Exhaled breath condensate cysteinyl leukotrienes and airway remodeling in childhood asthma: a pilot study

BACKGROUND: It has been suggested that cysteinyl leukotrienes (cysLTs) play an important role in airway remodeling. Previous reports have indicated that cysLTs augment human airway smooth muscle cell proliferation. Recently, cysLTs have been measured in exhaled breath condensate (EBC). The aim of this study was to evaluate the relationship between cysLTs in EBC and another marker of airway remodeling, reticular basement membrane (RBM) thickening, in endobronchial biopsies in children. METHODS: 29 children, aged 4–15 years, with moderate to severe persistent asthma, who underwent bronchoscopy as part of their clinical assessment, were included. Subjects underwent spirometry and EBC collection for cysLTs analysis, followed by bronchoscopy and endobronchial biopsy within 24 hours. RESULTS: EBC cysLTs were significantly lower in asthmatic children who were treated with montelukast than in those who were not (median (interquartile range) 36.62 (22.60–101.05) versus 249.1 (74.21–526.36) pg/ml, p = 0.004). There was a significant relationship between EBC cysLTs and RBM thickness in the subgroup of children who were not treated with montelukast (n = 13, r = 0.75, p = 0.003). CONCLUSION: EBC cysLTs appear to be associated with RBM thickening in asthma

Hyperresponsiveness to inhaled but not intravenous methacholine during acute respiratory syncytial virus infection in mice

BACKGROUND: To characterise the acute physiological and inflammatory changes induced by low-dose RSV infection in mice. METHODS: BALB/c mice were infected as adults (8 wk) or weanlings (3 wk) with 1 × 10(5 )pfu of RSV A2 or vehicle (intranasal, 30 μl). Inflammation, cytokines and inflammatory markers in bronchoalveolar lavage fluid (BALF) and airway and tissue responses to inhaled methacholine (MCh; 0.001 – 30 mg/ml) were measured 5, 7, 10 and 21 days post infection. Responsiveness to iv MCh (6 – 96 μg/min/kg) in vivo and to electrical field stimulation (EFS) and MCh in vitro were measured at 7 d. Epithelial permeability was measured by Evans Blue dye leakage into BALF at 7 d. Respiratory mechanics were measured using low frequency forced oscillation in tracheostomised and ventilated (450 bpm, flexiVent) mice. Low frequency impedance spectra were calculated (0.5 – 20 Hz) and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)] was fitted to the data. RESULTS: Inflammation in adult mouse BALF peaked at 7 d (RSV 15.6 (4.7 SE) vs. control 3.7 (0.7) × 10(4 )cells/ml; p < 0.001), resolving by 21 d, with no increase in weanlings at any timepoint. RSV-infected mice were hyperresponsive to aerosolised MCh at 5 and 7 d (PC(200 )Raw adults: RSV 0.02 (0.005) vs. control 1.1 (0.41) mg/ml; p = 0.003) (PC(200 )Raw weanlings: RSV 0.19 (0.12) vs. control 10.2 (6.0) mg/ml MCh; p = 0.001). Increased responsiveness to aerosolised MCh was matched by elevated levels of cysLT at 5 d and elevated VEGF and PGE(2 )at 7 d in BALF from both adult and weanling mice. Responsiveness was not increased in response to iv MCh in vivo or EFS or MCh challenge in vitro. Increased epithelial permeability was not detected at 7 d. CONCLUSION: Infection with 1 × 10(5 )pfu RSV induced extreme hyperresponsiveness to aerosolised MCh during the acute phase of infection in adult and weanling mice. The route-specificity of hyperresponsiveness suggests that epithelial mechanisms were important in determining the physiological effects. Inflammatory changes were dissociated from physiological changes, particularly in weanling mice

Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis

Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75432/1/j.1365-2222.2006.02498.x.pd

The role of thymic tolerance in CNS autoimmune disease

The contributions of the peripheral adaptive and innate immune systems to CNS autoimmunity have been extensively studied. However, the role of thymic selection in these conditions is much less well understood. The thymus is the primary lymphoid organ for the generation of T cells; thymic mechanisms ensure that cells with an overt autoreactive specificity are eliminated before they emigrate to the periphery and control the generation of thymic regulatory T cells. Evidence from animal studies demonstrates that thymic T cell selection is important for establishing tolerance to autoantigens. However, there is a considerable knowledge gap regarding the role of thymic selection in autoimmune conditions of the human CNS. In this Review, we critically examine the current body of experimental evidence for the contribution of thymic tolerance to CNS autoimmune diseases. An understanding of why dysfunction of either thymic or peripheral tolerance mechanisms rarely leads to CNS inflammation is currently lacking. We examine the potential of de novo T cell formation and thymic selection as novel therapeutic avenues and highlight areas for future study that are likely to make these targets the focus of future treatments

IMP(2)ART systematic review of education for healthcare professionals implementing supported self-management for asthma

Abstract Despite a robust evidence base for its effectiveness, implementation of supported self-management for asthma is suboptimal. Professional education is an implementation strategy with proven effectiveness, though the specific features linked with effectiveness are often unclear. We performed a systematic review of randomised controlled trials and controlled clinical trials (published from 1990 and updated to May 2017 using forward citation searching) to determine the effectiveness of professional education on asthma self-management support and identify features of effective initiatives. Primary outcomes reflected professional behaviour change (provision of asthma action plans) and patient outcomes (asthma control; unscheduled care). Data were coded using the Effective Practice and Organisation of Care Taxonomy, the Theoretical Domains Framework (TDF), and Bloom’s Taxonomy and synthesised narratively. Of 15,637 articles identified, 18 (reporting 15 studies including 21 educational initiatives) met inclusion criteria. Risk of bias was high for five studies, and unclear for 10. Three of 6 initiatives improved action plan provision; 1/2 improved asthma control; and 2/7 reduced unscheduled care. Compared to ineffective initiatives, effective initiatives were more often coded as being guideline-based; involving local opinion leaders; including inter-professional education; and addressing the TDF domains ‘social influences’; ‘environmental context and resources’; ‘behavioural regulation’; ‘beliefs about consequences’; and ‘social/professional role and identity’. Findings should be interpreted cautiously as many strategies were specified infrequently. However, identified features warrant further investigation as part of implementation strategies aiming to improve the provision of supported self-management for asthma

Effect of Naproxen, a Prostaglandin Inhibitor, on Acute Otitis Media and Persistence of Middle Ear Effusion in Children

Prostaglandins are thought to be of importance in the pathophysiology of otitis media with effusion (OME), and the possibility of reducing the frequency and persistence of this condition by using prostaglandin inhibitors has been suggested. In a double blind manner, naproxen was administered to children with acute otitis media, in addition to amoxicillin, and its influence on the subsequent occurrence and persistence of middle ear effusion was evaluated. Eighty-one children participated in the study. No significant difference was found in the number of patients with tympanograms consistent with OME in the two groups. After 10 days of treatment, 63% in the naproxen and 58% in the placebo group, and after 30 days, 41% and 59%, respectively, had type B tympanograms. Similarly, there were no differences between the two groups with respect to other parameters studied (duration of otalgia, fever, otoscopic findings). No side effects related to naproxen were observed.</jats:p