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        "titulo" => "Un inhibidor selectivo de la ciclooxigenasa-2 empeora la funci&#243;n respiratoria y fomenta la actividad de los mastocitos en ratones sensibilizados a la ovalb&#250;mina"
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><p class="elsevierStyleSimplePara elsevierViewall">Cyclooxygenase &#40;COX&#41;-2 activity has been said to have a protective effect in asthmatic patients as a result of prostaglandin E<span class="elsevierStyleInf">2</span> production&#46; In order to elucidate the mechanisms involved&#44; we evaluated the impact of selective inhibition of COX-2 with rofecoxib during ovalbumin &#40;OVA&#41; challenge&#44; assessing mast cell activity and airway response in a murine model of asthma&#46;</p> <span class="elsevierStyleSectionTitle">Material and methods</span><p class="elsevierStyleSimplePara elsevierViewall">Mice were sensitized to OVA &#40;10 &#956;g injected intraperitoneally&#41; and further challenged with 0&#46;5&#37; intranasal OVA&#46; Half the sensitized animals were treated orally with rofecoxib &#40;15 mg&#47;kg&#47;d during the challenge phase&#41;&#46; Lung function was measured by whole body plethysmography before and after exposure to OVA&#46; The severity of airway inflammation was evaluated by means of a scoring system&#46; Finally&#44; the serum level of mouse mast cell protease &#40;mMCP&#41;-1 was determined as an indicator of mucosal mast cell activity&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p class="elsevierStyleSimplePara elsevierViewall">Sensitized mice treated with rofecoxib exhibited 2&#46;4-fold greater airway hyperresponsiveness than did vehicle-treated mice at a methacholine concentration of 100 mg&#47;mL&#46; A clear trend toward worsening airway inflammation in the presence of rofecoxib was observed&#44; although the difference between rofecoxibtreated and vehicle-treated animals was not significant&#46; These changes were accompanied by a significant increase in mucosal mast cell activity&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p class="elsevierStyleSimplePara elsevierViewall">Selective pharmacological inhibition of COX-2 during the challenge phase worsens airway function in the OVA-induced murine model of acute asthma&#46; We suggest that this effect might be at least partially explained by the increase in airway mast cell activity&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introducci&#243;n y objetivo</span><p class="elsevierStyleSimplePara elsevierViewall">Se ha se&#241;alado que la ciclooxigenasa-2 &#40;COX-2&#41; ejerce una funci&#243;n protectora en pacientes con asma mediante la producci&#243;n de la prostaglandina E<span class="elsevierStyleInf">2</span>&#46; Con el objetivo de reproducir dicho efecto en un modelo experimental y dilucidar los mecanismos implicados&#44; hemos evaluado&#44; en un modelo de asma al&#233;rgica en el rat&#243;n&#44; el efecto de la inhibici&#243;n de la COX-2 en la respuesta de las v&#237;as a&#233;reas expuestas a ovalb&#250;mina y en la actividad de los mastocitos&#46;</p> <span class="elsevierStyleSectionTitle">Material y m&#233;todos</span><p class="elsevierStyleSimplePara elsevierViewall">Se sensibilizaron ratones a la ovalb&#250;mina &#40;10 &#956;g&#44; v&#237;a intraperitoneal&#41; y se reexpusieron a ovalb&#250;mina al 0&#44;5&#37; por v&#237;a intranasal&#46; La mitad de los animales sensibilizados recibi&#243; tratamiento con rofecoxib &#40;15 mg&#47;kg al d&#237;a&#44; por v&#237;a oral&#44; durante la fase de reexposici&#243;n&#41;&#46; Se evalu&#243; la funci&#243;n pulmonar mediante pletismograf&#237;a corporal antes y despu&#233;s de la reexposici&#243;n a ovalb&#250;mina&#44; y se estableci&#243; el grado de inflamaci&#243;n broncovascular&#46; Tambi&#233;n se midi&#243; la concentraci&#243;n s&#233;rica de la proteasa-1 de los mastocitos de rat&#243;n&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p class="elsevierStyleSimplePara elsevierViewall">Los ratones sensibilizados y tratados con rofecoxib mostraron una hiperreactividad bronquial 2&#44;4 veces mayor que los del grupo control a una concentraci&#243;n de 100 mg&#47;ml de metacolina&#46; Asimismo&#44; se apreci&#243; una clara tendencia hacia el empeoramiento del proceso inflamatorio en presencia de rofecoxib&#44; aunque sin significaci&#243;n estad&#237;stica&#46; Estos cambios se acompa&#241;aron de un aumento significativo de la actividad de los mastocitos de la mucosa&#46;</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p class="elsevierStyleSimplePara elsevierViewall">La inhibici&#243;n farmacol&#243;gica de la COX-2 durante la reexposici&#243;n a ovalb&#250;mina agrava la funci&#243;n pulmonar&#44; un fen&#243;meno que consideramos se debe&#44; al menos en parte&#44; al incremento de la actividad de los mastocitos de las v&#237;as a&#233;reas&#46;</p>"
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                      "titulo" => "Central and peripheral roles of prostaglandins in pain and their interactions with novel neuropeptides nociceptin and nocistatin"
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                          "etal" => false
                          "autores" => array:4 [
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                            2 => "E&#46; Shitaka"
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                          "autores" => array:2 [
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                        "tituloSerie" => "Treat Respir Med"
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                            2 => "H&#46; Tanaka"
                            3 => "Y&#46; Takahashi"
                            4 => "T&#46; Murata"
                            5 => "K&#46; Kabashima"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "2000"
                        "volumen" => "287"
                        "paginaInicial" => "2013"
                        "paginaFinal" => "2017"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10720327"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of inhaled PGE<span class="elsevierStyleInf">2</span> on exercise-induced bronchoconstriction in asthmatic subjects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "E&#46; Melillo"
                            1 => "K&#46;L&#46; Woolley"
                            2 => "P&#46;J&#46; Manning"
                            3 => "R&#46;M&#46; Watson"
                            4 => "P&#46;M&#46; O&#8217;Byrne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.149.5.8173753"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1994"
                        "volumen" => "149"
                        "paginaInicial" => "1138"
                        "paginaFinal" => "1141"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8173753"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhaled PGE<span class="elsevierStyleInf">2</span> prevents aspirin-induced bronchoconstriction and urinary LTC4 excretion in aspirin-sensitive asthmatics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Sestini"
                            1 => "L&#46; Armetti"
                            2 => "G&#46; Gambaro"
                            3 => "M&#46;G&#46; Pieroni"
                            4 => "R&#46;M&#46; Refini"
                            5 => "A&#46; Sala"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.153.2.8564100"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1996"
                        "volumen" => "153"
                        "paginaInicial" => "572"
                        "paginaFinal" => "575"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8564100"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Protective effects of inhaled PGE<span class="elsevierStyleInf">2</span> on allergen-induced airway responses and airway inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "G&#46;M&#46; Gauvreau"
                            1 => "R&#46;M&#46; Watson"
                            2 => "P&#46;M&#46; O&#8217;Byrne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.159.1.9804030"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1999"
                        "volumen" => "159"
                        "paginaInicial" => "31"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9872814"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The refractory period after exercise-induced asthma&#58; its duration and relation to the severity of exercise"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46;T&#46; Edmunds"
                            1 => "M&#46; Tooley"
                            2 => "S&#46; Godfrey"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/arrd.1978.117.2.247"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am Rev Respir Dis"
                        "fecha" => "1978"
                        "volumen" => "117"
                        "paginaInicial" => "247"
                        "paginaFinal" => "254"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/637407"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exercise-induced refractoriness in asthmatic subjects involves leukotriene and prostaglandin interdependent mechanisms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "P&#46;J&#46; Manning"
                            1 => "R&#46;M&#46; Watson"
                            2 => "P&#46;M&#46; O&#8217;Byrne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm/148.4_Pt_1.950"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am Rev Respir Dis"
                        "fecha" => "1993"
                        "volumen" => "148"
                        "paginaInicial" => "950"
                        "paginaFinal" => "954"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8214949"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cyclooxygenase-2 mRNA is downexpressed in nasal polyps from aspirin-sensitive asthmatics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Picado"
                            1 => "J&#46;C&#46; Fern&#225;ndez-Morata"
                            2 => "M&#46; Juan"
                            3 => "J&#46; Roca-Ferrer"
                            4 => "M&#46; Fuentes"
                            5 => "A&#46; Xaubet"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.160.1.9808048"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1999"
                        "volumen" => "160"
                        "paginaInicial" => "291"
                        "paginaFinal" => "296"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10390414"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;L&#46; Kowalski"
                            1 => "R&#46; Pawliczak"
                            2 => "J&#46; Wozniak"
                            3 => "K&#46; Siuda"
                            4 => "M&#46; Poniatowska"
                            5 => "J&#46; Iwaszkiewicz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.161.2.9902034"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2000"
                        "volumen" => "161"
                        "paginaInicial" => "391"
                        "paginaFinal" => "398"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10673176"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cyclooxygenase-1 and-2 expression is abnormally regulated in human nasal polyps"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Mullol"
                            1 => "J&#46;C&#46; Fern&#225;ndez-Morata"
                            2 => "J&#46; Roca-Ferrer"
                            3 => "L&#46; Pujols"
                            4 => "A&#46; Xaubet"
                            5 => "P&#46; Ben&#237;tez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2002"
                        "volumen" => "109"
                        "paginaInicial" => "824"
                        "paginaFinal" => "830"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11994707"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "PAR-2 activation&#44; PGE<span class="elsevierStyleInf">2</span>&#44; and COX-2 in human asthmatic and nonasthmatic airway smooth muscle cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;S&#46; Chambers"
                            1 => "J&#46;L&#46; Black"
                            2 => "Q&#46; Ge"
                            3 => "S&#46;M&#46; Carlin"
                            4 => "W&#46;W&#46; Au"
                            5 => "M&#46; Poniris"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/ajplung.00416.2002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Physiol Lung Cell Mol Physiol"
                        "fecha" => "2003"
                        "volumen" => "285"
                        "paginaInicial" => "L619"
                        "paginaFinal" => "L627"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12754192"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nuclear factor-kappaB activity is down-regulated in nasal polyps from aspirin-sensitive asthmatics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Picado"
                            1 => "G&#46; Bioque"
                            2 => "J&#46; Roca-Ferrer"
                            3 => "L&#46; Pujols"
                            4 => "J&#46; Mullol"
                            5 => "P&#46; Ben&#237;tez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Allergy"
                        "fecha" => "2003"
                        "volumen" => "58"
                        "paginaInicial" => "122"
                        "paginaFinal" => "126"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12622742"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Deficient prostaglandin E<span class="elsevierStyleInf">2</span> production by bronchial fibroblasts of asthmatic patients&#44; with special reference to aspirin-induced asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46; Pierzchalska"
                            1 => "Z&#46; Szabo"
                            2 => "M&#46; Sanak"
                            3 => "J&#46; Soja"
                            4 => "A&#46; Szczeklik"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2003"
                        "volumen" => "1111"
                        "paginaInicial" => "1041"
                        "paginaFinal" => "1048"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use of the mouse to unravel allergic asthma&#58; a review of the pathogenesis of allergic asthma in mouse models and its similarity to the condition in humans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Torres"
                            1 => "C&#46; Picado"
                            2 => "F&#46; de Mora"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2005"
                        "volumen" => "41"
                        "paginaInicial" => "141"
                        "paginaFinal" => "152"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15766467"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Allergic lung responses are increased in prostaglandin H synthase-deficient mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;H&#46; Gavett"
                            1 => "S&#46;L&#46; Madison"
                            2 => "P&#46;C&#46; Chulada"
                            3 => "P&#46;E&#46; Scarborough"
                            4 => "W&#46; Qu"
                            5 => "J&#46;E&#46; Boyle"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI6890"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1999"
                        "volumen" => "104"
                        "paginaInicial" => "721"
                        "paginaFinal" => "732"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10491407"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;S&#46; Peebles Jr"
                            1 => "R&#46; Dworski"
                            2 => "R&#46;D&#46; Collins"
                            3 => "K&#46; Jarzecka"
                            4 => "D&#46;B&#46; Mitchell"
                            5 => "B&#46;S&#46; Graham"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.162.2.9911063"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2000"
                        "volumen" => "162"
                        "paginaInicial" => "676"
                        "paginaFinal" => "681"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10934105"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;S&#46; Peebles Jr"
                            1 => "K&#46; Hashimoto"
                            2 => "J&#46;D&#46; Morrow"
                            3 => "R&#46; Dworski"
                            4 => "R&#46;D&#46; Collins"
                            5 => "Y&#46; Hashimoto"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.165.8.2106025"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2002"
                        "volumen" => "165"
                        "paginaInicial" => "1154"
                        "paginaFinal" => "1160"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11956061"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Augmentation of allergic inflammation in the airways of cyclooxygenase-2-deficient mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Nakata"
                            1 => "M&#46; Kondo"
                            2 => "J&#46; Tamaoki"
                            3 => "T&#46; Takemiya"
                            4 => "M&#46; Nohara"
                            5 => "K&#46; Yamagata"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1440-1843.2005.00687.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Respirology"
                        "fecha" => "2005"
                        "volumen" => "10"
                        "paginaInicial" => "149"
                        "paginaFinal" => "156"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15823178"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of the mast cell in the pathophysiology of asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "P&#46; Bradding"
                            1 => "A&#46;F&#46; Walls"
                            2 => "S&#46;T&#46; Holgate"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2006.02.039"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2006"
                        "volumen" => "117"
                        "paginaInicial" => "1277"
                        "paginaFinal" => "1284"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16750987"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human mast cells express multiple EP receptors for prostaglandin E<span class="elsevierStyleInf">2</span> that differentially modulate activation responses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "C&#46; Feng"
                            1 => "E&#46;M&#46; Beller"
                            2 => "S&#46; Bagga"
                            3 => "J&#46; Boyce"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2005-07-2772"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2006"
                        "volumen" => "107"
                        "paginaInicial" => "3243"
                        "paginaFinal" => "3250"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16357326"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prostaglandin E<span class="elsevierStyleInf">2</span> activates EP2 receptors to inhibit human lung mast cell degranulation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46;J&#46; Kay"
                            1 => "W&#46;Y&#46; Wilfred"
                            2 => "P&#46;T&#46; Peachell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.bjp.0706664"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Pharmacol"
                        "fecha" => "2006"
                        "volumen" => "147"
                        "paginaInicial" => "707"
                        "paginaFinal" => "713"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16432506"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Kobayashi"
                            1 => "T&#46; Miura"
                            2 => "T&#46; Haba"
                            3 => "M&#46; Sato"
                            4 => "I&#46; Serizawa"
                            5 => "H&#46; Nagai"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "2000"
                        "volumen" => "164"
                        "paginaInicial" => "3855"
                        "paginaFinal" => "3861"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10725747"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Hamelmann"
                            1 => "J&#46; Schwarze"
                            2 => "K&#46; Takeda"
                            3 => "A&#46; Oshiba"
                            4 => "G&#46;L&#46; Larsen"
                            5 => "C&#46;G&#46; Irvin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.156.3.9606031"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1997"
                        "volumen" => "156"
                        "paginaInicial" => "766"
                        "paginaFinal" => "775"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9309991"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Further exploration of the Penh parameter"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46; Lomask"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.etp.2006.02.014"
                      "Revista" => array:7 [
                        "tituloSerie" => "Exp Toxicol Pathol"
                        "fecha" => "2006"
                        "volumen" => "57"
                        "numero" => "Suppl 2"
                        "paginaInicial" => "13"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16638630"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "In situ detection of the mast cell proteases chymase and tryptase in human lung tissue using light and electron microscopy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "W&#46;J&#46; Beil"
                            1 => "J&#46; Pammer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00418-001-0339-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Histochem Cell Biol"
                        "fecha" => "2001"
                        "volumen" => "116"
                        "paginaInicial" => "483"
                        "paginaFinal" => "493"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11810190"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety of cyclooxygenase 2 inhibitors and increased leukotriene synthesis in chronic idiopathic urticaria with sensitivity to nonsteroidal anti-inflammatory drugs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46; Zembowicz"
                            1 => "L&#46; Mastalerz"
                            2 => "M&#46; Setkowicz"
                            3 => "W&#46; Radziszewski"
                            4 => "A&#46; Szczeklik"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/archderm.139.12.1577"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dermatol"
                        "fecha" => "2003"
                        "volumen" => "139"
                        "paginaInicial" => "1577"
                        "paginaFinal" => "1582"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14676074"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Mita"
                            1 => "S&#46; Endoh"
                            2 => "M&#46; Kudoh"
                            3 => "Y&#46; Kawagishi"
                            4 => "M&#46; Kobayashi"
                            5 => "M&#46; Taniguchi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Allergy"
                        "fecha" => "2001"
                        "volumen" => "56"
                        "paginaInicial" => "1061"
                        "paginaFinal" => "1067"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11703219"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
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Vol. 45. Issue 4.
Pages 162-167 (April 2009)
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Vol. 45. Issue 4.
Pages 162-167 (April 2009)
Original article
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A Cyclooxygenase-2 Selective Inhibitor Worsens Respiratory Function and Enhances Mast Cell Activity in Ovalbumin-Sensitized Mice
Un inhibidor selectivo de la ciclooxigenasa-2 empeora la función respiratoria y fomenta la actividad de los mastocitos en ratones sensibilizados a la ovalbúmina
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Rosa Torresa,c,d, Mónica Péreza, Alberto Marcob, César Picadoc,d, Fernando de Moraa,
Corresponding author
fernando.demora@uab.es

Corresponding author.
a Department of Pharmacology, Universitat Autònoma de Barcelona, Barcelona, Spain
b Department of Animal Pathology, Universitat Autònoma de Barcelona, Barcelona, Spain
c Department of Pneumology, Hospital Clínic, Barcelona, Spain
d CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias (CibeRes), Spain
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Abstract
Background

Cyclooxygenase (COX)-2 activity has been said to have a protective effect in asthmatic patients as a result of prostaglandin E2 production. In order to elucidate the mechanisms involved, we evaluated the impact of selective inhibition of COX-2 with rofecoxib during ovalbumin (OVA) challenge, assessing mast cell activity and airway response in a murine model of asthma.

Material and methods

Mice were sensitized to OVA (10 μg injected intraperitoneally) and further challenged with 0.5% intranasal OVA. Half the sensitized animals were treated orally with rofecoxib (15 mg/kg/d during the challenge phase). Lung function was measured by whole body plethysmography before and after exposure to OVA. The severity of airway inflammation was evaluated by means of a scoring system. Finally, the serum level of mouse mast cell protease (mMCP)-1 was determined as an indicator of mucosal mast cell activity.

Results

Sensitized mice treated with rofecoxib exhibited 2.4-fold greater airway hyperresponsiveness than did vehicle-treated mice at a methacholine concentration of 100 mg/mL. A clear trend toward worsening airway inflammation in the presence of rofecoxib was observed, although the difference between rofecoxibtreated and vehicle-treated animals was not significant. These changes were accompanied by a significant increase in mucosal mast cell activity.

Conclusions

Selective pharmacological inhibition of COX-2 during the challenge phase worsens airway function in the OVA-induced murine model of acute asthma. We suggest that this effect might be at least partially explained by the increase in airway mast cell activity.

Keywords:
Asthma
Cyclooxygenase-2
Hyperresponsiveness
Mast cell
Ovalbumin-sensitized mouse
Rofecoxib
Resumen
Introducción y objetivo

Se ha señalado que la ciclooxigenasa-2 (COX-2) ejerce una función protectora en pacientes con asma mediante la producción de la prostaglandina E2. Con el objetivo de reproducir dicho efecto en un modelo experimental y dilucidar los mecanismos implicados, hemos evaluado, en un modelo de asma alérgica en el ratón, el efecto de la inhibición de la COX-2 en la respuesta de las vías aéreas expuestas a ovalbúmina y en la actividad de los mastocitos.

Material y métodos

Se sensibilizaron ratones a la ovalbúmina (10 μg, vía intraperitoneal) y se reexpusieron a ovalbúmina al 0,5% por vía intranasal. La mitad de los animales sensibilizados recibió tratamiento con rofecoxib (15 mg/kg al día, por vía oral, durante la fase de reexposición). Se evaluó la función pulmonar mediante pletismografía corporal antes y después de la reexposición a ovalbúmina, y se estableció el grado de inflamación broncovascular. También se midió la concentración sérica de la proteasa-1 de los mastocitos de ratón.

Resultados

Los ratones sensibilizados y tratados con rofecoxib mostraron una hiperreactividad bronquial 2,4 veces mayor que los del grupo control a una concentración de 100 mg/ml de metacolina. Asimismo, se apreció una clara tendencia hacia el empeoramiento del proceso inflamatorio en presencia de rofecoxib, aunque sin significación estadística. Estos cambios se acompañaron de un aumento significativo de la actividad de los mastocitos de la mucosa.

Conclusiones

La inhibición farmacológica de la COX-2 durante la reexposición a ovalbúmina agrava la función pulmonar, un fenómeno que consideramos se debe, al menos en parte, al incremento de la actividad de los mastocitos de las vías aéreas.

Palabras clave:
Asma
Ciclooxigenasa-2
Hiperreactividad
Mastocitos
Ratones sensibilizados a ovalbúmina
Rofecoxib
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References
[1.]
S. Ito, A. Okuda, E. Shitaka, T. Minami.
Central and peripheral roles of prostaglandins in pain and their interactions with novel neuropeptides nociceptin and nocistatin.
Neurosci Res, 41 (2001), pp. 299-332
[2.]
A.N. Hata, R.M. Breyer.
Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation.
Pharmacol Ther, 103 (2004), pp. 147-166
[3.]
I.A. Mardini, G.A. Fitzgerald.
Selective inhibitors of cyclooxygenase-2: a growing class of anti-inflammatory drugs.
Mol Interv, 1 (2001), pp. 30-38
[4.]
M.L. Kowalski, J. Makowska.
Use of nonsteroidal anti-inflammatory drugs in patients with aspirin hypersensitivity: safety of cyclo-oxygenase-2 inhibitors.
Treat Respir Med, 5 (2006), pp. 399-406
[5.]
A. Prieto, M. de Barrio, E. Martín, M. Fernández-Bohórquez, F.J. de Castro, F.J. Ruiz, et al.
Tolerability to nabumetone and meloxicam in patients with nonsteroidal antiinflammatory drug intolerance.
J Allergy Clin Immunol, 119 (2007), pp. 960-964
[6.]
T. Matsuoka, M. Hirata, H. Tanaka, Y. Takahashi, T. Murata, K. Kabashima, et al.
Prostaglandin D2 as a mediator of allergic asthma.
Science, 287 (2000), pp. 2013-2017
[7.]
E. Melillo, K.L. Woolley, P.J. Manning, R.M. Watson, P.M. O’Byrne.
Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects.
Am J Respir Crit Care Med, 149 (1994), pp. 1138-1141
[8.]
P. Sestini, L. Armetti, G. Gambaro, M.G. Pieroni, R.M. Refini, A. Sala, et al.
Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTC4 excretion in aspirin-sensitive asthmatics.
Am J Respir Crit Care Med, 153 (1996), pp. 572-575
[9.]
G.M. Gauvreau, R.M. Watson, P.M. O’Byrne.
Protective effects of inhaled PGE2 on allergen-induced airway responses and airway inflammation.
Am J Respir Crit Care Med, 159 (1999), pp. 31-36
[10.]
A.T. Edmunds, M. Tooley, S. Godfrey.
The refractory period after exercise-induced asthma: its duration and relation to the severity of exercise.
Am Rev Respir Dis, 117 (1978), pp. 247-254
[11.]
P.J. Manning, R.M. Watson, P.M. O’Byrne.
Exercise-induced refractoriness in asthmatic subjects involves leukotriene and prostaglandin interdependent mechanisms.
Am Rev Respir Dis, 148 (1993), pp. 950-954
[12.]
C. Picado, J.C. Fernández-Morata, M. Juan, J. Roca-Ferrer, M. Fuentes, A. Xaubet, et al.
Cyclooxygenase-2 mRNA is downexpressed in nasal polyps from aspirin-sensitive asthmatics.
Am J Respir Crit Care Med, 160 (1999), pp. 291-296
[13.]
M.L. Kowalski, R. Pawliczak, J. Wozniak, K. Siuda, M. Poniatowska, J. Iwaszkiewicz, et al.
Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients.
Am J Respir Crit Care Med, 161 (2000), pp. 391-398
[14.]
J. Mullol, J.C. Fernández-Morata, J. Roca-Ferrer, L. Pujols, A. Xaubet, P. Benítez, et al.
Cyclooxygenase-1 and-2 expression is abnormally regulated in human nasal polyps.
J Allergy Clin Immunol, 109 (2002), pp. 824-830
[15.]
L.S. Chambers, J.L. Black, Q. Ge, S.M. Carlin, W.W. Au, M. Poniris, et al.
PAR-2 activation, PGE2, and COX-2 in human asthmatic and nonasthmatic airway smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol, 285 (2003), pp. L619-L627
[16.]
C. Picado, G. Bioque, J. Roca-Ferrer, L. Pujols, J. Mullol, P. Benítez, et al.
Nuclear factor-kappaB activity is down-regulated in nasal polyps from aspirin-sensitive asthmatics.
Allergy, 58 (2003), pp. 122-126
[17.]
M. Pierzchalska, Z. Szabo, M. Sanak, J. Soja, A. Szczeklik.
Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma.
J Allergy Clin Immunol, 1111 (2003), pp. 1041-1048
[18.]
R. Torres, C. Picado, F. de Mora.
Use of the mouse to unravel allergic asthma: a review of the pathogenesis of allergic asthma in mouse models and its similarity to the condition in humans.
Arch Bronconeumol, 41 (2005), pp. 141-152
[19.]
S.H. Gavett, S.L. Madison, P.C. Chulada, P.E. Scarborough, W. Qu, J.E. Boyle, et al.
Allergic lung responses are increased in prostaglandin H synthase-deficient mice.
J Clin Invest, 104 (1999), pp. 721-732
[20.]
R.S. Peebles Jr, R. Dworski, R.D. Collins, K. Jarzecka, D.B. Mitchell, B.S. Graham, et al.
Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice.
Am J Respir Crit Care Med, 162 (2000), pp. 676-681
[21.]
R.S. Peebles Jr, K. Hashimoto, J.D. Morrow, R. Dworski, R.D. Collins, Y. Hashimoto, et al.
Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice.
Am J Respir Crit Care Med, 165 (2002), pp. 1154-1160
[22.]
J. Nakata, M. Kondo, J. Tamaoki, T. Takemiya, M. Nohara, K. Yamagata, et al.
Augmentation of allergic inflammation in the airways of cyclooxygenase-2-deficient mice.
Respirology, 10 (2005), pp. 149-156
[23.]
P. Bradding, A.F. Walls, S.T. Holgate.
The role of the mast cell in the pathophysiology of asthma.
J Allergy Clin Immunol, 117 (2006), pp. 1277-1284
[24.]
C. Feng, E.M. Beller, S. Bagga, J. Boyce.
Human mast cells express multiple EP receptors for prostaglandin E2 that differentially modulate activation responses.
Blood, 107 (2006), pp. 3243-3250
[25.]
L.J. Kay, W.Y. Wilfred, P.T. Peachell.
Prostaglandin E2 activates EP2 receptors to inhibit human lung mast cell degranulation.
Br J Pharmacol, 147 (2006), pp. 707-713
[26.]
T. Kobayashi, T. Miura, T. Haba, M. Sato, I. Serizawa, H. Nagai, et al.
An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model.
J Immunol, 164 (2000), pp. 3855-3861
[27.]
E. Hamelmann, J. Schwarze, K. Takeda, A. Oshiba, G.L. Larsen, C.G. Irvin, et al.
Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography.
Am J Respir Crit Care Med, 156 (1997), pp. 766-775
[28.]
M. Lomask.
Further exploration of the Penh parameter.
Exp Toxicol Pathol, 57 (2006), pp. 13-20
[29.]
W.J. Beil, J. Pammer.
In situ detection of the mast cell proteases chymase and tryptase in human lung tissue using light and electron microscopy.
Histochem Cell Biol, 116 (2001), pp. 483-493
[30.]
A. Zembowicz, L. Mastalerz, M. Setkowicz, W. Radziszewski, A. Szczeklik.
Safety of cyclooxygenase 2 inhibitors and increased leukotriene synthesis in chronic idiopathic urticaria with sensitivity to nonsteroidal anti-inflammatory drugs.
Arch Dermatol, 139 (2003), pp. 1577-1582
[31.]
H. Mita, S. Endoh, M. Kudoh, Y. Kawagishi, M. Kobayashi, M. Taniguchi, et al.
Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma.
Allergy, 56 (2001), pp. 1061-1067

This work was supported by a grant (ref FIS PI060592) from the Carlos III Health Institute of the Spanish Ministry of Health.

Copyright © 2009. Sociedad Española de Neumología y Cirugía Torácica
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