Publications (16)51.68 Total impact
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Article: Superoxide anion mediates the L-selectin down-regulation induced by non-steroidal anti-inflammatory drugs in human neutrophils.
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ABSTRACT: Non-steroidal anti-inflammatory drugs(NSAIDs) induce the shedding of L-selectin in human neutrophils through a mechanism still not well understood. In this work we studied both the functional effect of NSAIDs on the neutrophils/endothelial cells dynamic interaction, and the potential involvement of reactive oxygen species(ROS) in the NSAIDs-mediated down-regulation of L-selectin. When human neutrophils were incubated with diclofenac, a significant reduction in the number of cells that rolled on activated endothelial cells was observed. Different NSAIDs (flufenamic acid, meclofenamic acid, diclofenac, indomethacin, nimesulide, flurbiprofen, meloxicam, phenylbutazone, piroxicam, ketoprofen and aspirin) caused variable increase in neutrophil intracellular ROS concentration, which was inversely proportional to the change produced in L-selectin surface expression. Pre-incubation of neutrophils with superoxide dismutase, but not with catalase, showed both a significant protective effect on the L-selectin down-regulation induced by several NSAIDs and a diminished effect of diclofenac on neutrophil rolling. Interestingly, diclofenac and flufenamic acid but not piroxicam significantly increased the extracellular superoxide anion production by neutrophils, and inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activity with diphenyleneiodonium prevented the down-regulation of L-selectin by diclofenac. In accordance with these results, neutrophils from patients with chronic granulomatous disease, a hereditary disease in which neutrophils show a reduced capacity to form superoxide radicals, exhibited a lower down-regulation of L-selectin (IC50:15.3μg/ml) compared to normal controls (IC50:5.6μg/ml) in response to diclofenac. CONCLUSION: A group of NSAIDs is capable of interfering with the ability of neutrophils to interact with endothelial cells by triggering L-selectin-shedding through the NADPH-oxidase-dependent generation of superoxide anion at the plasma membrane.Biochemical pharmacology 11/2012; · 4.25 Impact Factor -
Article: In vivo modulation of the inflammatory response by non-steroidal anti-inflammatory drug-related compounds that TRIGGER L-selectin shedding.
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ABSTRACT: Diphenylamine-based non-steroidal anti-inflammatory drugs (NSAIDs) are able to cause in vitro the shedding of L-selectin. The aim of this work was to determine the physiologic relevance of L-selectin shedding in the anti-inflammatory effect exerted by NSAIDs in vivo. Chemical compounds structurally-related to NSAIDs - including diphenylamine, N-phenylanthranilic acid (N-Ph), diphenylacetic acid - as well as the traditional NSAID indomethacin were studied using the zymosan air-pouch mouse model. Animals intramuscularly pre-treated with indomethacin or N-Ph, but not with diphenylamine or diphenylacetic acid, showed a significant dose-dependent reduction in the number of neutrophils compared with untreated animals (N-Ph, IC50 = 6.7 mg/kg). Except for indomethacin, none of these compounds caused any significant reduction in cyclooxygenase-1 activity in vivo. In flow chamber experiments, N-Ph reduced the capability of human neutrophils to pass across the endothelial barrier by interfering with leukocyte rolling step on HUVEC. N-Ph, but not diphenylacetic acid, induced activation-independent L-selectin shedding in mouse neutrophils. Interestingly, N-Ph exerted an anti-inflammatory effect similar to that of the anti-L-selectin blocking antibody Mel-14, although no additive action was observed when both compounds were combined. These data suggest that the L-selectin shedding induced by NSAIDs may be involved in the anti-inflammatory action exerted by these compounds in clinical settings.European Journal of Immunology 09/2012; · 5.10 Impact Factor -
Article: The metalloprotease ADAM8 is associated with and regulates the function of the adhesion receptor PSGL-1 through ERM proteins.
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ABSTRACT: The P-selectin glycoprotein ligand-1 (PSGL-1) is involved in the initial contact of leukocytes with activated endothelium, and its adhesive function is regulated through its proteolytic processing. We have found that the metalloprotease ADAM8 is both associated with PSGL-1 through the ezrin–radixin–moesin actin-binding proteins and able to cause the proteolytic cleavage of this adhesion receptor. Accordingly, ADAM8 knockdown increases PSGL-1 expression, and functional assays show that ADAM8 is able to reduce leukocyte rolling on P-selectin and hence on activated endothelial cells. We conclude that ADAM8 modulates the expression and function of PSGL-1.European Journal of Immunology 12/2011; 41(12):3436-42. · 5.10 Impact Factor -
Article: [Efficacy and safety of abatacept in patients with rheumatoid arthritis and no prior treatment with biologics].
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ABSTRACT: Abatacept (ABA) is a recombinant human fusion protein that blocks co-stimulation signals on T lymphocytes, impeding their activation. Randomized and controlled trials examining efficacy and safety have been performed with ABA combined with methotrexate (MTX), vs MTX monotherapy and vs infliximab (IFB) combined with MTX in patients with Rheumatoid Arthritis and who are naïve to biologic therapy. ABA has shown to be more effective than MTX and at least as effective as IFB+MTX, in terms of activity and clinical remission, physical function and reduction in radiological progression. Safety data at 7 years have shown that the drug is comparable to MTX in monotherapy and safer than the IFB+MTX combination, although infections still constitute the main risk when using ABA. This review summarizes the safety and efficacy data of the AIM, ATTEST, Phase IIb IM101-100 and AGREE trials.Reumatología clinica. 11/2011; 7(6):392-6. -
Article: Expression and regulation of the metalloproteinase ADAM-8 during human neutrophil pathophysiological activation and its catalytic activity on L-selectin shedding.
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ABSTRACT: A disintegrin and metalloproteinase domain (ADAM) proteins are a family of transmembrane glycoproteins with heterogeneous expression profiles and proteolytic, cell-adhesion, -fusion, and -signaling properties. One of its members, ADAM-8, is expressed by several cell types including neurons, osteoclasts, and leukocytes and, although it has been implicated in osteoclastogenesis and neurodegenerative processes, little is known about its role in immune cells. In this study, we show that ADAM-8 is constitutively present both on the cell surface and in intracellular granules of human neutrophils. Upon in vitro neutrophil activation, ADAM-8 was mobilized from the granules to the plasma membrane, where it was released through a metalloproteinase-dependent shedding mechanism. Adhesion of resting neutrophils to human endothelial cells also led to up-regulation of ADAM-8 surface expression. Neutrophils isolated from the synovial fluid of patients with active rheumatoid arthritis expressed higher amounts of ADAM-8 than neutrophils isolated from peripheral blood and the concentration of soluble ADAM-8 in synovial fluid directly correlated with the degree of joint inflammation. Remarkably, the presence of ADAM-8 both on the cell surface and in suspension increased the ectodomain shedding of membrane-bound L-selectin in mammalian cells. All these data support a potential relevant role for ADAM-8 in the function of neutrophils during inflammatory response.The Journal of Immunology 07/2007; 178(12):8053-63. · 5.79 Impact Factor -
Article: Clinical trial of a leucotriene B4 receptor antagonist, BIIL 284, in patients with rheumatoid arthritis.
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ABSTRACT: Several clinical and experimental lines of evidence suggest that leucotriene B4 (LTB4), an arachidonic acid derivative with potent proinflammatory properties, plays a key role in the pathophysiology of rheumatoid arthritis (RA). To evaluate the efficacy and safety of BIIL 284, an oral long-acting LTB4 receptor antagonist, as monotherapy for the treatment of patients with active RA. This was a multi-centre, randomised, double-blind, placebo-controlled trial of patients with active RA of 3 months' duration. A total of 342 patients were randomised to receive 5 mg, 25 mg or 75 mg of BIIL 284 or placebo. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR) 20. Although a higher percentage of ACR 20 responders was observed in the groups treated with 25 mg and 75 mg of BIIL 284 compared with those treated with placebo, no statistically significant differences were found between any of the three active treatment groups compared with the placebo group with regard to the primary or secondary end points. All trial treatments were safe and well tolerated. This clinical trial demonstrates that treatment of patients with active RA with a potent oral long-acting LTB4 receptor antagonist produced only modest improvements in disease activity. The results of this trial support the conclusion that LTB4 is not a major contributor to the inflammatory process in RA.Annals of the Rheumatic Diseases 06/2007; 66(5):628-32. · 8.73 Impact Factor -
Article: Chemical modulation of VLA integrin affinity in human breast cancer cells.
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ABSTRACT: The fact that disruption of integrin-extracellular matrix contacts leads to cell death, has converted cell adhesion into a potential target for the control of invasive cancer. In this work, we studied the functional consequences of the interference with the activity of the very late activation antigen (VLA) family of integrins in human breast cancer cell lines of distinct malignancy. The alpha2beta1-mediated adhesion reduced the entry of highly malignant, hormone-independent breast cancer cells into apoptosis. Adhesion of breast cancer cells through the VLA integrins alpha2beta1 and alpha5beta1 was significantly reduced by an apoptosis-inducing natural triterpenoid, dehydrothyrsiferol (DT), when studied on low amounts of extracellular matrix. This effect was dose-dependent, not related to cell toxicity and not shared with apoptosis-inducing standard chemotherapeutics, such as doxorubicin and taxol. The compound did not affect either the cell surface expression level of VLA integrins or cell distribution of vinculin and actin during cell spreading. In addition, neither phosphorylation of the focal adhesion kinase pp125FAK on Tyr397 nor the protein kinase B (Akt/PKB) on Ser473 was significantly altered by DT. The integrin activation level, assessed by binding of soluble collagen to the alpha2beta1 integrin, was reduced upon cell treatment with DT. Importantly, the TS2/16, an anti-beta1 activating monoclonal antibody was able to rescue DT-treated cells from apoptosis. Since the activation state of integrins is increasingly recognized as an essential factor in metastasis formation, findings presented herein reveal that the chemical regulation of integrin affinity may be a potential therapeutic strategy in cancer therapy.Experimental Cell Research 05/2007; 313(6):1121-34. · 3.58 Impact Factor -
Article: The role of CD69 in acute neutrophil-mediated inflammation.
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ABSTRACT: The leukocyte activation marker CD69 functions as a negative regulator of the immune response, both in NK-dependent tumor rejection and in the inflammation associated with lymphocyte-dependent collagen-induced arthritis. In contrast, it has been reported that CD69-deficient mice are refractory to the neutrophil-dependent acute inflammatory response associated with anti-type II collagen antibody-induced arthritis (CAIA), suggesting a positive regulatory role for CD69 in neutrophil function during arthritis induction. To clarify this discrepancy, the CAIA response was independently analyzed in our CD69-deficient mice. In these experiments, the inflammatory response was unaffected by CD69 deficiency. Additionally, the in vivo down-regulation of CD69 expression by treatment of wild-type mice with the anti-CD69 mAb 2.2, which mimics the CD69-deficient phenotype, did not affect the course of arthritis in this model. Moreover, down-regulation of CD69 expression increased expression in arthritic joints of key inflammatory mediators, including IL-1beta, IL-6 and the chemokine MCP-1. Neutrophil accumulation in zymosan-treated air pouches and in thioglycolate-treated peritoneal cavities was also unaffected in CD69-deficient mice. In addition, CD69 expression was absent in activated neutrophils. Taken together, these results rule out a significant stimulatory role for CD69 in acute inflammatory responses mediated by neutrophils.European Journal of Immunology 11/2006; 36(10):2632-8. · 5.10 Impact Factor -
Article: The CCR2 receptor as a therapeutic target
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ABSTRACT: The strict control of cell recruitment during the physiological inflammatory response fails in autoimmune inflammatory diseases. The chemokine system is a complex and redundant network of small soluble proteins and G-protein-coupled cell surface receptors that participate in the inflammatory response, mainly attracting cells to the inflammatory foci. Data inferred from animal models suggest that the chemokine system might be involved in the physiopathology of several human disorders. CCR2, a chemokine receptor widely expressed in haematopoietic and non-haematopoieic cells, has been functionally implicated in experimental models of rheumatoid arthritis, multiple sclerosis and atherosclerosis amongst others, which has prompted several pharmaceutical companies to develop and patent a number of compounds with anti-CCR2 activity. This review will consider disorders where CCR2 signalling has shown a relevant function in animal models for which correlative data exist in humans, as well as patents of synthetic and biological products with anti-CCR2 activity potentially useful in human pathology.12/2005; 16(1):49-57. -
Article: CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients.
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ABSTRACT: To explore the potential involvement of the chemokine system in synoviocyte-mediated tissue destruction in rheumatoid arthritis (RA), we studied the expression profile of chemokine receptors and their function in the migration, proliferation, and matrix metalloproteinase (MMP) production of cultured fibroblast-like synoviocytes (FLS) from RA patients. The presence of CC and CXC chemokine receptors on cultured FLS was studied at the messenger RNA (mRNA) level by reverse transcriptase-polymerase chain reaction and at the cell surface expression level by flow cytometry. Variations in cytosolic calcium influx induced by chemokine stimulation were assessed by flow cytometry on Fura Red-preloaded FLS. Two-compartment transwell chambers were used for FLS chemotaxis assays. Cell growth was measured by a fluorescence-based proliferation assay. Gelatinase and collagenase activities were determined by a fibril degradation assay and zymography. FLS constitutively expressed the receptors CCR2, CCR5, CXCR3, and CXCR4, both at the cell surface and mRNA levels, but failed to express CCR3 and CCR6. Significant intracytosolic calcium influx was observed on FLS challenged with monocyte chemotactic protein 1 (MCP-1), stromal cell-derived factor 1alpha (SDF-1alpha), and interferon-inducible protein 10 (IP-10). Stimulation with MCP-1, SDF-1alpha, IP-10, and monokine induced by interferon-gamma enhanced the migration and proliferation of FLS. These chemokines, in addition to RANTES, increased in a dose- and time-dependent manner the gelatinase and collagenase activities in cell-free supernatants of cultured FLS. Interestingly, the chemokine-mediated up-regulation of MMP activities was significantly abrogated by the presence of anti-interleukin-1beta, but not anti-tumor necrosis factor alpha, blocking antibodies. These data suggest that through modulation of the migration, proliferation, and MMP production by FLS, the chemokine system may play a more direct role in the destructive phase of RA than is currently suspected, and thus emphasize the relevance of chemokines and their receptors as potential therapeutic targets in this disease.Arthritis & Rheumatism 01/2005; 50(12):3866-77. · 7.87 Impact Factor -
Article: [Allergy to corticosteroids, a paradox?].
Medicina Clínica 03/2003; 120(4):141-5. · 1.38 Impact Factor -
Article: Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs.
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ABSTRACT: It has been recently described that some non-steroidal anti-inflammatory drugs (NSAIDs) are able to induce the shedding of L-selectin in neutrophils, an adhesion molecule that plays an essential role in the inflammatory response. We have found that, according to this capability, NSAIDs could be grouped into three categories. A high releaser group (flufenamic, meclofenamic, and mefenamic acids, diclofenac and aceclofenac), a group of moderate releasers (aspirin, indomethacin, nimesulide, flurbiprofen, and ketoprofen), and a non-releaser group (phenylbutazone and the oxicams, piroxicam and meloxicam). Only NSAIDs from the high releaser group shared diphenylamine in their chemical structure. The amine group of this chemical agent proved to be essential for the anti-L-selectin activity of diphenylamine-based NSAIDs. The presence of a carboxylic acid group in the diphenylamine (N-phenylanthranilic acid) highly increased its ability to reduce the L-selectin surface expression in neutrophils. Diphenylamine and N-phenylanthranilic acid neither affected COX activity in platelets nor modified the activation state of neutrophils. Diphenylamine-related compounds, which include the diphenylamine-based NSAIDs caused a variable reduction in the neutrophil intracellular ATP concentration, which correlated with the differential ability of such compounds to trigger L-selectin shedding (r = 0.97, p < 0.01). Diphenylamine-related compounds failed to down-regulate L-selectin in a tumor necrosis factor-alpha-converting enzyme (TACE)-deficient murine monocytic cell line. Our data indicate that diphenylamine seems to be the structural core of NSAIDs accounting for their down-regulatory activity of L-selectin leukocyte expression. Diphenylamine and its related compounds exert this action on L-selectin through a prostaglandin-independent, TACE-dependent mechanism that seems to be linked to the capability of these agents to uncouple the mitochondrial oxidative phosphorylation.Journal of Biological Chemistry 10/2002; 277(41):38212-21. · 4.77 Impact Factor -
Article: [Insulin resistance and rheumatoid arthritis].
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ABSTRACT: Resistance to insulin action is a feature that accompanies certain diseases among which chronic inflammatory states like rheumatoid arthritis are included. What is, what its pathogenesis is, how it is measured, and what clinical and therapeutic implications have in rheumatoid arthritis patients is a topic not familiar to rheumatologists that is reviewed in this paper.Reumatología clinica. 7(2):124-9. -
Article: [A woman with joint pain and enlarged upper limbs].
Reumatología clinica. 7(3):210-1. -
Article: Pattern of use and safety of non-steroidal anti-inflammatory drugs in rheumatoid arthritis patients. A prospective analysis from clinical practice.
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ABSTRACT: The aim of this study was to determine the prescription pattern and the safety profile of non-steroidal anti-inflammatory drugs (NSAID), including cyclooxygenase-2 inhibitors (COXIB) in patients with rheumatoid arthritis (RA) under a real life clinical setting. Data was obtained from the EMECAR study, a prospective cohort of randomly selected RA patients (n=789) followed up from 1999 to 2004 in Spain. Upon entry into the cohort, 613 (78%) patients included took or had taken NSAID because of RA. Patients treated with NSAID, compared to those who did not take these compounds, were younger (60 versus 66 years of age) and have had both less cardiovascular (11 versus 20%; p<0.001) and gastric ulcer (11 versus 23%; p<0.001) complications. In the group of patients that used NSAID, RA had been diagnosed earlier (age at onset 47 versus 53; p<0.001) and was more active (DAS28: 4.4 versus 3.7; p<0.001). During follow-up, the percentage of RA patients using NSAID decreased from 78% in year 2000 to 66% in 2004. The use of antiulcer agents increased from 11% in 2000 to 60% in 2004, independently of both the use of classic NSAID or COXIB and the presence of risk factors for NSAID-induced gastropathy. Severe gastric complications and cardiovascular events were infrequent and the incidence was not different between patient who took NSAID and those who did not, as well as between patients treated with classic NSAID or with COXIB. NSAID are commonly used in the management of RA. These compounds are well tolerated and the frequency of severe adverse events attributed to them is relatively low under daily practice conditions in these patients.Reumatología clinica. 5(6):252-8. -
Article: [Recommendations for the management of influenza A (H1N1) in rheumatic patients with immunosuppression].
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ABSTRACT: The Spanish Society of Rheumatology (SER), through a multidiscipline task force, has elaborated a document with specific recommendations for specialists in Rheumatology, emphasizing the special needs of patients with rheumatic diseases, with the objective of informing and orienting health professionals about the current influenza A/H1N1 virus pandemic. All of the recommendations are based on prior documents elaborated by the Ministry of Health and Social Policy task forces, as well as those from the autonomous communities, which are themselves based on the guidelines and documents routinely published by the Centers for Disease Control (CDC) in the US, this being the center designated by WHO for the coordination of efforts against the pandemic. All rheumatologists and potential users of these recommendations are encouraged to consult the original documents, as well as the general guidelines established at each health center.Reumatología clinica. 6(1):63-8.
Top co-authors
Top Journals
Institutions
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2007–2012
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Hospital Universitario de Canarias
La Laguna, Canary Islands, Spain
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2011
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Hospital Universitario Reina Sofía
Córdoba, Andalusia, Spain
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2002–2007
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Universidad Autónoma de Madrid
Madrid, Madrid, Spain -
Universidad de La Laguna
La Laguna, Canary Islands, Spain
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