Airway smooth muscle proliferation and inflammation in asthma.

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.

Inflammation-dependent and independent airway remodelling in asthma.

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.

Distribution of airway smooth muscle remodelling in asthma: relation to airway inflammation.

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.

Formation of a stable mimic of ambient particulate matter containing viable infectious respiratory syncytial virus and its dry-deposition directly onto cell cultures.

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.

Airway smooth muscle hypertrophy and hyperplasia in asthma.

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.

Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to respiratory syncytial virus and air pollution.

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.

Evidence for airway remodeling in chronic asthma.

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.

Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1.

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.

An evaluation of patients' willingness to trade symptom-free days for asthma-related treatment risks: a discrete choice experiment.

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.

Airway basement membrane perimeter distensibility and airway smooth muscle area in asthma.

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.

Predictors of a more favourable response to combined therapy with salmeterol and fluticasone as initial maintenance therapy in asthma.

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.

Lung structural changes in chronic obstructive pulmonary diseases.

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.

Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids.

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.

Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells.

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.

Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up.

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.

Structural changes in the airways in asthma: observations and consequences.

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.

On the terminology for describing the length-force relationship and its changes in airway smooth muscle.

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.

Reconcilable differences: a cross-sectional study of the relationship between socioeconomic status and the magnitude of short-acting beta-agonist use in asthma.

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.

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants.

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.

Adult Asthma Consensus Guidelines update 2003.

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.

Expression and effects of cardiotrophin-1 (CT-1) in human airway smooth muscle cells.

1. Cellular hypertrophy and/or a reduced rate of apoptosis could increase airway smooth muscle mass. As cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in cardiomyocytes, we tested for the expression and effects of CT-1 in human bronchial smooth muscle cells (HBSMC).

Estradiol in severe asthma with premenstrual worsening.

Objective: To describe the beneficial effects of estradiol in a severely asthmatic woman with premenstrual worsening of asthma.

Case Summary: A 50-year-old white woman, with a 14-year history of severe steroid-dependent asthma and monthly premenstrual worsening of asthma, was randomized to receive estradiol 2 mg or placebo for 6 days during the late luteal phase (days 23-28) of 2 successive menstrual cycles. Despite greater prednisone and inhaled beta-agonist use during the late luteal phase of the placebo cycle, the patient exhibited improved asthma symptoms, pulmonary function, and peak expiratory flows, as well as lower values for biomarkers of airway inflammation during the same time period of the estradiol cycle.

Characterization of airway plugging in fatal asthma.

Purpose: Case reports suggest that deaths due to asthma can occur without airway plugging. In this study, we examined the hypothesis that obstruction of the airway lumen by an exudate containing mucus and cells is a key feature of fatal asthma attacks.

Methods: We quantified airway narrowing and lumenal content in 275 airways from 93 patients with fatal asthma aged 10 to 49 years (59 white subjects and 34 Polynesian subjects, including 19 children), compared with airways from control patients who died suddenly without pulmonary diseases.

Estradiol in premenstrual asthma: a double-blind, randomized, placebo-controlled, crossover study.

Study Objectives: To characterize asthma symptoms and pulmonary function throughout two menstrual cycles, with and without exogenous estradiol administration, in women with premenstrual asthma, and to determine the effect of estradiol administration on asthma symptoms, pulmonary function, quality of life, and biomarkers of airway inflammation.

Design: Double-blind, randomized, placebo-controlled, crossover study.

Setting: Respiratory clinic and clinical research center.