T Cells localize with proliferating smooth muscle alpha-actin+ cell compartments in asthma.

RATIONALE: Airway remodeling in asthma comprises increased airway smooth muscle (ASM), an alteration linked to airway hyperresponsiveness and disease severity. Experimental studies showed that T cells adhere to ASM through vascular cell adhesion molecule-1 (VCAM-1) and drive ASM growth through direct contact between the T cells and smooth muscle alpha-actin (alpha-SMA)(+) cells. OBJECTIVES: To support the hypothesis of a T-cell/alpha-SMA(+) cell contact mechanism of ASM remodeling in asthma, using bronchial biopsies. METHODS: We performed quantitative morphology on T cells, proliferating cell nuclear antigen (PCNA), alpha-SMA, and VCAM-1 on biopsies from subjects with moderate and severe asthma and healthy control subjects. MEASUREMENTS AND MAIN RESULTS: We demonstrate ASM cell proliferation and infiltration by T cells in proportion to severity in the subjects with asthma. T cells localized with alpha-SMA(+)PCNA(+) cells, suggesting direct intercellular contact and a relationship with alpha-SMA(+) cell proliferation. Furthermore, the subjects with asthma developed a proliferating compartment of subepithelial alpha-SMA(+), nonorganized airway contractile elements (NOACE), suggesting a phenotype gradient from undifferentiated cells to smooth muscle-like cells. T-cell juxtaposition events were also observed in this compartment and correlated to its mass. The subjects with asthma showed VCAM-1 expression in postcapillary venules and clusters of VCAM-1 immunoreactivity in ASM and NOACE, consistent with a role of VCAM-1 in T-cell/alpha-SMA(+) cell interaction. CONCLUSIONS: T cells may induce alpha-SMA(+) cell proliferation through direct intercellular contact. NOACE may in part contribute to ASM growth through differentiation and translocation of alpha-SMA(+) cells. The findings support the role of the T cell in ASM remodeling in asthma.

An update on the use of indacaterol in patients with COPD.

Current guidelines for the management of chronic obstructive pulmonary disease (COPD) establish that bronchodilator medications are central to the symptomatic treatment of the disease. Regular treatment with long-acting bronchodilators is recommended as more effective and convenient than short-acting bronchodilators, because the long-acting agents provide greater bronchodilator efficacy and symptomatic relief, increased tolerance to exercise, and improved rate of exacerbations and quality of life test scores. Dosing regimens requiring less frequent dosing also provide improved treatment compliance. Indacaterol is a novel once-daily ultra-long-acting ß(2)-agonist bronchodilator now approved in the European Union for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD, to be administered as 150 or 300 microg once-daily dose by means of a single-dose dry powder inhaler. This review focuses on providing a clinical practice-oriented synopsis of the data generated from the randomized trials during the clinical development of indacaterol, published as of the time of writing. Indacaterol has been shown to provide effective 24-h bronchodilation and a fast onset of action, with an efficacy at least comparable or superior to current bronchodilator therapy standards and with a favourable safety and tolerability profile within the ß(2)-agonist drug class.

[Development of a murine model of airway inflammation and remodeling in experimental asthma]. / Desarrollo de un modelo murino de inflamación y remodelación de vías respiratorias en asma experimental.

BACKGROUND AND OBJECTIVE: Experimental animal models are necessary for studying asthma disease mechanisms and for identifying new therapeutic targets. We present a murine model of experimental asthma that allows integrated, quantitative assessment of airway inflammation and remodeling. MATERIAL AND METHODS: BALB/c mice were sensitized to ovalbumin (OVA) and challenged with OVA or vehicle 3 times per week for 12 weeks. RESULTS: On bronchoalveolar lavage, the OVA-sensitized mice had significantly higher total leukocyte counts, with a median (Q25-Q75) of 670.0 cells/mL x 10(3) (376.2, 952.5) in comparison with 40.0 cells/mL x 10(3) (60.0-85.0) in controls (P=.001), and higher eosinophil and differential lymphocyte counts. In sagittal sections of lungs inflated to a standard pressure, the OVA-sensitized animals showed goblet cell hyperplasia in the respiratory epithelium (periodic acid-Schiff staining, 53.89 [36.26-62.84]cells/mm(2) vs 0.66 [0.00-1.06]cells/mm(2), P<.001), dense mononuclear and eosinophilic inflammatory infiltrates (hematoxylin-eosin, 32.87 [27.34-37.13]eosinophils/mm(2) vs 0.06 [0.00-0.20]eosinophils/mm(2), P=.002), subepithelial infiltration by mast cells (toluidine blue, 2.88 [2.00-3.28] mast cells/mm(2) vs 0.28 [0.15-0.35] mast cells/mm(2), P<.001), increased contractile tissue mass (immunofluorescence analysis for alpha-smooth-muscle actin, 2.60 [2.28-2.98] vs 1.08 [0.93-1.16], dimensionless, P<.001) and enhanced extracellular matrix deposition (Masson's trichrome, 2.18 [1.85-2.80] vs 0.50 [0.37-0.65], dimensionless, P<.001). CONCLUSIONS: Our dataset describes an experimental model of asthma which is driven by prolonged allergen exposure and in which airway inflammation and remodeling develop and are assessed together.

Desarrollo de un modelo murino de inflamación y remodelación de vías respiratorias en asma experimental / Development of a Murine Model of Airway Inflammation and Remodeling in Experimental Asthma

IntroducciónLa investigación de los mecanismos de enfermedad del asma y la identificación de nuevas dianas terapéuticas requieren modelos animales experimentales. En este trabajo presentamos los datos del desarrollo de un modelo murino de asma experimental que permite valorar de forma conjunta parámetros de inflamación y remodelación de las vías respiratorias mediante morfología cuantitativa.Material y métodosSe sensibilizó a ovoalbúmina a ratones Balb/c y se les realizó broncoprovocación con ovoalbúmina o excipiente 3 veces por semana durante 12 semanas.ResultadosEn el lavado broncoalveolar, los ratones del grupo de ovoalbúmina presentaron un incremento significativo de leucocitos totales, con una mediana (cuartiles 25–75) de 670,0células/ml·103 (376,2–952,5), frente a 40,0células/ml·103 (60,0–85,0) en controles (p=0,001), y de las fracciones eosinófila y linfocitaria en recuento diferencial. En secciones sagitales de los pulmones inflados a presión estandarizada, estos ratones mostraron hiperplasia de células caliciformes en el epitelio respiratorio —reacción de ácido peryódico de Schiff: 53,89 (36,26–62,84) frente a 0,66 (0,00–1,06)células/mm2 (p<0,001)—, densa infiltración inflamatoria mononuclear y eosinófila —hematoxilina-eosina: 32,87 (27,34–37,13) frente a 0,06 (0,00–0,20)eosinófilos/mm2 (p=0,002)—, infiltración subepitelial por mastocitos —azul de toluidina: 2,88 (2,00–3,28) frente a 0,28 (0,15–0,35)mastocitos/mm2 (p<0,001)—, incremento de la masa de tejido contráctil —inmunofluorescencia para alfaactina de músculo liso: 2,60 (2,28–2,98) frente a 1,08 (0,93–1,16), adimensional (p<0,001)— e incremento del depósito de matriz extracelular (tricrómico de Masson: 2,18 (1,85–2,80) frente a 0,50 (0,37–0,65), adimensional (p<0,001)—.ConclusionesLos datos aportados configuran un modelo de asma experimental inducida por exposición alergénica prolongada, con desarrollo y evaluación integrada de inflamación y remodelación de vías respiratorias(AU)

Background and ObjectiveExperimental animal models are necessary for studying asthma disease mechanisms and for identifying new therapeutic targets. We present a murine model of experimental asthma that allows integrated, quantitative assessment of airway inflammation and remodeling.Material and MethodsBALB/c mice were sensitized to ovalbumin (OVA) and challenged with OVA or vehicle 3 times per week for 12 weeks.ResultsOn bronchoalveolar lavage, the OVA-sensitized mice had significantly higher total leukocyte counts, with a median (Q25–Q75) of 670.0cells/mL×103 (376.2, 952.5) in comparison with 40.0cells/mL×103 (60.0–85.0) in controls (P=.001), and higher eosinophil and differential lymphocyte counts. In sagittal sections of lungs inflated to a standard pressure, the OVA-sensitized animals showed goblet cell hyperplasia in the respiratory epithelium (periodic acid-Schiff staining, 53.89 [36.26–62.84]cells/mm2 vs 0.66 [0.00–1.06]cells/mm2, P<.001), dense mononuclear and eosinophilic inflammatory infiltrates (hematoxylin-eosin, 32.87 [27.34–37.13]eosinophils/mm2 vs 0.06 [0.00–0.20]eosinophils/mm2, P=.002), subepithelial infiltration by mast cells (toluidine blue, 2.88 [2.00–3.28] mast cells/mm2 vs 0.28 [0.15–0.35] mast cells/mm2, P<.001), increased contractile tissue mass (immunofluorescence analysis for α-smooth-muscle actin, 2.60 [2.28–2.98] vs 1.08 [0.93–1.16], dimensionless, P<.001) and enhanced extracellular matrix deposition (Masson's trichrome, 2.18 [1.85–2.80] vs 0.50 [0.37–0.65], dimensionless, P<.001).ConclusionsOur dataset describes an experimental model of asthma which is driven by prolonged allergen exposure and in which airway inflammation and remodeling develop and are assessed together(AU)