 5-aminosalicylic acid (5-ASA), regarded as the active moiety in aminosalicylate preparations such as sulfasalazine, can induce the heat shock protein, heme oxygenase-1 (HO-1) and up-regulate HO enzyme activity in the colon. As HO-1 can produce endogenous anti-oxidant and anti-inflammatory moieties such as bilirubin and carbon monoxide (CO), these findings suggest a novel mechanism of action for aminosalicylates, acting as anti-colitic agents through the up-regulation of HO-1 enzyme expression and activity. © by Institute of Pharmacy Polish Acadamy of Sciences.


Headland S.E.,The William Harvey Research Institute | Norling L.V.,The William Harvey Research Institute
Seminars in Immunology | Year: 2015

The concept that chemokines, cytokines and pro-inflammatory mediators act in a co-ordinated fashion to drive the initiation of the inflammatory reaction is well understood. The significance of such networks acting during the resolution of inflammation however is poorly appreciated. In recent years, specific pro-resolving mediators were discovered which activate resolution pathways to return tissues to homeostasis. These mediators are diverse in nature, and include specialized lipid mediators (lipoxins, resolvins, protectins and maresins) proteins (annexin A1, galectins) and peptides, gaseous mediators including hydrogen sulphide, a purine (adenosine), as well as neuromodulator release under the control of the vagus nerve. Functionally, they can act to limit further leukocyte recruitment, induce neutrophil apoptosis and enhance efferocytosis by macrophages. They can also switch macrophages from classical to alternatively activated cells, promote the return of non-apoptotic cells to the lymphatics and help initiate tissue repair mechanisms and healing. Within this review we highlight the essential cellular aspects required for successful tissue resolution, briefly discuss the pro-resolution mediators that drive these processes and consider potential challenges faced by researchers in the quest to discover how inflammation resolves and why chronic inflammation persists. © 2015 Elsevier Ltd.


PubMed | The William Harvey Research Institute
Type: Journal Article | Journal: Seminars in immunology | Year: 2015

The concept that chemokines, cytokines and pro-inflammatory mediators act in a co-ordinated fashion to drive the initiation of the inflammatory reaction is well understood. The significance of such networks acting during the resolution of inflammation however is poorly appreciated. In recent years, specific pro-resolving mediators were discovered which activate resolution pathways to return tissues to homeostasis. These mediators are diverse in nature, and include specialized lipid mediators (lipoxins, resolvins, protectins and maresins) proteins (annexin A1, galectins) and peptides, gaseous mediators including hydrogen sulphide, a purine (adenosine), as well as neuromodulator release under the control of the vagus nerve. Functionally, they can act to limit further leukocyte recruitment, induce neutrophil apoptosis and enhance efferocytosis by macrophages. They can also switch macrophages from classical to alternatively activated cells, promote the return of non-apoptotic cells to the lymphatics and help initiate tissue repair mechanisms and healing. Within this review we highlight the essential cellular aspects required for successful tissue resolution, briefly discuss the pro-resolution mediators that drive these processes and consider potential challenges faced by researchers in the quest to discover how inflammation resolves and why chronic inflammation persists.


PubMed | The William Harvey Research Institute
Type: | Journal: European journal of pharmacology | Year: 2016

Omega-3 polyunsaturated fatty acids are essential for health and are known to possess anti-inflammatory properties, improving cardiovascular health as well as benefiting inflammatory diseases. Indeed, dietary supplementation with omega-3 polyunsaturated fatty acids has proved efficacious in reducing joint pain, morning stiffness and nonsteroidal anti-inflammatory drugs usage in rheumatoid arthritis patients. However, the mechanisms by which omega-3 polyunsaturated fatty acids exert their beneficial effects have not been fully explored. Seminal discoveries by Serhan and colleagues have unveiled a novel class of bioactive lipid mediators that are enzymatically biosynthesized in vivo from omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed resolvins, protectins and maresins. These bioactive pro-resolving lipid mediators provide further rationale for the beneficial effects of fish-oil enriched diets. These endogenous lipid mediators are spatiotemporally biosynthesized to actively regulate resolution by acting on specific G protein-coupled receptors (GPCRs) to initiate anti-inflammatory and pro-resolving signals that terminate inflammation. In this review, we will discuss the mechanism of actions of these molecules, including their analgesic and bone-sparing properties making them ideal therapeutic agonists for the treatment of inflammatory diseases such as rheumatoid arthritis.


PubMed | Health Science University, The William Harvey Research Institute, NicOx, Harvard University and The Interdisciplinary Center
Type: | Journal: Life sciences | Year: 2015

Cyclooxygenase (COX)-inhibiting nitric oxide donors (CINODs) are a new class of drugs that structurally combine a COX inhibitor with a nitric oxide (NO) donating moiety. This combination reduces potential toxicity of the non-steroidal anti-inflammatory drugs (NSAIDs) whilst maintaining the analgesic and anti-inflammatory effects. The present study was undertaken to investigate the anti-inflammatory effects of NCX 429, a naproxen-based CINOD, and to assess the additional properties of NO donation beyond those related to naproxen.We evaluated the in vitro effects of NCX 429 on oxy-radical production, phagocytosis, cytokine release, MMP-9, PPAR expression and NF-B activation in human monocytes/MDM and compared to naproxen. Moreover, we compared the in vivo efficacy of NCX 429 and naproxen in a murine model of peritonitis.In all the experiments performed in vitro, NCX 429 reduced the inflammatory responses with equal or higher efficacy compared to naproxen. Moreover, in in vivo experiments, NCX 429, at the lowest dose tested, was able to significantly inhibit cell influx in response to IL-1 administration although naproxen was found to be more potent than NCX 429 at reducing PGE2 in inflammatory exudates.These results demonstrate that both in vitro and in vivo--in a murine model of peritonitis--NCX 429 elicits significant anti-inflammatory activity, beyond the simple COX inhibition or pure NO release. Therefore, NO donation along with COX inhibition may represent a strategy for investigating inflammatory diseases in which pain and function are not fully resolved by analgesics/anti-inflammatory drugs.


PubMed | The William Harvey Research Institute
Type: | Journal: Prostaglandins & other lipid mediators | Year: 2015

In this brief personal reminiscence I comment upon the friendship and mutual understanding that arose between two great scientists and co-travellers, John Vane and Jack McGiff. I relate the events that led up to their meeting and focus on the brief period of time when they worked together on eicosanoid pharmacology in the UK.

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