TLR3 is expressed inside airway epithelial cells and transduces synthetic dsRNA signals. These signals may increase expression of inflammatory cytokines, chemokines and ICAM-1 through activation of transcription factors NF-kappaB and/or IRF3 in airway epithelial cells.

To examine whether levels of inflammatory cytokines and eosinophil cationic protein (ECP) in the sputum reflect the severity of bronchial asthma, we measured their levels in the sputum of symptomatic and asymptomatic asthmatics. Interleukin (IL)-1β IL-5, IL-6, IL-8, RANTES, tumor necrosis factor-α and ECP concentrations in the sputum of symptomatic patients were significantly higher than in asymptomatic subjects. These findings suggest that these inflammatory cytokines are involved in the exacerbation of asthma.

These results indicate that OPN plays a role in the migration of eosinophils into the airways and may be involved in the pathogenesis of asthma.

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This study was designed to examine the possible mechanisms by which macrolide antibiotics favorably influence the clinical course of asthmatic patients. In the first set of experiments, we investigated the effect of roxithromycin (RXM), a newly synthesized macrolide antibiotic, on in vitro cytokine secretion by mitogen-activated human peripheral blood leukocytes. RXM suppressed the secretion of T cell cytokine interleukins (IL) 2-4 and monocyte cytokine tumor necrosis factor alpha. This inhibitory effects on cytokine secretion was dose dependent and firstly noted at a concentration of as little as 0.5 μg/ml which is much lower than therapeutic blood levels. In the second part of experiments, we examined the influence of RXM on cytokine appearance in mouse lung extract induced by lipopolysaccharide (LPS) inhalation and on bronchial responsiveness to methacholine in LPS-treated mice. As compared with mice pretreated with phosphate-buffered saline, RXM administred orally at a single dose of 5 mg/kg once a day for 21 days inhibited the appearance of IL-3, IL-4, IL-5, and tumor necrosis factor alpha in aqueous lung extracts. Pretreatment with RXM also decreased the bronchial responsiveness to methacholine induced by intratracheal injection of LPS. We conclude that the attenuating effect of macrolide antibiotics on asthmatic syndromes might be explained partially by their inhibitory effects on cytokine secretion from leukocytes.

Osteopontin (OPN) is an extracellular matrix protein and immune modulator with a wide range of functions. OPN is recognized as a key cytokine in Th1 immune responses, yet its potential involvement in allergic/asthmatic responses has been investigated only recently. Current data from molecular and cellular studies and studies of OPN-deficient mice provide evidence that OPN plays multiple roles in the regulation of allergic responses, including regulation of IgE response, inflammatory cell migration, and the development of airway fibrosis and angiogenesis. These results suggest that OPN is a pleiotropic cytokine that functions both systemically and locally in tissue mucosa. Notably, OPN is able to exert its effects through different functional domains, and the secreted and intracellular forms of OPN may have distinct functions. Future research to elucidate all aspects of OPN function is needed to ultimately establish its role in the regulation of immune responses and various disease processes, including those critically involved in the development of allergies and asthma.

Background: Oxidants including reactive oxygen species have been indicated to play an important role in the pathogenesis of asthma. Objective: We investigated oxidative status in patients with acute exacerbations of asthma and evaluated the therapeutic response using the D-ROM test which is simple to use and quick. Methods: We measured reactive oxygen metabolite (ROM) levels in the serum of 42 outpatients with acute exacerbations of asthma, 11 outpatients with stable asthma and 40 healthy subjects using the D-ROM test. Seven inpatients admitted due to acute exacerbations of asthma were also enrolled to evaluate the effects of treatment. Serum eosinophil cationic protein and plasma polymorphonuclear elastase were also measured by EIA or ELISA to evaluate the correlation between inflammation and oxidative status. Results: Serum ROM levels were significantly higher in patients with acute exacerbation of asthma than in patients with stable asthma or healthy subjects. Levels of serum eosinophil cationic protein and plasma polymorphonuclear elastase were increased in acute exacerbation and moderately correlated to ROM levels. Levels of ROM were significantly decreased after treatment with systemic steroids and bronchodilators. Conclusion: These findings suggest that acute exacerbation of asthma is associated with increased oxidative stress. Serum ROM levels would partly reflect the inflammation with eosinophils and neutrophils and may be useful as biomarkers of asthma.

Background: We hypothesized that synthetic double-stranded (ds)RNA may mimic viral infection and reported that dsRNA stimulates expression of inflammatory chemokines through a receptor of dsRNA Toll-like receptor (TLR) 3 in airway epithelial cells. In this study, we focused our study on the role of other receptors for dsRNA, such as retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA-5), and double-stranded RNA-dependent protein kinase (PKR). Methods: Airway epithelial cell BEAS-2B was cultured in vitro. Expression of target RNA and protein were analyzed by PCR and ELISA. To analyze the role of receptors for dsRNA, knockdown of theses genes was performed with short interfering RNA (siRNA). Results: We first investigated the effects of chloroquine, an inhibitor of lysosomal acidification, on the expression of chemokines. Preincubation with 100 µM chloroquine significantly inhibited the expression of mRNA for RANTES, IP-10, and IL-8, stimulated by poly I:C, indicating that poly I:C may react with a receptor expressed inside the cells. RIG-I, MDA-5, and PKR are supposed to be expressed inside the airway epithelial cells. However, the expression of chemokines stimulated with poly I:C was not significantly inhibited for these putative receptors in the cells which were transfected with siRNA. Conclusions: Synthetic dsRNA poly I:C stimulates the expression of inflammatory chemokines in airway epithelial cells, but the putative receptors for dsRNA such as RIG-I, MDA-5, or PKR may not play pivotal roles in this process. TLR3 may play a major role as reported previously.