RESUMEN
Asthma is a chronic condition with unknown pathogenesis, and recent evidence suggests that enhanced airway epithelial chloride (Cl-) secretion plays a role in the disease. However, the molecular mechanism underlying Cl- secretion and its relevance in asthma pathophysiology remain unknown. To determine the role of the solute carrier family 26, member 9 (SLC26A9) Cl- channel in asthma, we induced Th2-mediated inflammation via IL-13 treatment in wild-type and Slc26a9-deficient mice and compared the effects on airway ion transport, morphology, and mucus content. We found that IL-13 treatment increased Cl- secretion in the airways of wild-type but not Slc26a9-deficient mice. While IL-13-induced mucus overproduction was similar in both strains, treated Slc26a9-deficient mice exhibited airway mucus obstruction, which did not occur in wild-type controls. In a study involving healthy children and asthmatics, a polymorphism in the 3' UTR of SLC26A9 that reduced protein expression in vitro was associated with asthma. Our data demonstrate that the SLC26A9 Cl- channel is activated in airway inflammation and suggest that SLC26A9-mediated Cl- secretion is essential for preventing airway obstruction in allergic airway disease. These results indicate that SLC26A9 may serve as a therapeutic target for airway diseases associated with mucus plugging.
Asunto(s)
Obstrucción de las Vías Aéreas/prevención & control , Antiportadores/fisiología , Asma/genética , Bronquitis/fisiopatología , Cloruros/metabolismo , Transporte Iónico/fisiología , Moco/metabolismo , Traqueítis/fisiopatología , Regiones no Traducidas 3' , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/fisiopatología , Animales , Antiportadores/deficiencia , Antiportadores/genética , Asma/fisiopatología , Bronquitis/inducido químicamente , Bronquitis/genética , Bronquitis/inmunología , Calcio/farmacología , Niño , AMP Cíclico/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/deficiencia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/fisiología , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Interleucina-13/toxicidad , Pulmón/patología , Ratones , Ratones Noqueados , Transportadores de Sulfato , Células Th2/inmunología , Traqueítis/inducido químicamente , Traqueítis/genética , Traqueítis/inmunologíaRESUMEN
INTRODUCTION: It remains unknown why some intubated patients remain infection-free while others develop tracheobronchitis (VAT) or pneumonia (VAP). OBJECTIVE: To identify and compare VAP/VAT gene expression "signatures" using genome-wide oligonucleotide microarrays. MATERIAL AND METHODS: A prospective translational study of gene expression profiles of VAP and VAT groups was carried out, establishing comparisons in both pre-infection and infection phases. Pathway and functional analyses were performed with Ingenuity Pathway Analysis (IPA). Data analysis and hierarchical clustering of the genes involved in the signalling pathways expressed differentially in the two groups were performed with GeneSpring GX 11.0. RESULTS: Eight patients developing respiratory infections (3 VAP and 5 VAT) after 4 days of mechanical ventilation were assessed. Comparison of gene expression profiles in the pre-infection period revealed 5595 genes expressed differentially between VAP and VAT (p<0.01, fold change >2). Comparative IPA analysis identified a significant depression of the complement system signalling pathway in the VAP group, affecting the classical pathway along with the final common pathway (p<0.05). In addition, the cAMP and calcium signalling pathways were also significantly depressed in the VAP group during the pre-infection phase also. CONCLUSION: Intubated patients complicated with pneumonia developed immune impairment in the pre-infection period, manifesting as a relatively lower expression of genes involved in the complement system that differed from patients developing tracheobronchitis. These findings suggest that a significant proportion of VAP episodes cannot be prevented, but might be treatable through pre-emptive therapy.
Asunto(s)
Bronquitis/genética , Bronquitis/microbiología , Intubación Intratraqueal/efectos adversos , Neumonía Asociada al Ventilador/genética , Neumonía Asociada al Ventilador/microbiología , Traqueítis/genética , Traqueítis/microbiología , Femenino , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios ProspectivosRESUMEN
Chronic inflammation is associated with blood vessel proliferation and enlargement and changes in vessel phenotype. We sought to determine whether these changes represent different types of angiogenesis and whether they are stimulus dependent. Chronic airway inflammation, produced by infection with Mycoplasma pulmonis, was compared in strains of mice known to be resistant (C57BL/6) or susceptible (C3H). Tracheal vascularity, assessed in whole mounts after Lycopersicon esculentum lectin staining, increased in both strains at 1, 2, 4, and 8 weeks after infection, but the type of vascular remodeling was different. The number of vessels doubled in tracheas of C57BL/6 mice, with corresponding increases of capillaries and venules. In contrast, neither the number nor the length of vessels changed in C3H mice. Instead, vessel diameter and endothelial cell number doubled, and the proportion of venules doubled with a corresponding decrease of capillaries. Although the infection had no effect on baseline plasma leakage, in both strains it potentiated the leakage produced by substance P. We conclude that the same stimulus can result in blood vessel proliferation or enlargement, depending on the host response. Endothelial cells proliferate in both cases, but in one case new capillaries form whereas in the other capillaries convert to venules.