RESUMEN
In asthma, it is unclear if the airway smooth muscle cells proliferate more or are increased at the onset of asthma and remain stable. This study aimed to compare smooth muscle cell proliferation in individuals with and without asthma and correlate proliferation rates with cell size and number and with granulocytic airway inflammation. Postmortem airway sections were labeled with proliferating cell nuclear antigen (PCNA) and percent positive muscle cells calculated. On the same sections, smooth muscle cell size and number and the number of eosinophils and neutrophils were estimated and compared in cases of nonfatal ( n = 15) and fatal ( n = 15) asthma and control subjects ( n = 15). The %PCNA+ muscle cells was not significantly different in fatal (29.4 ± 7.7%, mean ± SD), nonfatal asthma (28.6 ± 8.3%), or control subjects (24.6 ± 6.7%) and not related to mean muscle cell size ( r = 0.09), number ( r = 0.36), thickness of the muscle layer ( r = 0.05), or eosinophil numbers ( r = 0.04) in the asthma cases. These data support the hypothesis that in asthma the increased thickness of the smooth muscle layer may be present before or at the onset of asthma and independent of concurrent granulocytic inflammation or exacerbation. NEW & NOTEWORTHY There is debate regarding the origins of the increased airway smooth muscle in asthma. It may be independent of inflammation or arise as a proliferative response to inflammation. The present study found no increase in the proportion of proliferating smooth muscle cells in asthma and no relation of proliferation to numbers of airway smooth muscle cells or inflammation. These results support a stable increase in smooth muscle in asthma that is independent of airway inflammation.
Asunto(s)
Asma/fisiopatología , Bronquios/fisiopatología , Músculo Liso/fisiopatología , Miocitos del Músculo Liso/fisiología , Adolescente , Adulto , Asma/inmunología , Asma/patología , Bronquios/patología , Estudios de Casos y Controles , Proliferación Celular , Femenino , Humanos , Inflamación , Masculino , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: The pathology of asthma is characterized by airway inflammation (granulocytic (GA) or paucigranulocytic (PGA)) and remodelling of airway structures. However, the relationship between inflammatory phenotypes and remodelling is unclear. We hypothesized that some features of airway remodelling are dependent on granulocytic airway inflammation while others are not. METHODS: Post-mortem airway sections from control subjects (n = 48) and cases of asthma with (n = 51) or without (n = 29) granulocytic inflammation in the inner airway wall were studied. The thickness of the airway smooth muscle (ASM) layer, basement membrane and inner and outer airway walls, the size and number of ASM cells, the volume fraction of extracellular matrix within the ASM layer, ASM shortening and luminal mucus were estimated. Airway dimensions were compared between the three subject groups. RESULTS: In cases of PGA, only the thickness of the ASM layer and basement membrane was increased compared with control subjects. In cases of GA, not only the ASM and basement membrane were increased in thickness, but there was also increased inner and outer airway wall thickness and increased narrowing of the airway lumen due to ASM shortening and mucus obstruction, compared with control subjects. Granulocytic inflammation was observed more often in cases of fatal asthma. CONCLUSION: These findings suggest that inner and outer wall thickening coexists with inflammation, whereas thickening of the ASM layer and basement membrane may be present even in the absence of inflammation. Remodelling of the ASM layer and basement membrane may therefore be less susceptible to anti-inflammatory therapy.
Asunto(s)
Asma , Sistema Respiratorio , Adulto , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma/inmunología , Asma/patología , Autopsia , Membrana Basal/patología , Femenino , Humanos , Inflamación/patología , Masculino , Sistema Respiratorio/inmunología , Sistema Respiratorio/patologíaRESUMEN
BACKGROUND AND OBJECTIVE: Pathological phenotypes of asthma have been based predominantly on inflammation, rather than airway wall remodelling. Differences in the distribution of airway smooth muscle (ASM) remodelling between large and small airways may affect clinical outcomes in asthma. The aim of this study was to examine the distribution of ASM remodelling and its relation to airway inflammation. METHODS: Post-mortem cases of asthma (n = 68) were categorized by the distribution of increased thickness of the ASM layer (relative to nonasthmatic controls, n = 37), into 'large only' (LO, n = 15), 'small only' (SO, n = 4) 'large/small' (LS, n = 24) or no increase (NI, n = 25). Subject characteristics, ASM and airway wall dimensions and inflammatory cell numbers were compared between groups. RESULTS: Apart from reduced clinical severity of asthma in NI cases (P = 0.002), subject characteristics did not distinguish asthma groups. Compared with control subjects, ASM cell number, reticular basement membrane thickness, airway wall thickness, percent muscle shortening and eosinophil number were increased (P < 0.05) in both large and small airways in LS cases and only the large airways in LO cases. Increased numbers of neutrophils were observed only in the small airways of LO cases. CONCLUSIONS: Distinct distributions of ASM remodelling are seen in asthma. Pathology limited to the small airways was uncommon. Increased thickness of the ASM layer was associated with airway remodelling and eosinophilia, but not neutrophilia. These data support the presence of distinct pathological phenotypes based on the site of increased ASM.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/patología , Bronquios/patología , Bronquitis/patología , Eosinofilia/patología , Músculo Liso/patología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocitos del Músculo Liso , Adulto JovenRESUMEN
Epidemiological associations of worse respiratory outcomes from combined exposure to ambient particulate matter (PM) and respiratory viral infection suggest possible interactions between PM and viruses. To characterize outcomes of such exposures, we developed an in vitro mimic of the in vivo event of exposure to PM contaminated with respiratory syncytial virus (RSV). Concentration of infectious RSV stocks and a particle levitation apparatus were the foundations of the methodology developed to generate specific numbers of PM mimics (PM(Mimics)) of known composition for dry, direct deposition onto airway epithelial cell cultures. Three types of PM(Mimics) were generated for this study: (i) carbon alone (P(C)), (ii) carbon and infectious RSV (P(C+RSV)), and (iii) aerosols consisting of RSV (A(RSV)). P(C+RSV) were stable in solution and harbored infectious RSV for up to 6 months. Unlike A(RSV) infection, P(C+RSV) infection was found to be dynamin dependent and to cause lysosomal rupture. Cells dosed with PM(Mimics) comprised of RSV (A(RSV)), carbon (P(C)), or RSV and carbon (P(C+RSV)) responded differentially as exemplified by the secretion patterns of IL-6 and IL-8. Upon infection, and prior to lung cell death due to viral infection, regression analysis of these two mediators in response to incubation with A(RSV), P(C), or P(C+RSV) yielded higher concentrations upon infection with the latter and at earlier time points than the other PM(Mimics). In conclusion, this experimental platform provides an approach to study the combined effects of PM-viral interactions and airway epithelial exposures in the pathogenesis of respiratory diseases involving inhalation of environmental agents.
Asunto(s)
Material Particulado/química , Infecciones por Virus Sincitial Respiratorio , Virus Sincitiales Respiratorios/química , Humanos , Tamaño de la Partícula , Virus Sincitiales Respiratorios/aislamiento & purificación , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
RATIONALE: Increased thickness of the airway smooth muscle (ASM) layer in asthma may result from hyperplasia or hypertrophy of muscle cells or increased extracellular matrix (ECM). OBJECTIVES: To relate ASM hypertrophy, ASM hyperplasia, and deposition of ECM to the severity and duration of asthma. METHODS: Airways from control subjects (n = 51) and from cases of nonfatal (n = 49) and fatal (n = 55) asthma were examined postmortem. Mean ASM cell volume (V(C)), the number of ASM cells per length of airway (N(L)), and the volume fraction of extracellular matrix (f(ECM)) within the ASM layer were estimated. Comparisons between subject groups were made on the basis of general linear regression models. MEASUREMENTS AND MAIN RESULTS: Mean V(C) was increased in the large airways of cases of nonfatal asthma (P = 0.015) and fatal asthma (P < 0.001) compared with control subjects. N(L) was similar in nonfatal cases and control subjects but increased in large (P < 0.001), medium (P < 0.001), and small (P = 0.034) airways of cases of fatal asthma compared with control subjects and with nonfatal cases (large and medium airways, P ≤ 0.003). The f(ECM) was similar in cases of asthma and control subjects. Duration of asthma was associated with a small increase in N(L). CONCLUSIONS: Hypertrophy of ASM cells occurs in the large airways in both nonfatal and fatal cases of asthma, but hyperplasia of ASM cells is present in the large and small airways in fatal asthma cases only. Both are associated with an absolute increase in ECM. Duration of asthma has little or no effect on ASM hypertrophy or hyperplasia or f(ECM).
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/patología , Bronquios/patología , Matriz Extracelular/patología , Músculo Liso/patología , Adolescente , Adulto , Asma/mortalidad , Estudios de Casos y Controles , Femenino , Humanos , Hiperplasia , Hipertrofia , Modelos Lineales , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
A substantial proportion of healthcare cost associated with asthma is attributable to exacerbations of the disease. Within the airway, the epithelium forms the mucosal immune barrier, the first structural cell defense against common environmental insults such as respiratory syncytial virus (RSV) and particulate matter. We sought to characterize the phenotype of differentiated asthmatic-derived airway epithelial cultures and their intrinsic inflammatory responses to environmental challenges. Air-liquid interface (ALI) cultures were generated from asthmatic (n = 6) and nonasthmatic (n = 6) airway epithelial cells. Airway tissue and ALI cultures were analyzed by immunohistochemistry for cytokeratin-5, E-cadherin, Ki67, Muc5AC, NF-κB, the activation of p38, and apoptosis. ALI cultures were exposed to RSV (4 × 10(6) plaque forming unit/ml), particulate matter collected by Environmental Health Canada (EHC-93, 100 µg/ml), or mechanically wounded for 24, 48, and 96 hours and basolateral supernatants analyzed for inflammatory cytokines, using Luminex and ELISA. The airway epithelium in airway sections of patients with asthma as well as in vitro ALI cultures demonstrated a less differentiated epithelium, characterized by elevated numbers of basal cells marked by the expression of cytokeratin-5, increased phosphorylation of p38 mitogen-activated protein kinase, and less adherens junction protein E-cadherin. Transepithelial resistance was not different between asthmatic and nonasthmatic cultures. In response to infection with RSV, exposure to EHC-93, or mechanical wounding, asthmatic ALI cultures released greater concentrations of IL-6, IL-8, and granulocyte macrophage colony-stimulating factor, compared with nonasthmatic cultures (P < 0.05). This parallel ex vivo and in vitro study of the asthmatic epithelium demonstrates an intrinsically altered phenotype and aberrant inflammatory response to common environmental challenges, compared with nonasthmatic epithelium.
Asunto(s)
Contaminación del Aire/efectos adversos , Asma/metabolismo , Asma/virología , Material Particulado/efectos adversos , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Virus Sincitiales Respiratorios/metabolismo , Adulto , Apoptosis , Asma/inducido químicamente , Cadherinas/metabolismo , Células Cultivadas , Niño , Preescolar , Citocinas/metabolismo , Femenino , Humanos , Queratina-5/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Mucina 5AC/metabolismo , FN-kappa B/metabolismo , Fosforilación , Adulto Joven , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
PURPOSE OF REVIEW: This review focuses on recent findings in relation to potential functional consequences of structural changes in the asthmatic airway. RECENT FINDINGS: Increases in smooth muscle mass have been shown to be an early finding in childhood asthma, related to clinical severity and predictive of greater airflow obstruction. Both hyperplasia and hypertrophy contribute to the increase in smooth muscle mass. A phenotypic shift in the epithelium of asthmatic airways related to stress and injury is suggested by recent data, with likely direct transformation of epithelial cells into mesenchymal cells. Fibrocyte in-migration from the vasculature may be an additional source of increased smooth muscle mass. The increased smooth muscle may contribute to neovascularization via vascular endothelial growth factor. Computed tomography studies continue to show some correlations between wall thickness and airway physiology. Exacerbations are predictive of greater lung function decline and hence remodeling. SUMMARY: On balance, recent evidence continues to show that structural changes contribute to asthma persistence, airflow obstruction, lung function decline, and clinical severity, though there is increased recognition of the heterogeneity of asthma and in some phenotypes inflammatory cell influx or vascular effects may be more important than structural effects.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/fisiopatología , Hiperplasia , Miocitos del Músculo Liso/patología , Mucosa Respiratoria/patología , Obstrucción de las Vías Aéreas , Animales , Asma/diagnóstico , Asma/patología , Transformación Celular Neoplásica , Preescolar , Humanos , Neovascularización Patológica , Pronóstico , Mucosa Respiratoria/irrigación sanguíneaRESUMEN
RATIONALE: Airway remodeling in asthma is associated with the accumulation of fibroblasts, the primary cell responsible for synthesis and secretion of extracellular matrix proteins. The process by which the number of fibroblasts increases in asthma is poorly understood, but epithelial-mesenchymal transition (EMT) may play a significant role. OBJECTIVES: To evaluate whether EMT occurs in primary airway epithelial cells (AECs), the mechanisms involved, and if this process is altered in asthmatic AECs. METHODS: AECs were obtained from subjects with asthma (n = 8) and normal subjects without asthma (n = 10). Monolayer and air-liquid interface-AEC (ALI-AEC) cultures were treated with transforming growth factor (TGF)-beta1 (10 ng/ml) for 72 hours and assayed for mesenchymal and epithelial markers using quantitative polymerase chain reaction, confocal microscopy, and immunoblot. The involvement of BMP-7, Smad3, and MAPK-mediated signaling were also evaluated. MEASUREMENTS AND MAIN RESULTS: TGF-beta1-induced EMT in AEC monolayers derived from subjects with asthma and normal donors. EMT was characterized by changes in cell morphology, increased expression of mesenchymal markers EDA-fibronectin, vimentin, alpha-smooth muscle actin, and collagen-1, and loss of epithelial markers E-cadherin and zonular occludin-1. Inhibition of TGF-beta1-induced signaling with Smad3-inhibiting siRNA or TGF-beta1-neutralizing antibodies prevented and reversed EMT, respectively, whereas BMP-7 had no effect. In ALI-AEC cultures derived from normal subjects, EMT was confined to basally situated cells, whereas in asthmatic ALI-AEC cultures EMT was widespread throughout the epithelium. CONCLUSIONS: TGF-beta1 induces EMT in a Smad3-dependent manner in primary AECs. However, in asthmatic-derived ALI-AEC cultures, the number of cells undergoing EMT is greater. These findings support the hypothesis that epithelial repair in asthmatic airways is dysregulated.
Asunto(s)
Asma/patología , Desdiferenciación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Factor de Crecimiento Transformador beta1/farmacología , Adolescente , Asma/etiología , Asma/metabolismo , Estudios de Casos y Controles , Técnicas de Cultivo de Célula , Niño , Preescolar , Células Epiteliales/fisiología , Proteínas de la Matriz Extracelular/fisiología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/fisiología , Masculino , Células Madre Mesenquimatosas , Proteínas Recombinantes , Transducción de Señal , Adulto JovenRESUMEN
BACKGROUND: Not taking treatment preferences into account may lead to patients' inappropriate use of asthma treatments. The objective of this study was to quantify these preferences, in terms of risk-benefits trade-offs, for six asthma treatment attributes using a discrete choice experiment (DCE). METHODS: Adult asthma patients (n = 157) participated in the study. The custom-designed DCE measured preferences for treatment effectiveness (symptom-free days), potential risk (oral thrush and tremor/heart palpitation), ease of use (frequency of daily administration and number of inhalers required), and cost. A nested logit model was used to determine the relative preferences of each attribute, from which the marginal rates of substitution were calculated. Segmented models were used to test for interactions between cost and treatment benefit with socioeconomic status and medication use. RESULTS: Relationships between preferences and all attributes were in the hypothesized direction. On average, patients were willing to pay an additional $14 per month to receive one additional symptom-free day, and $26, $79, and $112 monthly to avoid one, two, and three annual episodes of oral thrush, respectively. Income and the magnitude of short-acting beta -agonist use also affected treatment preferences. CONCLUSIONS: Overall, asthma patients desired treatments that offered more symptom-free days, but they were willing to trade days without symptoms in exchange for a reduction in adverse events and greater convenience.
Asunto(s)
Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Asma/psicología , Aceptación de la Atención de Salud , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/economía , Asma/economía , Análisis Costo-Beneficio , Estudios Transversales , Toma de Decisiones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Psicológicos , Proyectos Piloto , Calidad de Vida , Factores Socioeconómicos , Encuestas y CuestionariosRESUMEN
The perimeter of the basement membrane (Pbm) of an airway viewed in cross section is used as a marker of airway size because in normal lungs it is relatively constant, despite variations in airway smooth muscle (ASM) shortening and airway collapse. In vitro studies (McParland BE, Pare PD, Johnson PR, Armour CL, Black JL. J Appl Physiol 97: 556-563, 2004; Noble PB, Sharma A, McFawn PK, Mitchell HW. J Appl Physiol 99: 2061-2066, 2005) have suggested that differential stretch of the Pbm between asthmatic and nonasthmatic airways fixed in inflation may occur and lead to an overestimation of ASM thickness in asthma. The relationships between the Pbm and the area of ASM were compared in transverse sections of airways from cases of fatal asthma (F) and from nonasthmatic control (C) cases where the lung tissue had been fixed inflated (Fi; Ci) or uninflated (Fu; Cu). When all available airways were used, the regression slopes were increased in Fu and Cu, compared with Fi and Ci, and increased in Fu and Fi, compared with Cu and Ci, suggesting effects of both inflation and asthma group, respectively. When analyses were limited to airway sizes that were available for all groups (Pbm < 15 mm), the slopes of Fi and Fu were similar, but both were greater than Ci and Cu, which were also similar. It was calculated that the effect of asthma group accounted for 80% and inflation for 20% of the differences between Fi and Ci. We conclude that the effects of inflation on the relationship between Pbm and ASM are small and do not account for the differences observed in ASM between cases of asthma and nonasthmatic controls.
Asunto(s)
Asma/fisiopatología , Membrana Basal/fisiopatología , Pulmón/fisiopatología , Músculo Liso/fisiopatología , Adolescente , Adulto , Anciano , Asma/mortalidad , Asma/patología , Australia , Membrana Basal/patología , Brasil , Colombia Británica , Estudios de Casos y Controles , Niño , Femenino , Humanos , Pulmón/patología , Rendimiento Pulmonar , Masculino , Persona de Mediana Edad , Músculo Liso/patología , Nueva ZelandaRESUMEN
BACKGROUND: Orally inhaled corticosteroids represent the usually recommended initial controller therapy for most patients with persistent asthma. Some patients might benefit from earlier use of a combination of an inhaled corticosteroid and an orally inhaled long-acting beta agonist, however. We wished to identify clinical characteristics of patients which would enable one to identify a sub-group of patients who would benefit most from initiating sustained controller therapy with combination therapy. METHODS: We carried out a secondary analysis of five randomized clinical trials including 1606 subjects in order to examine whether differences in baseline characteristics of patients might predict a greater preferential response to combination therapy with salmeterol and fluticasone. RESULTS: Subjects whose asthma had been present for 10 or more years were 2.2 times more likely to achieve well-controlled asthma by 12 weeks on combination therapy, while subjects with a shorter duration of asthma were only 1.4 times as likely to achieve asthma control with combination therapy as opposed to inhaled corticosteroids alone. None of the other factors examined including symptom frequency or severity, rescue beta-agonist use, severity of lung function impairment or degree of reversibility, was able to distinguish subjects who would benefit preferentially from such combination therapy. CONCLUSIONS: Longer duration of asthma might be used to identify subjects who will benefit more from combined maintenance therapy with a long-acting beta agonist and an inhaled corticosteroid rather than an inhaled corticosteroid alone.
Asunto(s)
Corticoesteroides/administración & dosificación , Albuterol/análogos & derivados , Androstadienos/administración & dosificación , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Administración por Inhalación , Adolescente , Adulto , Albuterol/administración & dosificación , Niño , Quimioterapia Combinada , Femenino , Fluticasona , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Xinafoato de Salmeterol , Resultado del TratamientoRESUMEN
Endothelin-1 (ET-1), a G protein-coupled receptor-activating peptide, is increased in airway epithelium, plasma, and bronchoalveolar lavage fluid of asthmatic patients. We hypothesized that ET-1 may contribute to the increased airway smooth muscle mass found in severe asthma by inducing hypertrophy and inhibiting apoptosis of smooth muscle cells. To investigate this hypothesis, we determined that treatment of primary human bronchial smooth muscle cells with ET-1 dose dependently [10(-11)-10(-7) M] inhibited the apoptosis induced by serum withdrawal. ET-1 treatment also resulted in a significant increase in total protein synthesis, mediated through both ET(A) and ET(B) receptors, cell size, as well as increased expression of myosin heavy chain, alpha-smooth muscle actin, and calponin. ET-1-induced hypertrophy was accompanied by activation of JAK1/STAT-3 and MAPK1/2 (ERK1/2) cell signaling pathways. Inhibition of JAK1/STAT-3 pathways by piceatannol or ERK1/2 by the MAPK/ERK kinase 1/2 inhibitor U0126 blunted the increase in total protein synthesis. The hypertrophic effect of ET-1 was equivalent to that of the gp130 cytokine oncostatin M and greater than that induced by cardiotrophin-1. ET-1 induced release of IL-6 but not IL-11, leukemia inhibitory factor, oncostatin M, or cardiotrophin-1, although treatment of cells with IL-6 alone did not induce hypertrophy. These results suggest that ET-1 is a candidate mediator for the induction of increased smooth muscle mass in asthma and identify signaling pathways activated by this mediator.
Asunto(s)
Bronquios/efectos de los fármacos , Bronquios/patología , Endotelina-1/farmacología , Músculo Liso/efectos de los fármacos , Músculo Liso/patología , Apoptosis/efectos de los fármacos , Butadienos/farmacología , Aumento de la Célula/efectos de los fármacos , Células Cultivadas , Citocinas/farmacología , Humanos , Interleucina-6/biosíntesis , Interleucina-6/farmacología , Janus Quinasa 1/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Musculares/metabolismo , Nitrilos/farmacología , Oncostatina M/farmacología , Proteínas Recombinantes/farmacología , Factor de Transcripción STAT3/metabolismoRESUMEN
Long-acting beta-agonists are a pillar of therapy for many patients with asthma because they are the preferred add-on therapy to inhaled corticosteroids. However, a recent meta-analysis documented a substantial increase in severe exacerbations requiring hospital admission and life-threatening asthma exacerbations in patients treated with long-acting beta-agonists. A careful evaluation of this meta-analysis raises several concerns about its applicability to current practice. Pivotal trials evaluating the benefit of adding long-acting beta-agonists to inhaled corticosteroids were not included. The authors of the current paper call for physicians to continue their usual practice of using long-acting beta-agonists as adjunctive therapy, as well as for an independent meta-analysis of individual patients using inhaled corticosteroids and long-acting beta-agonists concomitantly.
Asunto(s)
Corticoesteroides/administración & dosificación , Agonistas Adrenérgicos beta/administración & dosificación , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Administración por Inhalación , Corticoesteroides/efectos adversos , Agonistas Adrenérgicos beta/efectos adversos , Asma/complicaciones , Broncodilatadores/efectos adversos , Quimioterapia Combinada , Hospitalización , Humanos , Metaanálisis como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: The long-term outcome and spectrum of disease of nontuberculous mycobacterial immune reconstitution syndrome have not been described. METHODS: We report the findings of an observational study. RESULTS: Among 51 patients (43 with Mycobacterium avium complex [MAC] infection, 2 with Mycobacterium genavense infection, and 6 whose samples were smear positive but culture negative) from 1993-2004, the median follow-up period was 29 months. The incidence of nontuberculous mycobacterial immune reconstitution syndrome was 3.5% among patients initiating highly active antiretroviral therapy (HAART) with a baseline CD4+ cell count of <100 cells/microL. Three main clinical presentations were peripheral lymphadenitis (in 17 patients), pulmonary-thoracic disease (in 15 patients), and intra-abdominal disease (in 13 patients). Six other patients had cases that involved joint, spine, prostate, skin, soft tissue, and spontaneously resolving MAC bacteremia. Disease was usually localized. Median CD4+ cell counts before initiation of HAART and at diagnosis were 20 and 120 cells/microL, respectively, and the median reduction in human immunodeficiency virus (HIV) RNA load was 2.5 log10 copies/mL. Intra-abdominal disease was frequently preceded by disseminated MAC infection (in 62% of cases, compared with 6%-33% of cases for other groups; P=.003) and accounted for 16 (43%) of 36 hospitalizations (compared with 5%-35% for other groups; P=.008). The relapse rate was not higher among 10 patients who received no MAC therapy or received MAC therapy for < or =2 weeks. Prednisone was associated with clinical responses in 8 (89%) of 9 patients with evaluable cases. In total, 7 patients (14%) had 13 subsequent culture-positive MAC events (6 of which were cases of immune reconstitution syndrome, and 7 of which were cases of disseminated MAC infection). Ten patients (20%) died (2 of disseminated MAC infection, 5 of other opportunistic infections, and 3 of HIV-unrelated causes). CONCLUSIONS: Nontuberculous mycobacterial immune reconstitution syndrome has a wide range of clinical presentations and severity. The long-term prognosis is favorable for HAART-adherent patients. Intra-abdominal disease is associated with greater morbidity than is peripheral lymphadenitis. The role of antimycobacterial therapy is uncertain, given the self-limited course of most nonabdominal cases.
Asunto(s)
Infecciones por VIH/complicaciones , Infecciones por Mycobacterium/inmunología , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Tolerancia Inmunológica , Inflamación , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium/etiología , ARN Viral/sangre , Factores de Riesgo , Carga ViralRESUMEN
Structural changes reported in the airways of asthmatics include epithelial fragility, goblet cell hyperplasia, enlarged submucosal mucus glands, angiogenesis, increased matrix deposition in the airway wall, increased airway smooth muscle mass, wall thickening and abnormalities in elastin. Genetic influences, as well as fetal and early life exposures, may contribute to structural changes such as subepithelial fibrosis from an early age. Other structural alterations are related to duration of disease and/or long-term uncontrolled inflammation. The increase in smooth muscle mass in both large and small airways probably occurs via multiple mechanisms, and there are probably changes in the phenotype of smooth muscle cells, some showing enhanced synthetic capacity, others enhanced proliferation or contractility. Fixed airflow limitation is probably due to remodelling, whereas the importance of structural changes to the phenomenon of airways hyperresponsiveness may be dependent on the specific clinical phenotype of asthma evaluated. Reduced compliance of the airway wall secondary to enhanced matrix deposition may protect against airway narrowing. Conversely, in severe asthma, disruption of alveolar attachments and adventitial thickening may augment airway narrowing. The encroachment upon luminal area by submucosal thickening may be disadvantageous by increasing the risk of airway closure in the presence of the intraluminal cellular and mucus exudate associated with asthma exacerbations. Structural changes may increase airway narrowing by alteration of smooth muscle dynamics through limitation of the ability of the smooth muscle to periodically lengthen.
Asunto(s)
Asma/patología , Sistema Respiratorio/patología , Adulto , Asma/fisiopatología , Hiperreactividad Bronquial , Broncoconstricción , Niño , Humanos , Pulmón/patología , Pulmón/fisiopatología , Moco/fisiología , Músculo Liso/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Mecánica Respiratoria/fisiología , Sistema Respiratorio/fisiopatología , Esputo/fisiologíaRESUMEN
Structural changes in COPD are found in the central airways, peripheral airways, lung parenchyma, and pulmonary vasculature. Broadly there are two different pathways leading to the same physiologic phenotype: one centered on the small airways and involving mucosal inflammation and structural change, and the other centered on the parenchyma involving excessive proteolysis and /or disordered repair processes. A highly variable combination of these changes exists in different patients, in part due to genetic factors. The composite picture seen on pulmonary function tests is evidence of over-inflation of the lung, decreased airflow and abnormalities in gas exchange. Earlier stages of the airway disease are associated with more potentially reversible changes, whereas later stages show more collagen deposition and hence irreversibility. Thus a careful assessment of the structural phenotype of subpopulations of COPD patients is likely to lead to optimal categorization for therapeutic trials, and earlier disease is more likely to response to interventions.
Asunto(s)
Pulmón/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Vasos Sanguíneos/patología , Bronquios/patología , Células Caliciformes/patología , Humanos , Alveolos Pulmonares/patología , Fumar/patología , Tomografía Computarizada por Rayos X , Tráquea/patologíaRESUMEN
The observation that the length-force relationship in airway smooth muscle can be shifted along the length axis by accommodating the muscle at different lengths has stimulated great interest. In light of the recent understanding of the dynamic nature of length-force relationship, many of our concepts regarding smooth muscle mechanical properties, including the notion that the muscle possesses a unique optimal length that correlates to maximal force generation, are likely to be incorrect. To facilitate accurate and efficient communication among scientists interested in the function of airway smooth muscle, a revised and collectively accepted nomenclature describing the adaptive and dynamic nature of the length-force relationship will be invaluable. Setting aside the issue of underlying mechanism, the purpose of this article is to define terminology that will aid investigators in describing observed phenomena. In particular, we recommend that the term "optimal length" (or any other term implying a unique length that correlates with maximal force generation) for airway smooth muscle be avoided. Instead, the in situ length or an arbitrary but clearly defined reference length should be used. We propose the usage of "length adaptation" to describe the phenomenon whereby the length-force curve of a muscle shifts along the length axis due to accommodation of the muscle at different lengths. We also discuss frequently used terms that do not have commonly accepted definitions that should be used cautiously.
Asunto(s)
Contracción Muscular/fisiología , Músculo Liso/fisiología , Terminología como Asunto , Tráquea/fisiología , Animales , HumanosRESUMEN
STUDY OBJECTIVE: To assess the association between socioeconomic status (SES) and short-acting (SA) beta-agonist use, controlling for asthma severity. DESIGN: Cross-sectional study. SETTING: Vancouver, BC, Canada. PARTICIPANTS: Two hundred two asthmatics between 19 years and 50 years of age and residing in the greater Vancouver regional district. MEASUREMENTS: The quantity of SA beta-agonist used in the previous year was collected by self-report; pulmonary function and beta-receptor genotype were measured on each participant. SES was measured at both the individual and population levels. Five methods of adjustment for asthma severity were used, as follows: the Canadian Asthma Consensus Guidelines, three previously developed asthma-severity scores, and forward stepwise multiple regression modeling. Polychotomous logistic regression was used to assess all relationships. RESULTS: Independent of the method used to measure SES or adjust for asthma severity, lower SES was consistently and significantly associated with the use of greater amounts of SA beta-agonist. Adjusting for severity using the multivariate model explained the most variance of SA beta-agonist use (R(2) adjusted, 0.35 to 0.37). In this model, social assistance recipients were more likely to use greater amounts of SA beta-agonist (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.7 to 6.5). An inverse relationship between SA beta-agonist use and both annual household income (> $50,000; OR, 0.28; 95% CI, 0.13 to 0.60; and $20,000 to $50,000; OR, 0.44; 95% CI, 0.21 to 0.96; relative to <$20,000) and education (completing a bachelor's degree vs no formal education; OR, 0.25; 95% CI, 0.14 to 0.71). Participants living in a neighborhood with higher median household income (OR, 0.91; 95% CI, 0.84 to 0.98 per $1,000 increase) or a higher prevalence of having attained a bachelor's degree (OR, 0.96; 95% CI, 0.84 to 0.98 per 1% increase) were also less likely use greater amounts of SA beta-agonist. Results were consistent for neighborhood unemployment rate. CONCLUSIONS: The social gradient in asthma-related outcomes may be at least partially attributable to poorer asthma control in lower-SES asthmatics.
Asunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Asma/tratamiento farmacológico , Adulto , Asma/prevención & control , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Clase SocialRESUMEN
BACKGROUND: Several sets of Canadian guidelines for the diagnosis and management of asthma have been published over the past 15 years. Since the last revision of the 1999 Canadian Asthma Consensus Report, important new studies have highlighted the need to incorporate new information into the asthma guidelines. OBJECTIVES: To review the literature on adult asthma management published between January 2000 and June 2003; to evaluate the influence of the new evidence on the recommendations made in the 1999 Canadian Asthma Consensus Guidelines and its 2001 update; and to report new recommendations on adult asthma management. METHODS: Three specific topics for which new evidence affected the previous recommendations were selected for review: initial treatment of asthma, add-on therapies in the treatment of asthma and asthma education. The resultant reviews were discussed in June 2003 at a meeting under the auspices of the Canadian Thoracic Society, and recommendations for adult asthma management were reviewed. RESULTS: The present report emphasises the importance of the early introduction of inhaled corticosteroids in symptomatic patients with mild asthma; stresses the benefit of adding additional therapy, preferably long-acting beta2-agonists, to patients incompletely controlled on low doses of inhaled corticosteroids; and documents the essential role of asthma education. CONCLUSION: The present report generally supports many of the previous recommendations published in the 1999 Canadian Asthma Consensus Report and provides higher levels of evidence for a number of those recommendations.
Asunto(s)
Asma/tratamiento farmacológico , Educación Médica Continua , Educación del Paciente como Asunto , Corticoesteroides/uso terapéutico , Agonistas Adrenérgicos beta/uso terapéutico , Adulto , Canadá , Humanos , Antagonistas de Leucotrieno/uso terapéuticoRESUMEN
Induction of hypertrophy and inhibition of apoptosis may be important mechanisms contributing to increased airway smooth muscle (ASM) mass in asthma. Data from our laboratory indicate that cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in isolated human ASM cells. To determine whether these novel effects of CT-1 also occur in the airway tissue milieu and to determine whether structural changes are accompanied by functional changes, matched pairs of guinea pig airway explants were treated with or without CT-1 for 7 days, and structural features as well as isometric and isotonic contractile and relaxant mechanical properties were measured. CT-1 (0.2-5 ng/ml) increased both myocyte mass and extracellular matrix in a concentration-dependent fashion. CT-1 (10 ng/ml)-treated tissues exhibited a significant increase in passive tension at all lengths on day 7; at optimal length, passive tension generated by CT-1-treated tissues was 1.72 +/- 0.12 vs. 1.0 +/- 0.1 g for control. Maximal isometric stress was decreased in the CT-1-treated group on day 7 (0.39 +/- 0.10 kg/cm(2)) vs. control (0.77 +/- 0.15 kg/cm(2), P < 0.05). Isoproterenol-induced relaxant potency was reduced in CT-1-treated tissues, log EC(50) being -7.28 +/- 0.34 vs. -8.12 +/- 0.25 M in control, P < 0.05. These data indicate that CT-1 alters ASM structural and mechanical properties in the tissue environment and suggest that structural changes found in the airway wall in asthma are not necessarily associated with increased responsiveness.