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Repeated ovalbumin (OA) or saline exposure of sensitized Brown Norway rats was examined on agonist reactivity, airway smooth muscle (ASM) content, and contractile protein expression in small bronchioles at 24 h, 7 days, and 35 days after challenge. OA increased ASM content (P < 0.05 vs. saline) at 24 h, which resolved by 7 days. Maximum developed tension ([T.sub.max]) to carbachol, KCl, and 4-[beta]-phorbol 12,13-dibutyrate was increased (P < 0.05) by OA in bronchioles at 24 h but was abrogated after correction for ASM. Differences in [T.sub.max] were not present at 7 days. In contrast, at 35 days, [T.sub.max] was increased (P < 0.05) after correction for ASM. Smooth muscle (sm)-[alpha]-actin, sm-myosin heavy chain (MHC) isoform 1, calponin, smoothelin-A, and sm-myosin light chain kinase expression were reduced (P < 0.05) by OA at 24 h in bronchioles but not in trachealis. Consistent with contraction findings, no difference in expression of these proteins was detected at 7 days. At 35 days, however, with the exception of sm-[alpha]-actin, their abundance was again reduced (P < 0.05) by OA. Nonmuscle MHC and [beta]-actin were unchanged throughout by OA. These findings indicate persistent changes in contractile protein content, consistent with ASM phenotypic modulation in vivo, which occur in response to repeated OA inhalation. Thus, OA exposure induces structural changes in bronchiole ASM content and in agonist responsiveness ex vivo that resemble remodeling in asthma. asthma; inflammation; airway wall structural remodeling

Treatment of persistent asthma with oral theophylline and low-dose inhaled budesonide may provide similar improvements as treatment with high-dose inhaled glucocorticoids. Sixty-two asthmatic patients still symptomatic while using high-dose inhaled budesonide were randomly assigned to treatment with either low inhaled dosages and oral theophylline or the standard high-dose treatment. All patients showed improvements in lung function, while the theophylline group showed greater enhancement in two areas of performance. Theophylline was given at dosages lower than established therapeutic values. This strategy could avoid side effects from both theophylline and glucocorticoid therapy, and also cost less.

Analysis of the influence of tumor necrosis factor-alpha (TNF-alpha) on interleukin-8 (IL-8) expression and generation in primary cultured human airway epithelial cells (HAEC) by Northern blot analysis and radioimmunoassay reveals the dose- and time-dependent increase of IL-8 mRNA and protein expression in HAEC by TNF-alpha. Glucocorticosteroid dexamethasone inhibits IL-8 expression in both normal and TNF-alpha-induced cells. A comparative study suggests that TNF-alpha-induced IL-8 immunoreactivity is higher in human lung epithelial cell line A549 than in HAEC, indicating the absence of a inhibitory regulatory mechanism in A549.

The safety of the most widely prescribed antiasthma drugs, [[Beta].sub.2]-adrenoceptor agonists, has recently been questioned. Issues such as their suitability for long-term and regular prophylactic use are addressed in this Comment article by Peter Barnes and Fan Chung, who examine the possibility that the [[Beta].sub.2]-agonists themselves contribute to worsening symptoms in asthma patients, thus setting up a vicious circle with greater use of the drugs. They conclude that it would be prudent to restrict the use of [[Beta].sub.2]-agonists in asthma to on-demand immediate symptom control.

Abstract Background Asthma is characterised by increased numbers of Th2-like cells in the airways and IgE secretion. Generation of Th2 cells requires interleukin (IL)-4 and IL-13 acting through their specific receptors and activating the transcription factor, signal transducer and activator of transcription 6 (STAT6). STAT6 knockout mice fail to produce IgE, airway hyperresponsiveness and bronchoalveolar lavage eosinophilia after allergen sensitisation, suggesting a critical role for STAT6 in allergic responses. Methods We have investigated the expression of STAT6 in peripheral blood T-lymphocytes, alveolar macrophages and bronchial biopsies from 17 normal subjects and 18 mild-moderate steroid-naïve stable asthmatic patients. Results STAT6 expression was variable and was detected in T-lymphocytes, macrophages and bronchial epithelial cells from all subjects with no difference between normal and stable asthmatic subjects. Conclusions STAT6 expression in different cells suggests that it may be important in regulating the expression of not only Th2-like cytokines in T cells of man, but may also regulate STAT-inducible genes in alveolar macrophages and airway epithelial cells.

Abstract Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.