31 results on '"Cernadas M"'
Search Results
2. 4: The effect of elexacaftor/tezacaftor/ivacaftor on glycemia in adults with cystic fibrosis: A prospective continuous glucose monitoring study
- Author
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Scully, K., primary, Marchetti, P., additional, Sawicki, G., additional, Uluer, A., additional, Cernadas, M., additional, Cagnina, R., additional, Kennedy, J., additional, and Putman, M., additional
- Published
- 2021
- Full Text
- View/download PDF
3. CD1a expression defines an interleukin-12 producing population of human dendritic cells
- Author
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Cernadas, M., Lu, J., Watts, G., and Brenner, M. B.
- Published
- 2009
- Full Text
- View/download PDF
4. Nutrition and dietary intake and their association with mortality and hospitalisation in adults with chronic kidney disease treated with haemodialysis: protocol for DIET-HD, a prospective multinational cohort study
- Author
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Palmer, Sc, Ruospo, M, Campbell, Kl, Garcia Larsen, V, Saglimbene, V, Natale, P, Gargano, L, Craig, Jc, Johnson, Dw, Tonelli, M, Knight, J, Bednarek Skublewska, A, Celia, E, Del Castillo, D, Dulawa, J, Ecder, T, Fabricius, E, Frazão, Jm, Gelfman, R, Hoischen, Sh, Schön, S, Stroumza, P, Timofte, D, Török, M, Hegbrant, J, Wollheim, C, Frantzen, L, Strippoli, Gf, Raña, S, Serrano, M, Claros, S, Arias, M, Petracci, L, Arana, M, De Rosa, P, Gutierrez, A, Simon, M, Vergara, V, Tosi, M, Cernadas, M, Vilamajó, I, Gravac, D, Paulón, M, Penayo, L, Carrizo, G, Ghiani, M, Perez, G, Da Cruz, O, Galarce, D, Gravielle, M, Vescovo, E, Paparone, R, Mato Mira, C, Mojico, E, Hermida, O, Florio, D, Yucoswky, M, Labonia, W, Rubio, D, Di Napoli, G, Fernandez, A, Altman, H, Rodriguez, J, Serrano, S, Valle, G, Lobos, M, Acosta, V, Corpacci, G, Jofre, M, Gianoni, L, Chiesura, G, Capdevila, M, Montenegro, J, Bequi, J, Dayer, J, Gómez, A, Calderón, C, Abrego, E, Cechín, C, García, J, Corral, J, Natiello, M, Coronel, A, Muñiz, M, Muñiz, V, Bonelli, A, Sanchez, F, Maestre, S, Olivera, S, Camargo, M, Avalos, V, Geandet, E, Canteli, M, Escobar, A, Sena, E, Tirado, S, Peñalba, A, Neme, G, Cisneros, M, Oliszewski, R, Nascar, V, Daud, M, Mansilla, S, Paredes Álvarez, A, Gamín, L, Arijón, M, Coombes, M, Zapata, M, Boriceanu, C, Lankester, M, Poignet, Jl, Saingra, Y, Indreies, M, Santini, J, Amar, M, Robert, A, Bouvier, P, Merzouk, T, Villemain, F, Pajot, A, Tollis, F, Brahim Bounab, M, Benmoussa, A, Albitar, S, Guimont, Mc, Ciobotaru, P, Guerin, A, Diaconita, M, Shh, Saupe, J, Ullmann, I, Grosser, S, Kunow, J, Grueger, S, Bischoff, D, Benders, J, Worch, P, Pfab, T, Kamin, N, Roesch, M, Albert, K, Csaszar, I, Kiss, E, Kosa, D, Orosz, A, Redl, J, Kovacs, L, Varga, E, Szabo, M, Magyar, K, Zajko, E, Bereczki, A, Csikos, J, Kerekes, E, Mike, A, Steiner, K, Nemeth, E, Tolnai, K, Toth, A, Vinczene, J, Szummer, S, Tanyi, E, Szilvia, M, Murgo, Am, Sanfilippo, N, Dambrosio, N, Saturno, C, Matera, G, Benevento, M, Greco, V, di Leo, G, Papagni, S, Alicino, F, Marangelli, A, Pedone, F, Cagnazzo, Av, Antinoro, R, Sambati, Ml, Donatelli, C, Ranieri, F, Torsello, F, Steri, P, Riccardi, C, Flammini, A, Moscardelli, L, Boccia, E, Mantuano, M, Di Toro Mammarella, R, Meconizzi, M, Fichera, R, D'Angelo, A, Latassa, G, Molino, A, Fici, M, Lupo, Antonio, Montalto, G, Messina, S, Capostagno, C, Randazzo, G, Pagano, S, Marino, G, Rallo, D, Maniscalco, A, Trovato, Om, Strano, C, Failla, A, Bua, A, Campo, S, Nasisi, P, Salerno, A, Laudani, S, Grippaldi, F, Bertino, D, Di Benedetto, Dv, Puglisi, A, Chiarenza, S, Lentini Deuscit, M, Incardona, Cm, Scuto, G, Todaro, C, Dino, A, Novello, D, Coco, A, Bocheńska Nowacka, E, Jaroszyński, A, Drabik, J, Wypych Birecka, M, Daniewska, D, Drobisz, M, Doskocz, K, Wyrwicz Zielińska, G, Kosicki, A, Ślizień, Ws, Rutkowski, P, Arentowicz, S, Dzimira, S, Grabowska, M, Ostrowski, J, Całka, A, Grzegorczyk, T, Dżugan, W, Mazur, M, Myślicki, M, Piechowska, M, Kozicka, D, Mira, Ar, Martins, V, Velez, B, Pinheiro, T, Agapi, E, Ardelean, Cl, Baidog, A, Bako, G, Barb, M, Blaga, A, Bodurian, E, Bumbea, V, Dragan, E, Dumitrache, D, Florescu, L, Havasi, N, Hint, S, Ilies, R, Mandita, Ag, Marian, Ri, Medrihan, Sl, Mitea, L, Mitea, S, Mocanu, R, Moro, Dc, Nitu, M, Popa, Ml, Popa, M, Railean, E, Scuturdean, Ar, Szentendrey, K, Teodoru, Cl, Varga, A, Bernat, A, De la Torre, B, Lopez, A, Martin, J, Cuesta, G, Rodriguez, Rm, Ros, F, Garcia, M, Orero, E, Ros, E, Goch, J, Katzarski, Ks, Wulcan, A, Akbiber, H, Arslan, H, Bicen, L, Buyukkiraz, A, Celik, R, Dogan, Is, Erkalkan, S, Ertas, A, Hark, U, Iravul, E, Karakaya, M, Mengu, K, Ongun, S, Ozkan, Z, Ozlu, A, Ozveren, N, Sifil, Hm, Sonmez Turksoz, N, and Yilmaz, Z.
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Turkey ,medicine.medical_treatment ,Argentina ,NUTRITION & DIETETICS ,Nutritional Status ,Infections ,Young Adult ,Informed consent ,Renal Dialysis ,Cause of Death ,Fatty Acids, Omega-6 ,Epidemiology ,Fatty Acids, Omega-3 ,medicine ,Protocol ,Humans ,EPIDEMIOLOGY ,Social determinants of health ,hemodialysis ,Prospective Studies ,Prospective cohort study ,Dialysis ,Renal Medicine ,business.industry ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,General Medicine ,medicine.disease ,Europe ,Hospitalization ,Cardiovascular Diseases ,Food ,Research Design ,Emergency medicine ,Kidney Failure, Chronic ,Female ,Hemodialysis ,business ,Energy Intake ,Kidney disease ,Cohort study - Abstract
Contains fulltext : 153534.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Adults with end-stage kidney disease (ESKD) treated with haemodialysis experience mortality of between 15% and 20% each year. Effective interventions that improve health outcomes for long-term dialysis patients remain unproven. Novel and testable determinants of health in dialysis are needed. Nutrition and dietary patterns are potential factors influencing health in other health settings that warrant exploration in multinational studies in men and women treated with dialysis. We report the protocol of the "DIETary intake, death and hospitalisation in adults with end-stage kidney disease treated with HaemoDialysis (DIET-HD) study," a multinational prospective cohort study. DIET-HD will describe associations of nutrition and dietary patterns with major health outcomes for adults treated with dialysis in several countries. METHODS AND ANALYSIS: DIET-HD will recruit approximately 10,000 adults who have ESKD treated by clinics administered by a single dialysis provider in Argentina, France, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and Turkey. Recruitment will take place between March 2014 and June 2015. The study has currently recruited 8000 participants who have completed baseline data. Nutritional intake and dietary patterns will be measured using the Global Allergy and Asthma European Network (GA(2)LEN) food frequency questionnaire. The primary dietary exposures will be n-3 and n-6 polyunsaturated fatty acid consumption. The primary outcome will be cardiovascular mortality and secondary outcomes will be all-cause mortality, infection-related mortality and hospitalisation. ETHICS AND DISSEMINATION: The study is approved by the relevant Ethics Committees in participating countries. All participants will provide written informed consent and be free to withdraw their data at any time. The findings of the study will be disseminated through peer-reviewed journals, conference presentations and to participants via regular newsletters. We expect that the DIET-HD study will inform large pragmatic trials of nutrition or dietary interventions in the setting of advanced kidney disease.
- Published
- 2015
5. Integrating Murine Gene Expression Studies to Understand Obstructive Lung Disease Due to Chronic Inhaled Endotoxin
- Author
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Lenburg, M, Lai, PS, Hofmann, O, Baron, RM, Cernadas, M, Meng, QR, Bresler, HS, Brass, DM, Yang, IV, Schwartz, DA, Christiani, DC, Hide, W, Lenburg, M, Lai, PS, Hofmann, O, Baron, RM, Cernadas, M, Meng, QR, Bresler, HS, Brass, DM, Yang, IV, Schwartz, DA, Christiani, DC, and Hide, W
- Abstract
RATIONALE: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease. METHODS: We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke. RESULTS: A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature. CONCLUSIONS: Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observe
- Published
- 2013
6. CD1a expression defines an interleukin-12 producing population of human dendritic cells
- Author
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Cernadas, M, primary, Lu, J, additional, Watts, G, additional, and Brenner, M B, additional
- Published
- 2008
- Full Text
- View/download PDF
7. Role of nitric oxide-related mechanisms in renal function in ageing rats
- Author
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Tan, D., primary, Cernadas, M., additional, Aragoncillo, P., additional, Castilla, M., additional, Arroyo, M., additional, Farre, A., additional, Casad, S., additional, and Caramelo, C., additional
- Published
- 1998
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8. Inhibition of T cell costimulation abrogates airway hyperresponsiveness in a murine model.
- Author
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Krinzman, S J, primary, De Sanctis, G T, additional, Cernadas, M, additional, Mark, D, additional, Wang, Y, additional, Listman, J, additional, Kobzik, L, additional, Donovan, C, additional, Nassr, K, additional, Katona, I, additional, Christiani, D C, additional, Perkins, D L, additional, and Finn, P W, additional
- Published
- 1996
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9. Effect of endothelin-1 on neutrophil adhesion to endothelial cells and perfused heart.
- Author
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López Farré, A, primary, Riesco, A, additional, Espinosa, G, additional, Digiuni, E, additional, Cernadas, M R, additional, Alvarez, V, additional, Montón, M, additional, Rivas, F, additional, Gallego, M J, additional, and Egido, J, additional
- Published
- 1993
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10. It takes a microbiome: commensals, immune regulation, and allergy.
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Cernadas M
- Published
- 2011
- Full Text
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11. Surfactant Protein D Influences Mortality During Abdominal Sepsis by Facilitating Escherichia coli Colonization in the Gut.
- Author
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Varon J, Arciniegas Rubio A, Amador-Munoz D, Corcoran A, DeCorte JA, Isabelle C, Pinilla Vera M, Walker K, Brown L, Cernadas M, Bry L, Yang H, Kitsios GD, McVerry BJ, Morris A, Lee H, Howrylak J, Englert JA, and Baron RM
- Abstract
Determine the role of surfactant protein D (SPD) in sepsis., Design: Murine in vivo study., Setting: Research laboratory at an academic medical center., Patients: SPD knockout (SPD
-/- ) and wild-type (SPD+/+ ) mice., Interventions: SPD-/- and SPD+/+ mice were subjected to cecal ligation and puncture (CLP). After CLP, Escherichia coli bacteremia was assessed in both groups. Cecal contents from both groups were cultured to assess for colonization by E. coli . To control for parental effects on the microbiome, SPD-/- and SPD+/+ mice were bred from heterozygous parents, and levels of E. coli in their ceca were measured. Gut segments were harvested from mice, and SPD protein expression was measured by Western blot. SPD-/- mice were gavaged with green fluorescent protein, expressing E. coli and recombinant SPD (rSPD)., Measurements and Main Results: SPD-/- mice had decreased mortality and decreased E. coli bacteremia compared with SPD+/+ mice following CLP. At baseline, SPD-/- mice had decreased E. coli in their cecal flora. When SPD-/- and SPD+/+ mice were bred from heterozygous parents and then separated after weaning, less E. coli was cultured from the ceca of SPD-/- mice. E. coli gut colonization was increased by gavage of rSPD in SPD-/- mice. The source of enteric SPD in SPD+/+ mice was the gallbladder., Conclusions: Enteral SPD exacerbates mortality after CLP by facilitating colonization of the mouse gut with E. coli ., Competing Interests: Dr. Baron reports serving on Advisory Boards for Merck and Genentech. Dr. Kitsios has received research funding from Karius. Dr. McVerry receives research funding from Bayer Pharmaceuticals. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)- Published
- 2022
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12. The effect of elexacaftor/tezacaftor/ivacaftor (ETI) on glycemia in adults with cystic fibrosis.
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Scully KJ, Marchetti P, Sawicki GS, Uluer A, Cernadas M, Cagnina RE, Kennedy JC, and Putman MS
- Subjects
- Adult, Aminophenols adverse effects, Benzodioxoles adverse effects, Blood Glucose, Blood Glucose Self-Monitoring, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Humans, Indoles, Pyrazoles, Pyridines, Pyrrolidines, Quinolones, Cystic Fibrosis complications, Cystic Fibrosis diagnosis, Cystic Fibrosis drug therapy, Hypoglycemia
- Abstract
Background: Cystic fibrosis related diabetes (CFRD) is associated with pulmonary decline and compromised nutritional status. Emerging data suggest that CFTR dysfunction may play a direct role in the pathogenesis of CFRD; however, studies investigating the effect of CFTR modulators on glycemic outcomes in patients with cystic fibrosis (CF) have shown mixed results. The impact of elexacaftor-tezacaftor-ivacaftor (ETI) on glycemic control is currently unknown. Our objective was to investigate the effect of ETI initiation on glycemia in adults with CF using continuous glucose monitoring (CGM)., Methods: In this prospective observational study, 34 adults with CF and at least one F508del CFTR mutation wore CGM sensors for 14 days prior to starting ETI and again 3-12 months after ETI initiation. Hypoglycemia symptoms were queried at each visit, and most recent anthropometric measures and spirometry data were obtained by chart review., Results: Twenty-three participants completed the study. Compared to baseline, average glucose (AG), standard deviation (SD), % time >200 mg/dL, and peak sensor glucose decreased with ETI treatment, and % time in target range 70-180 mg/dL increased. Improvements in glycemic parameters were most notable in individuals with CFRD. There was no significant change in CGM-measured or self-reported hypoglycemia before and after ETI initiation., Conclusion: Initiation of ETI in adults with CF was associated with improvement CGM-derived measures of hyperglycemia and glycemic variability with no effect on hypoglycemia. Further studies are needed to investigate underlying etiology of these changes and the long-term impact of ETI on glycemic control in patients with CF., Competing Interests: Declaration of Competing Interest Dr. Putman reports grants from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, outside the submitted work. Dr. Sawicki reports personal fees from Vertex Pharmaceuticals, outside the submitted work. Dr. Uluer reports grants from the Cystic Fibrosis Foundation and serves an advisory board for Vertex Pharmaceuticals and as an unpaid board member for the Cystic Fibrosis Research Institute. Dr. Kennedy reports grants from the Cystic Fibrosis Foundation. The other authors have nothing to disclose., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2022
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13. Atypical presentation of subdural block resulting in Horner's syndrome and loss of consciousness.
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Chua KJ and Cernadas M
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- Adult, Cesarean Section, Female, Humans, Lidocaine adverse effects, Pregnancy, Unconsciousness, Anesthesia, Epidural adverse effects, Horner Syndrome chemically induced, Horner Syndrome diagnosis
- Abstract
Horner's syndrome is a rare side effect for patients receiving epidural anaesthesia. Studies described Horner's syndrome due to cephalic spread of injected anaesthetics, a high spinal anaesthesia, or a sign of an inadvertent subdural block. A 31-year-old woman (Gravida 1 Para 0) at 40 weeks and 2 days had a caesarean section secondary to second stage arrest. Fourteen minutes after she received the lidocaine bolus, she became unresponsive with nystagmus, unequal pupils and no pupillary reflex. Head CT and MRI showed no intracranial haemorrhage and 2 hours later, she had spontaneous resolution of neurological symptoms with no further sequelae. Although Horner's syndrome is a benign, transient process, clinicians should be mindful regarding epidural catheter placement causing subdural blocks resulting in spontaneous, reversible neurological deficits., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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14. [Home births in Spain].
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Sánchez Redondo MD, Cernadas M, and Couce ML
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- Female, Humans, Pregnancy, Spain, Home Childbirth, Midwifery
- Published
- 2021
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15. CFTR regulates B cell activation and lymphoid follicle development.
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Polverino F, Lu B, Quintero JR, Vargas SO, Patel AS, Owen CA, Gerard NP, Gerard C, and Cernadas M
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- Adolescent, Animals, Cystic Fibrosis pathology, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, B-Lymphocytes metabolism, Cystic Fibrosis metabolism, Cystic Fibrosis Transmembrane Conductance Regulator physiology, Tertiary Lymphoid Structures metabolism
- Abstract
Background: Cystic fibrosis (CF) is an inherited disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that promotes persistent lung infection and inflammation and progressive loss of lung function. Patients with CF have increased lung lymphoid follicles (LFs) and B cell-activating factor of tumor necrosis factor family (BAFF) that regulates B cell survival and maturation. A direct role for CFTR in B cell activation and disease pathogenesis in CF remains unclear., Methods: The number of LFs, BAFF
+ , TLR4+ and proliferation marker Ki67+ B cells in lung explants or resections from subjects with CF and normal controls was quantified by immunostaining. The role of CFTR in B cell activation and LF development was then examined in two independent cohorts of uninfected CFTR-deficient mice (Cftr-/- ) and wild type controls. The number of lung LFs, B cells and BAFF+ , CXCR4+ , immunoglobulin G+ B cells was examined by immunostaining. Lung and splenocyte B cell activation marker and major histocompatibility complex class II (MHC class II) expression was quantified by flow cytometry. Inflammatory cytokine levels were measured in supernatants from isolated B cells from Cftr-/- and wild type mice stimulated in vitro with Pseudomonas aeruginosa lipopolysaccharide (LPS)., Results: There was a significant increase in well-formed LFs in subjects with CF compared to normal controls. Increased B cell activation and proliferation was observed in lung LFs from CF subjects as was quantified by a significant increase in B cell BAFF, TLR4 and Ki67 expression. Uninfected Cftr-/- mice had increased lung LFs and BAFF+ and CXCR4+ B cells compared to wild type controls. Lung B cells isolated from uninfected Cftr-/- mice demonstrated increased MHC class II expression. In vitro, isolated B cells from Cftr-/- mice produced increased IL-6 when stimulated with LPS compared to wild type controls., Conclusions: These data support a direct role for CFTR in B cell activation, proliferation and inflammatory cytokine production that promotes lung LF follicle development in cystic fibrosis.- Published
- 2019
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16. ALX receptor ligands define a biochemical endotype for severe asthma.
- Author
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Ricklefs I, Barkas I, Duvall MG, Cernadas M, Grossman NL, Israel E, Bleecker ER, Castro M, Erzurum SC, Fahy JV, Gaston BM, Denlinger LC, Mauger DT, Wenzel SE, Comhair SA, Coverstone AM, Fajt ML, Hastie AT, Johansson MW, Peters MC, Phillips BR, and Levy BD
- Published
- 2018
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17. ALX receptor ligands define a biochemical endotype for severe asthma.
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Ricklefs I, Barkas I, Duvall MG, Cernadas M, Grossman NL, Israel E, Bleecker ER, Castro M, Erzurum SC, Fahy JV, Gaston BM, Denlinger LC, Mauger DT, Wenzel SE, Comhair SA, Coverstone AM, Fajt ML, Hastie AT, Johansson MW, Peters MC, Phillips BR, and Levy BD
- Abstract
Background: In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA)., Methods: ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47])., Results: Bronchoalveolar lavage (BAL) fluid LXA4 and 15-epi-LXA4 were decreased and SAA was increased in SA relative to NSA. BAL macrophage ALX expression was increased in SA. Subjects with LXA4loSAAhi levels had increased BAL neutrophils, more asthma symptoms, lower lung function, increased relative risk for asthma exacerbation, sinusitis, and gastroesophageal reflux disease, and were assigned more frequently to SA clinical clusters. SAA and aliquots of LXA4loSAAhi BAL fluid induced IL-8 production by lung epithelial cells expressing ALX receptors, which was inhibited by coincubation with 15-epi-LXA4., Conclusions: Together, these findings have established an association between select ALX receptor ligands and asthma severity that define a potentially new biochemical endotype for asthma and support a pivotal functional role for ALX signaling in the fate of lung inflammation., Trial Registration: Severe Asthma Research Program-3 (SARP-3; ClinicalTrials.gov NCT01606826)FUNDING Sources. National Heart, Lung and Blood Institute, the NIH, and the German Society of Pediatric Pneumology.
- Published
- 2017
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18. Alternative Macrophage Activation Is Increased in Asthma.
- Author
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Girodet PO, Nguyen D, Mancini JD, Hundal M, Zhou X, Israel E, and Cernadas M
- Abstract
The immune responses of type 2 T helper cells (Th2) play an important role in asthma and promote the differentiation of alternatively activated (M2) macrophages. M2 macrophages have been increasingly understood to contribute to Th2 immunity. We hypothesized that M2 macrophages are altered in asthma and modulate Th2 responses. The aim of this study was to characterize the phenotype and function of human monocyte-derived M2 and bronchoalveolar lavage fluid (BALF) macrophages from healthy control subjects and subjects with asthma. Phenotypic characteristics and effector function of M2 macrophages were examined using monocyte-derived and BALF macrophages obtained from subjects with asthma (n = 28) and healthy volunteers (n = 9) by flow cytometry and quantitative PCR. Resting monocyte-derived (M0) and M2 macrophages were generated by the addition of macrophage colony-stimulating factor or macrophage colony-stimulating factor plus IL-4, respectively. M2 macrophage cytokine expression and their impact on dendritic and CD4
+ T cell activation were examined in vitro. High levels of CD206 and major histocompatibility complex class II expression identify macrophages with an M2 phenotype that are increased 2.9-fold in the BALF of subjects with asthma compared with control subjects. M2 macrophages have elevated IL-6, IL-10, and IL-12p40 production compared with conventional macrophages and modulate dendritic and CD4+ T cell interactions. Histamine receptor 1 and E-cadherin expression identify M2 macrophage subsets associated with increased airflow obstruction. M2 macrophages have a distinct cell surface and effector phenotype and are found in increased numbers in subjects with asthma. These findings suggest that M2 macrophages may play an important role in allergic asthma through their bidirectional interactions with immune and structural cells, and inflammatory mediators.- Published
- 2016
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19. Circadian rhythm reprogramming during lung inflammation.
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Haspel JA, Chettimada S, Shaik RS, Chu JH, Raby BA, Cernadas M, Carey V, Process V, Hunninghake GM, Ifedigbo E, Lederer JA, Englert J, Pelton A, Coronata A, Fredenburgh LE, and Choi AM
- Subjects
- Animals, CLOCK Proteins immunology, CLOCK Proteins metabolism, Circadian Rhythm immunology, Circadian Rhythm Signaling Peptides and Proteins genetics, Circadian Rhythm Signaling Peptides and Proteins immunology, Circadian Rhythm Signaling Peptides and Proteins metabolism, Endotoxins toxicity, Gene Expression Regulation, Granulocytes immunology, Leukocyte Count, Lung immunology, Lymphocytes immunology, Mice, Pneumonia chemically induced, Pneumonia metabolism, CLOCK Proteins genetics, Circadian Rhythm genetics, Lung metabolism, Pneumonia genetics, RNA, Messenger metabolism
- Abstract
Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian programme exhibits unique features, including a divergent group of rhythmic genes and metabolites compared with the basal state and a distinct periodicity and phase distribution. At the cellular level, endotoxin treatment also alters circadian rhythms of leukocyte counts within the lung in a bmal1-dependent manner, such that granulocytes rather than lymphocytes become the dominant oscillating cell type. Our results show that inflammation produces a complex re-organization of cellular and molecular circadian rhythms that are relevant to early events in lung injury.
- Published
- 2014
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20. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin.
- Author
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Lai PS, Hofmann O, Baron RM, Cernadas M, Meng QR, Bresler HS, Brass DM, Yang IV, Schwartz DA, Christiani DC, and Hide W
- Subjects
- Administration, Inhalation, Algorithms, Animals, Asthma chemically induced, Asthma physiopathology, Gene Expression Profiling, Lung physiopathology, Mice, Multigene Family, Pulmonary Disease, Chronic Obstructive chemically induced, Pulmonary Disease, Chronic Obstructive physiopathology, Smoking, Transcriptome, Asthma genetics, Endotoxins pharmacology, Gene Expression, Lung metabolism, Pulmonary Disease, Chronic Obstructive genetics, Nicotiana chemistry
- Abstract
Rationale: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease., Methods: We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke., Results: A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature., Conclusions: Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observed. The endotoxin component of tobacco smoke may play an important role in disease development.
- Published
- 2013
- Full Text
- View/download PDF
21. Chronic endotoxin exposure produces airflow obstruction and lung dendritic cell expansion.
- Author
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Lai PS, Fresco JM, Pinilla MA, Macias AA, Brown RD, Englert JA, Hofmann O, Lederer JA, Hide W, Christiani DC, Cernadas M, and Baron RM
- Subjects
- Airway Resistance drug effects, Airway Resistance genetics, Airway Resistance immunology, Animals, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Antigen-Presenting Cells pathology, Bronchial Hyperreactivity genetics, Bronchial Hyperreactivity immunology, Bronchial Hyperreactivity metabolism, Bronchial Hyperreactivity pathology, Bronchoalveolar Lavage Fluid immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Dendritic Cells pathology, Endotoxins immunology, Gene Expression, Interleukin-10 genetics, Interleukin-10 immunology, Interleukin-10 metabolism, Interleukin-6 genetics, Interleukin-6 immunology, Interleukin-6 metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear pathology, Lipopolysaccharides immunology, Lipopolysaccharides pharmacology, Lung immunology, Lung metabolism, Lung pathology, Macrophages immunology, Macrophages metabolism, Macrophages pathology, Male, Mice, Mice, Inbred C57BL, Models, Animal, Myeloid Cells drug effects, Myeloid Cells immunology, Myeloid Cells metabolism, Myeloid Cells pathology, Neutrophils drug effects, Neutrophils immunology, Neutrophils metabolism, Neutrophils pathology, Occupational Exposure, Pneumonia genetics, Pneumonia immunology, Pneumonia metabolism, Pneumonia pathology, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, Up-Regulation, Dendritic Cells drug effects, Endotoxins pharmacology, Lung drug effects, Pulmonary Disease, Chronic Obstructive immunology
- Abstract
Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development.
- Published
- 2012
- Full Text
- View/download PDF
22. PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.
- Author
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Chang HH, Tai TS, Lu B, Iannaccone C, Cernadas M, Weinblatt M, Shadick N, Miaw SC, and Ho IC
- Subjects
- Arthritis, Rheumatoid genetics, Blotting, Western, Cell Line, Tumor, DNA Primers genetics, DNA, Complementary genetics, Enzyme-Linked Immunosorbent Assay, Humans, Immunoprecipitation, Leukocytes, Mononuclear, Linear Models, Luciferases, Lymphocyte Activation genetics, Mutation, Missense genetics, Polymorphism, Single Nucleotide genetics, Protein Isoforms blood, Protein Isoforms genetics, Real-Time Polymerase Chain Reaction, Alternative Splicing genetics, Arthritis, Rheumatoid blood, Biomarkers blood, Models, Biological, Protein Tyrosine Phosphatase, Non-Receptor Type 22 blood, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, T-Lymphocytes immunology
- Abstract
PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.
- Published
- 2012
- Full Text
- View/download PDF
23. Synovial fibroblasts self-direct multicellular lining architecture and synthetic function in three-dimensional organ culture.
- Author
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Kiener HP, Watts GF, Cui Y, Wright J, Thornhill TS, Sköld M, Behar SM, Niederreiter B, Lu J, Cernadas M, Coyle AJ, Sims GP, Smolen J, Warman ML, Brenner MB, and Lee DM
- Subjects
- Animals, Extracellular Matrix ultrastructure, Glycoproteins biosynthesis, Humans, Inflammation physiopathology, Macrophages cytology, Mice, Organ Culture Techniques, Synovial Membrane anatomy & histology, Fibroblasts physiology, Synovial Fluid chemistry, Synovial Membrane cytology
- Abstract
Objective: To define the intrinsic capacity of fibroblast-like synoviocytes (FLS) to establish a 3-dimensional (3-D) complex synovial lining architecture characterized by the multicellular organization of the compacted synovial lining and the elaboration of synovial fluid constituents., Methods: FLS were cultured in spherical extracellular matrix (ECM) micromasses for 3 weeks. The FLS micromass architecture was assessed histologically and compared with that of dermal fibroblast controls. Lubricin synthesis was measured via immunodetection. Basement membrane matrix and reticular fiber stains were performed to examine ECM organization. Primary human and mouse monocytes were prepared and cocultured with FLS in micromass to investigate cocompaction in the lining architecture. Cytokine stimuli were applied to determine the capacity for inflammatory architecture rearrangement., Results: FLS, but not dermal fibroblasts, spontaneously formed a compacted lining architecture over 3 weeks in the 3-D ECM micromass organ cultures. These lining cells produced lubricin. FLS rearranged their surrounding ECM into a complex architecture resembling the synovial lining and supported the survival and cocompaction of monocyte/macrophages in the neo-lining structure. Furthermore, when stimulated by cytokines, FLS lining structures displayed features of the hyperplastic rheumatoid arthritis synovial lining., Conclusion: This 3-D micromass organ culture method demonstrates that many of the phenotypic characteristics of the normal and the hyperplastic synovial lining in vivo are intrinsic functions of FLS. Moreover, FLS promote survival and cocompaction of primary monocytes in a manner remarkably similar to that of synovial lining macrophages. These findings provide new insight into inherent functions of the FLS lineage and establish a powerful in vitro method for further investigation of this lineage.
- Published
- 2010
- Full Text
- View/download PDF
24. Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphingolipids presented by CD1d [corrected].
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Muindi K, Cernadas M, Watts GF, Royle L, Neville DC, Dwek RA, Besra GS, Rudd PM, Butters TD, and Brenner MB
- Subjects
- Animals, Biological Transport immunology, Cell Line, Chromatography, High Pressure Liquid, Enzyme-Linked Immunosorbent Assay, Fluorescence, Glycosphingolipids metabolism, Humans, Mice, Microscopy, Confocal, Natural Killer T-Cells metabolism, Antigen Presentation immunology, Antigen-Presenting Cells immunology, Antigens, CD1d immunology, Glycosphingolipids immunology, Lymphocyte Activation immunology, Natural Killer T-Cells immunology
- Abstract
Myeloid antigen-presenting cells (APC) express CD1d molecules that present exogenous and endogenous lipid antigens that activate CD1d-restricted T cells, natural killer T (NKT) cells. NKT cell activation has been shown to mediate the potent downstream activation of other immune cells through cell-cell interactions and rapid, prolific cytokine production. Foreign antigens are not required for NKT cell activation. The endogenous lipids bound to CD1d are sufficient for activation of NKT cells in the setting of Toll-like receptor-induced cytokines. The most potent NKT cell antigens identified are glycosphingolipids (GSL). The GSL repertoire of endogenous ligands bound to CD1d molecules that are expressed in myeloid APC at steady state and in the setting of activation has not been delineated. This report identifies the range of GSL bound to soluble murine CD1d (mCD1d) molecules that sample the endoplasmic reticulum/secretory routes and cell surface-cleaved mCD1d that also samples the endocytic system. Specific GSL species are preferentially bound by mCD1d and do not solely reflect cellular GSL. GM1a and GD1a are prominent CD1d ligands for molecules following both the ER/secretory and lysosomal trafficking routes, whereas GM2 was eluted from soluble CD1d but not lysosomal trafficking CD1d. Further, after LPS activation, the quantities of soluble CD1d-bound GM3 and GM1a markedly increased. A unique alpha-galactose-terminating GSL was also found to be preferentially bound to mCD1d at steady state, and it increased with APC activation. Together, these studies identify the range of GSL presented by CD1d and how presentation varies based on CD1d intracellular trafficking and microbial activation.
- Published
- 2010
- Full Text
- View/download PDF
25. The role of alpha and beta chains in ligand recognition by beta 7 integrins.
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Higgins JM, Cernadas M, Tan K, Irie A, Wang J, Takada Y, and Brenner MB
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal metabolism, CHO Cells, Cadherins metabolism, Cell Adhesion, Cell Adhesion Molecules, Cricetinae, Electrophoresis, Polyacrylamide Gel, Epitope Mapping, Fibronectins metabolism, Flow Cytometry, Glutamic Acid chemistry, Humans, Immunoglobulins metabolism, Integrins genetics, Integrins metabolism, K562 Cells, Ligands, Models, Molecular, Molecular Sequence Data, Mucoproteins metabolism, Mutation, Phenylalanine chemistry, Precipitin Tests, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Transfection, Vascular Cell Adhesion Molecule-1 metabolism, Integrin beta Chains, Integrins chemistry
- Abstract
Integrins alpha(E)beta(7) and alpha(4)beta(7) are involved in localization of leukocytes at mucosal sites. Although both alpha(E)beta(7) and alpha(4)beta(7) utilize the beta(7) chain, they have distinct binding specificities for E-cadherin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), respectively. We found that mutation of the metal ion-dependent adhesion site (MIDAS) in the alpha(E) A-domain (D190A) abolished E-cadherin binding, as did mutation F298A on the A-domain surface near the MIDAS cleft. A docking model of the A-domain with E-cadherin domain 1 indicates that coordination of the alpha(E) MIDAS metal ion by E-cadherin Glu(31) and a novel projection of Phe(298) into a hydrophobic pocket on E-cadherin provide the basis for the interaction. The location of the binding site on the alpha(E) A-domain resembles that on other integrins, but its structure appears distinctive and particularly adapted to recognize the tip of E-cadherin, a unique integrin ligand. Additionally, mutation of the beta(7) MIDAS motif (D140A) abolished alpha(E)beta(7) binding to E-cadherin and alpha(4)beta(7)-mediated adhesion to MAdCAM-1, and alpha(4) chain mutations that abrogated binding of alpha(4)beta(1) to vascular cell adhesion molecule-1 and fibronectin similarly reduced alpha(4)beta(7) interaction with MAdCAM-1. Thus, although specificity can be determined by the integrin alpha or beta chain, common structural features of both subunits are required for recognition of dissimilar ligands.
- Published
- 2000
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26. B7-1 (CD80) and B7-2 (CD86) have complementary roles in mediating allergic pulmonary inflammation and airway hyperresponsiveness.
- Author
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Mark DA, Donovan CE, De Sanctis GT, He HZ, Cernadas M, Kobzik L, Perkins DL, Sharpe A, and Finn PW
- Subjects
- Animals, Antigens, CD genetics, B7-1 Antigen genetics, B7-2 Antigen, Eosinophilia genetics, Eosinophilia immunology, Gene Deletion, Germ-Line Mutation, Immunoglobulin E blood, Interferon-gamma blood, Interleukin-4 blood, Interleukin-5 blood, Lung immunology, Male, Membrane Glycoproteins genetics, Mice, Mice, Knockout, Tumor Necrosis Factor-alpha metabolism, Antigens, CD immunology, B7-1 Antigen immunology, Bronchial Hyperreactivity immunology, Membrane Glycoproteins immunology, Respiratory Hypersensitivity immunology
- Abstract
We examined the roles of B7-1 (CD80) and B7-2 (CD86) in a model of allergic pulmonary inflammation and airway hyperresponsiveness (AHR) by using mice with germline deletions of the B7-1 and/or B7-2 molecules. Multiple parameters of the allergic response were affected to varying degrees by the absence of B7-1 and/or B7-2. Mice lacking both B7-1 and B7-2 had no elevation of serum immunoglobulin E, lack of airway eosinophilia, and no AHR. These same disease parameters were also reduced in mice lacking either B7-1 or B7-2. Lack of B7-1 and/or B7-2 resulted in an increase in T-helper 1 cytokine production. Our observations suggest that whereas B7-2 is quantitatively more significant in the induction of this response, B7-1 and B7-2 may have complementary roles in mediating the development of allergic pulmonary inflammation.
- Published
- 2000
- Full Text
- View/download PDF
27. CD23 and allergic pulmonary inflammation: potential role as an inhibitor.
- Author
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Cernadas M, De Sanctis GT, Krinzman SJ, Mark DA, Donovan CE, Listman JA, Kobzik L, Kikutani H, Christiani DC, Perkins DL, and Finn PW
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Bronchoalveolar Lavage Fluid cytology, CD8-Positive T-Lymphocytes immunology, Female, Immunoglobulin E blood, Immunoglobulin Fab Fragments pharmacology, Leukocyte Count, Lymphocyte Activation, Male, Mice, Mice, Inbred BALB C, Ovalbumin immunology, Receptors, IgE antagonists & inhibitors, Receptors, IgE deficiency, Receptors, IgE immunology, Respiratory Hypersensitivity immunology
- Abstract
CD23, a receptor for immunoglobulin E, is expressed at increased levels in asthmatic and atopic individuals and has been associated with disorders characterized by chronic inflammation. Using an established murine model, we employed several complementary strategies to investigate the role of CD23 in allergic pulmonary inflammation and airway hyperresponsiveness (AHR). Specifically, these approaches included the modulation of CD23 function in vivo by administration of anti-CD23 monoclonal antibody (mAb) or Fab fragments to wild-type mice and the analysis of CD23-deficient mice. Administration of anti-CD23 mAb, but not anti-CD23 Fab fragments, produced attenuation of pulmonary inflammation, AHR, and CD8(+) T-cell activation. On the basis of a model that the anti-CD23 mAb transduces, whereas the Fab fragment inhibits, CD23 signaling, these results suggest that CD23 negatively regulates pulmonary inflammation and AHR. This hypothesis is supported by our observation that CD23-deficient mice developed increased inflammation and AHR after sensitization and challenge with allergen. Together, these results indicate that CD23 negatively regulates pulmonary inflammation and airway hyperreactivity.
- Published
- 1999
- Full Text
- View/download PDF
28. Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats.
- Author
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Cernadas MR, Sánchez de Miguel L, García-Durán M, González-Fernández F, Millás I, Montón M, Rodrigo J, Rico L, Fernández P, de Frutos T, Rodríguez-Feo JA, Guerra J, Caramelo C, Casado S, and López-Farré
- Subjects
- Acetylcholine pharmacology, Animals, Aorta metabolism, Arginine analogs & derivatives, Arginine pharmacology, Blood Pressure drug effects, Bradykinin pharmacology, Calcium metabolism, Cattle, Endothelium, Vascular drug effects, Enzyme Induction, Enzyme Inhibitors pharmacology, Male, Nitric Oxide Synthase genetics, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Nitroprusside pharmacology, Penicillamine analogs & derivatives, Penicillamine pharmacology, Rats, Rats, Wistar, S-Nitroso-N-Acetylpenicillamine, Vasodilator Agents pharmacology, Aging metabolism, Endothelium, Vascular enzymology, Nitric Oxide Synthase biosynthesis
- Abstract
Two NO synthase (NOS) isoforms have been described in vessels, an endothelial constitutive NOS (eNOS) and an inducible NOS (iNOS). The purpose of the present study was to examine the endothelium-dependent and endothelium-independent hypotensive response in aging rats, analyzing the ability of their vessels to produce NO. The studies were performed in 2 groups of euvolemic, conscious, male Wistar rats: aging rats (n=20, 18 months old) and young rats (n=20, 5 months old). The hypotensive responses to acetylcholine, bradykinin, and sodium nitroprusside were determined. Furthermore, the expression of the NOS isoforms by Western blot and the eNOS and iNOS activities, defined as Ca2+-dependent and Ca2+-independent conversion of [14C]L-arginine into [14C]L-citrulline, respectively, were also determined. In the aging rats, we found an impaired hypotensive response to acetylcholine and bradykinin (2 NO- and endothelium-dependent hypotensive agents) that was accompanied by a preserved hypotensive response to sodium nitroprusside. Aging rats also demonstrated an enhanced sensitivity response to the pressor effect of the L-arginine antagonist L-Nomega-nitro-L-arginine and a reduced vasoconstrictor response to angiotensin II. The inhibition of NO synthesis normalized the pressor effect of angiotensin II in the aging animals. Nitrite plus nitrate plasma levels were increased in aging rats. Furthermore, cGMP content was also higher in the aging vessels. In the aging aortas, the expression of both eNOS and iNOS isoforms was enhanced. However, in aging rats, the activity of the eNOS isoform was markedly reduced, a finding that was accompanied by the presence of iNOS activity. The vessel wall of aging rats showed an enhanced expression of eNOS and iNOS isoforms. However, eNOS activity was reduced in the aging animals. These findings could explain the impaired endothelium-dependent hypotensive response associated with aging.
- Published
- 1998
- Full Text
- View/download PDF
29. Role of endothelium-related mechanisms in the pathophysiology of renal ischemia/reperfusion in normal rabbits.
- Author
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Caramelo C, Espinosa G, Manzarbeitia F, Cernadas MR, Pérez Tejerizo G, Tan D, Mosquera JR, Digiuni E, Montón M, Millás I, Hernando L, Casado S, and López-Farré A
- Subjects
- Animals, Arginine physiology, Hemodynamics, Ischemia pathology, Kidney metabolism, Kidney pathology, Kidney physiopathology, Male, Neutrophils pathology, Nitric Oxide physiology, Nitrites urine, Peroxidase metabolism, Rabbits, Reference Values, Time Factors, Vasodilation physiology, Endothelium, Vascular physiology, Ischemia physiopathology, Renal Circulation, Reperfusion
- Abstract
The present study addressed the effect of interventions aimed to increase NO in the setting of acute renal ischemia/reperfusion (I/R) in uninephrectomized rabbits. In the 60-minute post-I/R period, L-arginine+superoxide (O2.-) dismutase (SOD) synergistically improved the renal functional (69.4% versus 10.4% of the pre-I/R glomerular filtration rate with or without L-arginine+SOD, respectively; p < .01) and histological parameters (82.9% decrease of medullary congestion in L-arginine+SOD, P < .01 versus vehicle) and blocked the I/R-dependent neutrophil accumulation (89.3% reduction). In spite of these results over the short term, a second set of experiments disclosed that the protection by L-arginine+SOD was no longer present at 24 and 48 hours (plasma creatinine in vehicle-treated versus L-arginine+SOD-treated animals [mg/100 mL]: 24 hours after I/R, 9.4 +/- 1.9 versus 8.07 +/- 0.65; 48 hours after I/R, 11.6 +/- 3.6 versus 9.7 +/- 0.9; P = NS in all the cases). Additional experiments were conducted using a milder 30-minute ischemic model, which showed no significant functional or histological protection by using L-arginine+SOD. In conclusion, our experiments disclosed the following: (1) the critical importance of the interaction between NO and O2.- in the acute protective effect of L-arginine (this effect not only improved renal function and histology but also reduced neutrophil accumulation) and (2) the discordance existing between the immediate protection afforded by L-arginine+SOD and the lack of protection observed at 24 and 48 hours. This finding suggests that a punctual intervention on the NO system at the time of I/R is not sufficient to reduce renal damage over the long term.
- Published
- 1996
- Full Text
- View/download PDF
30. Role of endothelin in the pathophysiology of renal ischemia-reperfusion in normal rabbits.
- Author
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Espinosa G, López Farré A, Cernadas MR, Manzarbeitia F, Tan D, Digiuni E, Mosquera JR, Montón M, Millás I, Hernando L, Casado S, and Caramelo C
- Subjects
- Animals, Endothelin-1 blood, Endothelin-1 pharmacology, Flow Cytometry, Kidney cytology, Kidney Diseases immunology, Kidney Function Tests, Leukocyte Count, Male, Neutrophils cytology, Neutrophils enzymology, Neutrophils immunology, Organ Culture Techniques, Perfusion, Peroxidase metabolism, Rabbits, Endothelin-1 physiology, Kidney blood supply, Kidney Diseases physiopathology, Reperfusion Injury physiopathology
- Abstract
The present study addressed the acute effects of endothelin-1 on renal function and neutrophils accumulation in the setting of in vivo severe (60 min) acute ischemia/reperfusion. Ischemia/reperfusion decreased renal functional parameters and increased renal neutrophil accumulation and medullary congestion. All these parameters markedly improved with the intrarenal administration of anti-endothelin-1 antiserum. Comparatively, the intrarenal infusion of endothelin-1 decreased renal function and increased neutrophil accumulation. Abnormalities in renal histology were, however, less pronounced than with ischemia/ reperfusion. In experiments using rabbit isolated perfused kidneys, endothelin-1 induced the accumulation of labeled neutrophils. This accumulation was similar to that observed in kidneys obtained after 60 minutes of ischemia plus 60 minutes of reperfusion. Both endothelin and ischemia/ reperfusion effects were counteracted by an anti-endothelin antibody. In further in vitro studies, we found that endothelin-1-induced the expression of the CD18 antigens on the neutrophil surface. In subsequent experiments based on this effect of ET-1 on CD18 antigens, a blockade of both ischemia/reperfusion-induced and endothelin-1-induced neutrophil accumulation was obtained by infusion an anti-CD18 antibody. In conclusion, our experiments disclosed the critical role of endothelin-1 as a major promoter of early neutrophil accumulation after ischemia/reperfusion, which occurred through an integrin-mediated mechanism.
- Published
- 1996
- Full Text
- View/download PDF
31. Aspirin-stimulated nitric oxide production by neutrophils after acute myocardial ischemia in rabbits.
- Author
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López-Farré A, Riesco A, Digiuni E, Mosquera JR, Caramelo C, de Miguel LS, Millás I, de Frutos T, Cernadas MR, Montón M, Alonso J, and Casado S
- Subjects
- Animals, Male, Neutrophils physiology, Nitric Oxide physiology, Platelet Activation drug effects, Platelet Aggregation drug effects, Rabbits, Superoxides metabolism, Aspirin pharmacology, Myocardial Ischemia metabolism, Neutrophils metabolism, Nitric Oxide biosynthesis
- Abstract
Background: In recent studies, it has been hypothesized that the protective anti-ischemic effects of aspirin outweigh the effects of inhibition of platelet thromboxane A2 synthesis. Recently, we have found that the antiaggregating effects of aspirin significantly affect nitric oxide (NO) generation by neutrophils., Methods and Results: The present study used circulating neutrophils from myocardial ischemic rabbits to assess the effect of aspirin on the circulating neutrophil-derived NO production and, subsequently, on the modulation of platelet activation. Neutrophils were obtained after 60 minutes of coronary artery occlusion followed by 60 minutes of reperfusion. Sham-operated animals were used as controls. The results demonstrated that aspirin stimulated the production of NO by neutrophils obtained from both sham-operated rabbits and rabbits with myocardial ischemia. However, neutrophils isolated from animals with myocardial ischemia showed an enhanced ability to generate NO in the presence of aspirin. As a functional in vitro marker, we observed that neutrophils had a NO-dependent, platelet-antiactivating effect in the presence of aspirin. In the absence of aspirin, ischemic neutrophils did not modify platelet activation, even though they produced increased amounts of NO. An inhibitory role of superoxide anion on the neutrophil-related antiplatelet effect was suggested because superoxide dismutase induced significant platelet inhibition by myocardial ischemic neutrophils in the absence of aspirin., Conclusions: Our results show that myocardial ischemia/reperfusion stimulates production of NO by circulating neutrophils, an effect that was enhanced in the presence of aspirin. These results suggest a novel interpretation of the protective effect of aspirin on myocardial ischemia damage.
- Published
- 1996
- Full Text
- View/download PDF
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