Sachiko Saeki

Cysteinyl Leukotrienes Regulate Dendritic Cell Functions in a Murine Model of Asthma

Dendritic cells (DCs) act as APCs in the airway and play a critical role in allergy. Cysteinyl leukotrienes (cysLTs) synthesized from arachidonic acid are primary mediators of immediate asthmatic reaction. The aim of this study was to investigate the effects of cysLTs on Dermatophagoides farinae (Der f)-pulsed mouse myeloid DCs in inducing allergic airway inflammation in vitro and in vivo. Control DC (medium-pulsed), Der f-pulsed DC, cysLT-pulsed DC, Der f- and cysLT-pulsed DC, and Der f-pulsed and cysLT receptor antagonist (LTRA)-treated DC were prepared from murine bone marrow, and the production of cytokines ws compared. Subsequently, these DCs were intranasally instilled into another group of naive mice, followed by intranasal Der f challenge to induce allergic airway inflammation in vivo. Der f-pulsed DC produced significantly higher amounts of IL-10 and IL-12 compared with control DC. Der f- and cysLT-pulsed DC further increased IL-10 production compared with Der f-pulsed DC. In contrast, treatment of Der f-pulsed DC with LTRA increased IL-12 and decreased IL-10. Intranasal instillation of Der f-pulsed DC resulted in airway eosinophilia associated with a significant rise in IL-5 levels in the airway compared with control DC. Pulmonary eosinophilia and excess IL-5 were further enhanced in Der f- and cysLT-pulsed DC-harboring mice. In contrast, Der f-pulsed and LTRA-treated DC significantly inhibited airway eosinophilia, reduced IL-5, and increased IFN-γ in the airway. Our results suggest that cysLTs play an important role in the development of allergic airway inflammation by regulating the immunomodulatory functions of DCs.

Polymorphisms in the CYP1A2 gene and theophylline metabolism in patients with asthma

Cytochrome P450 (CYP) 1A2 gene polymorphisms are thought to be involved in theophylline metabolism.

Clinical Evaluation of Anaphylactic Reactions to Intravenous Corticosteroids in Adult Asthmatics

Background: Corticosteroids form an important component of the treatment of acute asthma. Systemic anaphylactic reactions to intravenous corticosteroids have been reported, although their incidence is extremely rare. Objectives: To determine the clinical features and underlying mechanisms of anaphylactic reactions to intravenous corticosteroids in adult asthmatics. Subjects and Methods: The clinical features of 7 adult asthmatics (4 males, 3 females, mean age 39.4 ± 16.9 years), who had developed systemic anaphylactic reactions to intravenous administration of corticosteroids for the treatment of acute asthma, were studied retrospectively on the basis of their medical records. Skin tests using various injectable steroid preparations were performed in 3 cases to determine the mechanism of this reaction. Results: Systemic anaphylactic reactions to intravenous administration of corticosteroids occurred in severe atopic asthmatics with previous exposure to parenteral corticosteroids, irrespective of age and gender. Aspirin-intolerant asthma was identified in only 3 subjects. In all cases, anaphylactic reactions were induced following intravenous administration of succinate-containing corticosteroid preparations, i.e. hydrocortisone and methylprednisolone. Administration of phosphate-containing corticosteroids, i.e. dexamethasone and betamethasone, was safe and resulted in a resolution of anaphylactic symptoms. Immunological examination with skin tests suggested that anaphylactic reactions were an IgE-mediated hypersensitivity. Conclusions: Intravenous injection of succinate-containing corticosteroids in high-risk asthmatics should be performed slowly by drip injection under continuous monitoring. Once anaphylactic reactions occur, it is important to stop the injection immediately and to use conventional medication for anaphylaxis.

Bronchial hyperresponsiveness and airway inflammation in adolescents with asymptomatic childhood asthma.

Background:  About 70% of childhood asthmatics become free of asthma‐related symptoms during adolescence. Little is known about bronchial hyperresponsiveness (BHR) and airway inflammation in young adults with “outgrown” childhood asthma.

Naturally Occurring Parainfluenza Virus 3 Infection in Adults Induces Mild Exacerbation of Asthma Associated with Increased Sputum Concentrations of Cysteinyl Leukotrienes

Background:Viral respiratory tract infections represent the most frequent cause of asthma exacerbation in both children and adults, but the precise mechanism of such exacerbation remains unknown. Objectives: To determine the critical mediator of naturally occurring parainfluenza virus (PIV) 3-induced mild asthma exacerbations in adults. Methods: The study subjects were 19 adult asthmatics with mild asthma exacerbation (peak expiratory flow = 60–80% of predicted before bronchodilator use and >80% of predicted after initial bronchodilator treatment). Differential cell counts and concentrations of inflammatory markers including eosinophil cationic protein (ECP), cysteinyl leukotrienes (cysLTs), interleukin (IL)-5, IL-10 and IL-12 were measured in the induced sputum obtained from adults with PIV3- (n = 9) and non-cold-induced (n = 10) exacerbation of asthma during both acute and convalescent phases. Results: PIV3 infection was confirmed by the presence of viral RNA in nasopharyngeal aspirates. Mild exacerbation of asthma was not associated with significant changes in sputum differential cell counts. Concentrations of sputum ECP and cytokines were comparable between PIV3 and non-cold-induced patients. In contrast, PIV3 infection was associated with a significant increase in sputum cysLTs during the acute phase of mild asthma exacerbation. Conclusions: Our results identified cysLTs as a critical mediator of PIV3-induced acute asthma exacerbation.

Salivary IgA and Oral Candidiasis in Asthmatic Patients Treated with Inhaled Corticosteroid

Background. Inhaled corticosteroids are used for the treatment of bronchial asthma. Systemic side effects are rare, but local problems, such as oral candidiasis, can occur. Only a proportion of patients encounter this problem, and the mechanism of oral candidiasis induced by inhaled corticosteroids remains obscure. According to reports in immunodeficient patients, oral candidiasis is related to deficiencies in topical immunity, such as salivary IgA. Objectives. We evaluated differences in salivary IgA between asthmatics in whom Candida was detected or not detected from the pharynges, respectively. Methods. Saliva was collected from 18 healthy controls and 37 asthmatic patients treated with inhaled corticosteroids. The amounts of total IgA and the Candida-specific IgA of the saliva were measured. Fungal culture of the pharyngeal wall was also performed. Results. There were no differences in salivary total IgA and Candida-specific IgA between healthy controls and culture-negative asthmatic patients. Salivary total IgA of Candida-positive asthmatic patients was significantly lower than that of Candida-negative patients. However, there was no difference in Candida-specific IgA levels between these two groups. Conclusions. Our results suggest that inhaled corticosteroids can potentially decrease salivary total IgA but that host factors are also important in the development of oral candidiasis.

Acetaldehyde Induces Histamine Release from Human Airway Mast Cells to Cause Bronchoconstriction

Backgrounds: Approximately half of the Japanese asthmatics experience exacerbation of asthma after alcohol consumption. We previously reported that this phenomenon is probably caused by histamine release from mast cells by acetaldehyde stimulation. However, no reports have described the effects of acetaldehyde on human airway mast cells. The purpose of the present study was to demonstrate acetaldehyde-induced histamine release from human airway mast cells with subsequent airway smooth muscle contraction and to investigate the ensuing mechanisms. Methods: Human tissue samples were prepared from the lungs resected from patients with lung cancer. The effect of acetaldehyde on airway muscle tone and the concentration of chemical mediators released in the organ bath were measured before and after acetaldehyde stimulation. Mast cells were prepared from lung parenchyma by the immunomagnetic method and then stimulated with acetaldehyde to determine the chemical mediators released. Results: Acetaldehyde (>3 × 10–4M) increased airway muscle tone, which was associated with a significant increase in the release of histamine, but not thromboxane B2 or cysteinyl-leukotrienes. A histamine (H1 receptor) antagonist completely inhibited acetaldehyde-induced bronchial smooth muscle contraction. Acetaldehyde also induced a significant histamine release from human lung mast cells and degranulation of mast cells. Conclusions: The present results strongly suggest that acetaldehyde stimulates human airway mast cells to release histamine, which may be involved in bronchial smooth muscle contraction following alcohol consumption.

Effects of primary and secondary low-grade respiratory syncytial virus infections in a murine model of asthma.

Background Respiratory syncytial virus (RSV) infection is known to develop and exacerbate asthma in young children. In adult, RSV causes recurrent but asymptomatic infections. However, the impact of asymptomatic RSV infection on adult asthma is yet to be determined. The present study is designed to determine the effects of primary and secondary low‐grade RSV infections on allergic airway inflammation in a murine model of allergic asthma.

Pranlukast, a leukotriene receptor antagonist, inhibits interleukin-5 production via a mechanism distinct from leukotriene receptor antagonism.

Background: Pranlukast, a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist, inhibits not only airway smooth muscle contraction, but also allergic inflammation. The aim of this study was to determine the mechanism of pranlukast-induced interleukin-5 (IL-5) inhibition in allergic inflammation. Methods: Surgically resected human lung tissue was passively sensitized in vitro with mite-allergen-sensitized sera, followed by stimulation with mite allergen after pretreatment of the tissue with pranlukast, dexamethasone, or both. The IL-5 protein level in the culture medium was measured, and in situ hybridization of IL-5 and CysLTR1 mRNA was performed using lung tissues. Results: Pretreatment of lung tissues with pranlukast alone significantly decreased the amount of IL-5 protein in the culture medium by 40%. The combination of pranlukast and dexamethasone synergistically enhanced this effect. Quantitative in situ hybridization with image analysis revealed abundant expression of IL-5 mRNA in eosinophils, lymphocytes, and mast cells in sensitized and allergen-stimulated lung tissues. CysLTR1 mRNA was detected in macrophages, smooth muscle cells, eosinophils, and mast cells, but was less expressed in lymphocytes. Pranlukast-induced inhibition of IL-5 mRNA expression was noted in various cells, irrespective of their CysLTR1 mRNA expression status. In addition, cysteinyl leukotrienes per se failed to upregulate the IL-5 production. Conclusion: Our results indicate that pranlukast inhibits IL-5 synthesis via a mechanism distinct from CysLTR1 antagonism.

Effects of anti-inflammatory therapies on recurrent and low-grade respiratory syncytial virus infections in a murine model of asthma

BACKGROUND Recurrent and subclinical viral respiratory tract infections could immunologically exacerbate allergic airway inflammation. However, the most appropriate treatment for virus-induced asthma exacerbation is yet to be established. The effects of glucocorticoids in virus-induced acute asthma are controversial. OBJECTIVE To determine the effects of representative anti-inflammatory therapies for asthma--glucocorticoids and leukotriene receptor antagonists (LTRAs)--in mite allergen-sensitized and repeatedly low-grade respiratory syncytial virus (RSV)--infected mice. METHODS Dermatophagoides farinae-sensitized mice were inoculated twice with low-grade RSV and subcutaneously injected with either a glucocorticoid or an LTRA for 4 consecutive days. Lung inflammation, cytokine profiles, LT production, and viral RNA in lung tissues were compared in 5 groups of 8 mice each: controls, D farinae allergen sensitized, D farinae sensitized and RSV infected, D farinae sensitized and RSV infected with dexamethasone, and D farinae sensitized and RSV infected with pranlukast, an LTRA. RESULTS Allergic airway inflammation in D farinae mice was significantly enhanced by recurrent and low-grade RSV infections (RLRIs). The glucocorticoid attenuated allergic airway inflammation, which was associated with interleukin 5 (IL-5) and interferon-gamma (IFN-gamma) suppression in lung-draining lymph nodes without affecting viral quantity. The LTRA also attenuated allergic airway inflammation in D farinae-RSV mice with concomitant inhibition of IL-5 but not IFN-gamma. Dermatophagoides farinae allergen sensitization significantly increased LTs in the airway, whereas RLRIs did not further enhance LT production. CONCLUSIONS Glucocorticoids and LTRAs significantly inhibit RLRI-induced exacerbation of allergic airway inflammation by distinct pathways. Dexamethasone suppressed nonspecific cytokines, whereas viral RNA did not increase via suppression of immunity. In contrast, pranlukast specifically inhibited IL-5 but not IFN-gamma.