Allergic rhinitis and asthma: inflammation in a one-airway condition

BACKGROUND: Allergic rhinitis and asthma are conditions of airway inflammation that often coexist. DISCUSSION: In susceptible individuals, exposure of the nose and lungs to allergen elicits early phase and late phase responses. Contact with antigen by mast cells results in their degranulation, the release of selected mediators, and the subsequent recruitment of other inflammatory cell phenotypes. Additional proinflammatory mediators are released, including histamine, prostaglandins, cysteinyl leukotrienes, proteases, and a variety of cytokines, chemokines, and growth factors. Nasal biopsies in allergic rhinitis demonstrate accumulations of mast cells, eosinophils, and basophils in the epithelium and accumulations of eosinophils in the deeper subepithelium (that is, lamina propria). Examination of bronchial tissue, even in mild asthma, shows lymphocytic inflammation enriched by eosinophils. In severe asthma, the predominant pattern of inflammation changes, with increases in the numbers of neutrophils and, in many, an extension of the changes to involve smaller airways (that is, bronchioli). Structural alterations (that is, remodeling) of bronchi in mild asthma include epithelial fragility and thickening of its reticular basement membrane. With increasing severity of asthma there may be increases in airway smooth muscle mass, vascularity, interstitial collagen, and mucus-secreting glands. Remodeling in the nose is less extensive than that of the lower airways, but the epithelial reticular basement membrane may be slightly but significantly thickened. CONCLUSION: Inflammation is a key feature of both allergic rhinitis and asthma. There are therefore potential benefits for application of anti-inflammatory strategies that target both these anatomic sites

Synthesis of tenascin and laminin beta2 chain in human bronchial epithelial cells is enhanced by cysteinyl leukotrienes via CysLT1 receptor

<p>Abstract</p> <p>Background</p> <p>Cysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood. Recent evidence suggests that increased expression of tenascin (Tn) and laminin (Ln) β2 chain is indicative of the remodeling activity in asthma, but represents also an example of deposition of extracellular matrix, which affects the airway wall compliance. We tested the hypothesis that CysLTs affect production of Tn and Ln β2 chain by human bronchial epithelial cells and elucidated, which of the CysLT receptors, CysLT₁or CysLT₂, mediate this effect.</p> <p>Methods</p> <p>Cultured BEAS-2B human bronchial epithelial cells were stimulated with leukotriene D₄(LTD₄) and E₄(LTE₄) and evaluated by immunocytochemistry, Western blotting, flow cytometry, and RT-PCR. CysLT receptors were differentially blocked with use of montelukast or BAY u9773.</p> <p>Results</p> <p>LTD₄and LTE₄significantly augmented the expression of Tn, whereas LTD₄, distinctly from LTE₄, was able to increase also the Ln β2 chain. Although the expression of CysLT₂prevailed over that of CysLT₁, the up-regulation of Tn and Ln β2 chain by CysLTs was completely blocked by the CysLT₁-selective antagonist montelukast with no difference between montelukast and the dual antagonist BAY u9773 for the inhibitory capacity.</p> <p>Conclusion</p> <p>These findings suggest that the CysLT-induced up-regulation of Tn and Ln β2 chain, an important epithelium-linked aspect of airway remodeling, is mediated predominantly by the CysLT₁receptor. The results provide a novel aspect to support the use of CysLT₁receptor antagonists in the anti-remodeling treatment of asthma.</p

Prolonged ozone exposure in an allergic airway disease model: Adaptation of airway responsiveness and airway remodeling

BACKGROUND: Short-term exposure to high concentrations of ozone has been shown to increase airway hyper-responsiveness (AHR). Because the changes in AHR and airway inflammation and structure after chronic ozone exposure need to be determined, the goal of this study was to investigate these effects in a murine model of allergic airway disease. METHODS: We exposed BALB/c mice to 2 ppm ozone for 4, 8, and 12 weeks. We measured the enhanced pause (Penh) to methacholine and performed cell differentials in bronchoalveolar lavage fluid. We quantified the levels of IL-4 and IFN-γ in the supernatants of the bronchoalveolar lavage fluids using enzyme immunoassays, and examined the airway architecture under light and electron microscopy. RESULTS: The groups exposed to ozone for 4, 8, and 12 weeks demonstrated decreased Penh at methacholine concentrations of 12.5, 25, and 50 mg/ml, with a dose-response curve to the right of that for the filtered-air group. Neutrophils and eosinophils increased in the group exposed to ozone for 4 weeks compared to those in the filtered-air group. The ratio of IL-4 to INF-γ increased significantly after exposure to ozone for 8 and 12 weeks compared to the ratio for the filtered-air group. The numbers of goblet cells, myofibroblasts, and smooth muscle cells showed time-dependent increases in lung tissue sections from the groups exposed to ozone for 4, 8, and 12 weeks. CONCLUSION: These findings demonstrate that the increase in AHR associated with the allergic airway does not persist during chronic ozone exposure, indicating that airway remodeling and adaptation following repeated exposure to air pollutants can provide protection against AHR

A randomized controlled trial to assess the clinical and cost effectiveness of a nurse-led Antenatal Asthma Management Service in South Australia (AAMS study)

Background: Pregnancy presents a unique situation for the management of asthma as it can alter the course of asthma severity and its treatment, which in turn can affect pregnancy outcomes. Despite awareness of the substantial adverse effects associated with asthma during pregnancy, little has been done to improve its management and reduce associated perinatal morbidity and mortality. The aim of this randomized controlled trial is to evaluate the clinical and cost effectiveness of an Antenatal Asthma Management Service. Methods/design: Design: Multicentre, randomized controlled trial. Inclusion criteria: Women with physician diagnosed asthma, which is not currently in remission, who are less than 20 weeks gestation with a singleton pregnancy and do not have a chronic medical condition. Trial entry and randomization: Eligible women with asthma, stratified by treatment site, disease severity and parity, will be randomized into either the ‘Standard Care Group’ or the ‘Intervention Group’. Study groups: Both groups will be followed prospectively throughout pregnancy. Women in the ‘Standard Care Group’ will receive routine obstetric care reflecting current clinical practice in Australian hospitals. Women in the ‘Intervention Group’ will receive additional care through the nurse-led Antenatal Asthma Management Service, based in the antenatal outpatient clinic. Women will receive asthma education with a full assessment of their asthma at 18, 24, 30 and 36 weeks gestation. Each antenatal visit will include a 60 min session where asthma management skills are assessed including: medication adherence and knowledge, inhaler device technique, recognition of asthma deterioration and possession of a written asthma action plan. Furthermore, subjects will receive education about asthma control and management skills including trigger avoidance and smoking cessation counseling when appropriate. Primary study outcome: Asthma exacerbations during pregnancy. Sample size: A sample size of 378 women will be sufficient to show an absolute reduction in asthma exacerbations during pregnancy of 20% (alpha 0.05 two-tailed, 90% power, 5% loss to follow-up). Discussion: The integration of an asthma education program within the antenatal clinic setting has the significant potential to improve the participation of pregnant women in the self-management of their asthma, reduce asthma exacerbations and improve perinatal health outcomes.Luke E Grzeskowiak, Gustaaf Dekker, Karen Rivers, Kate Roberts-Thomson, Anil Roy, Brian Smith, Jeffery Bowden, Robert Bryce, Michael Davies, Justin Beilby, Anne Wilson, Philippa Middleton, Richard Ruffin, Jonathan Karnon, Vicki L Clifton and for the AAMS study grou

A Trigger Enzyme in Mycoplasma pneumoniae: Impact of the Glycerophosphodiesterase GlpQ on Virulence and Gene Expression

Mycoplasma pneumoniae is a causative agent of atypical pneumonia. The formation of hydrogen peroxide, a product of glycerol metabolism, is essential for host cell cytotoxicity. Phosphatidylcholine is the major carbon source available on lung epithelia, and its utilization requires the cleavage of deacylated phospholipids to glycerol-3-phosphate and choline. M. pneumoniae possesses two potential glycerophosphodiesterases, MPN420 (GlpQ) and MPN566. In this work, the function of these proteins was analyzed by biochemical, genetic, and physiological studies. The results indicate that only GlpQ is an active glycerophosphodiesterase. MPN566 has no enzymatic activity as glycerophosphodiesterase and the inactivation of the gene did not result in any detectable phenotype. Inactivation of the glpQ gene resulted in reduced growth in medium with glucose as the carbon source, in loss of hydrogen peroxide production when phosphatidylcholine was present, and in a complete loss of cytotoxicity towards HeLa cells. All these phenotypes were reverted upon complementation of the mutant. Moreover, the glpQ mutant strain exhibited a reduced gliding velocity. A comparison of the proteomes of the wild type strain and the glpQ mutant revealed that this enzyme is also implicated in the control of gene expression. Several proteins were present in higher or lower amounts in the mutant. This apparent regulation by GlpQ is exerted at the level of transcription as determined by mRNA slot blot analyses. All genes subject to GlpQ-dependent control have a conserved potential cis-acting element upstream of the coding region. This element overlaps the promoter in the case of the genes that are repressed in a GlpQ-dependent manner and it is located upstream of the promoter for GlpQ-activated genes. We may suggest that GlpQ acts as a trigger enzyme that measures the availability of its product glycerol-3-phosphate and uses this information to differentially control gene expression

Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production

Acute exacerbations are the major cause of asthma morbidity, mortality, and health-care costs and are difficult to treat and prevent. The majority of asthma exacerbations are associated with rhinovirus (RV) infection, but evidence supporting a causal relationship is weak and mechanisms are poorly understood. We hypothesized that in asthmatic, but not normal, subjects RV infection would induce clinical, physiologic, and pathologic lower airway responses typical of an asthma exacerbation and that these changes would be related to virus replication and impaired T helper 1 (Th1)/IL-10 or augmented Th2 immune responses. We investigated physiologic, virologic, and immunopathologic responses to experimental RV infection in blood, induced sputum, and bronchial lavage in 10 asthmatic and 15 normal volunteers. RV infection induced significantly greater lower respiratory symptoms and lung function impairment and increases in bronchial hyperreactivity and eosinophilic lower airway inflammation in asthmatic compared with normal subjects. In asthmatic, but not normal, subjects virus load was significantly related to lower respiratory symptoms, bronchial hyperreactivity, and reductions in blood total and CD8+ lymphocytes; lung function impairment was significantly related to neutrophilic and eosinophilic lower airway inflammation. The same virologic and clinical outcomes were strongly related to deficient IFN-γ and IL-10 responses and to augmented IL-4, IL-5, and IL-13 responses. This study demonstrates increased RV-induced clinical illness severity in asthmatic compared with normal subjects, provides evidence of strong relationships between virus load, lower airway virus-induced inflammation and asthma exacerbation severity, and indicates augmented Th2 or impaired Th1 or IL-10 immunity are likely important mechanisms