Tomoko Tsuchida

Prevalence of chronic obstructive pulmonary diseases in general clinics in terms of FEV1/FVC.

Background:  The prevalence of chronic obstructive pulmonary disease (COPD) continues to increase all over the world. Nonetheless, COPD is often misdiagnosed in general clinics because of insufficient use of spirometry.

Effect of Respiratory Syncytial Virus Infection on Plasmacytoid Dendritic Cell Regulation of Allergic Airway Inflammation

Background: Respiratory syncytial virus (RSV) can infect myeloid dendritic cells (mDCs) and regulate their function in the development of allergy. It has been widely reported that plasmacytoid DCs (pDCs) play a critical role in antiviral innate immunity. In contrast, not much is known about the role of pDCs in the interaction between allergy and viral infection. The purpose of the present study was to investigate the effect of RSV infection on pDC function in the regulation of allergic airway inflammation in a murine model of Dermatophagoides farinae-sensitized allergic asthma. Methods: Splenic pDCs isolated from D. farinae-sensitized donor mice were infected with live RSV ex vivo. Subsequently, these pDCs were inoculated into the airways of D. farinae-sensitized recipient mice. Lung pathology, lung tissue cytokine profiles, the number of regulatory T cells (Treg) and mDCs as well as the effects of IL-10 neutralization in the lung tissue of recipient mice were determined. Results: Intranasal inoculation of D. farinae-sensitized pDCs significantly inhibited the development of allergic airway inflammation and both Th1 and Th2 immunity. Live RSV infection of these pDCs prior to inoculation interfered with their inhibitory effects through decreasing Treg and IL-10 and increasing mDCs. Conclusions: In asthmatic airways, pDCs mediate tolerance to inhaled allergens through the regulation of Treg, IL-10 and mDCs. RSV infection of pDCs potentially inhibits their immunotolerogenic effects and thus exacerbates allergic airway inflammation.

Acetaldehyde at a low concentration synergistically exacerbates allergic airway inflammation as an endocrine-disrupting chemical and as a volatile organic compound.

Background: Acetaldehyde is an endocrine-disrupting chemical (EDC) and a volatile organic compound (VOC). It is also a carcinogen and teratogen that causes bronchoconstriction in a subset of asthmatics. However, the mechanism through which acetaldehyde acts as an EDC/VOC causing allergic airway inflammation remains unknown. Objectives: To determine the effects of a low concentration of acetaldehyde, which itself did not trigger airway inflammation, on extant allergic airway inflammation in a murine model of allergic asthma. Methods: We compared airway hyperresponsiveness (AHR), lung pathology, serum IgE and airway concentrations of cytokines among four groups of BALB/c mice [control, Dermatophagoides farinae(Df) allergen-sensitized (AS), intranasally acetaldehyde-injected (ALD) and AS-ALD mice]. Results: Physiological and histological differences were not evident between ALD and control mice. AS mice developed AHR and allergic airway inflammation characterized by goblet cell hyperplasia and eosinophilic infiltration. Both AHR and airway eosinophilia were significantly enhanced in AS-ALD compared with AS mice. Serum total and Df-specific IgE were significantly increased in both AS and AS-ALD mice compared with control and ALD mice, but comparable between AS and AS-ALD mice. Mite allergen sensitization significantly increased interleukin-5 and granulocyte macrophage colony-stimulating factor, and decreased interferon-γ levels in the airways; injecting acetaldehyde into airways with allergic inflammation significantly increased the levels of these inflammatory cytokines. Conclusions: Exposure to acetaldehyde can enhance allergic airway inflammation in asthma.

Differential effects of dexamethasone and itraconazole on Aspergillus fumigatus-exacerbated allergic airway inflammation in a murine model of mite-sensitized asthma.

Background: Fungal exposure is associated with particularly severe asthma. Nevertheless, the effects of anti-fungal treatments on fungus-exacerbated asthma need to be determined. Objectives: The present study aimed to compare the effects of itraconazole (ITCZ) and dexamethasone (Dex) on Aspergillus fumigatus (Af)-exacerbated preexisting Dermatophagoides farinae (Df) allergen-sensitized allergic airway inflammation. Methods: Four groups of BALB/c mice were prepared: control, Df-sensitized plus Af-infected mice (Df-Af), and Df-Af mice treated with Dex (Df-Af-Dex) or with ITCZ (Df-Af-ITCZ). Pulmonary pathology and cytokine profiles in the airway were evaluated. In a different set of experiments, the effects of Dex on alveolar macrophage (AM) phagocytosis of Af conidia were determined in Df-sensitized mice. Results:Af infection significantly increased the level of eosinophils and neutrophils in the airway of Df-sensitized mice. While Dex significantly decreased eosinophils, ITCZ significantly decreased both eosinophils and neutrophils in Df-Af mice. Dex significantly decreased IL-5, whereas ITCZ significantly reduced MIP-2 in the airway. Compared to controls, AM isolated from Df-sensitized mice had significantly reduced phagocytotic activity of Af conidia. However, Dex significantly improved phagocytotic activity of AM in Df-sensitized mice. Conclusions: The present study showed that Dex and ITCZ differently regulated Af-exacerbated allergic airway inflammation; the former inhibits eosinophilic inflammation and the latter inhibits neutrophilic as well as eosinophilic inflammation by regulating different cytokines. Additionally, Dex enhanced the phagocytotic activity of AM in allergic asthma. Thus, a combination of Dex and ITCZ might be effective for the management of fungus-exacerbated asthma.

Differential Airway Inflammatory Responses in Asthma Exacerbations Induced by Respiratory Syncytial Virus and Influenza Virus A

Background: Although respiratory viral infections cause acute exacerbations of asthma, the inflammatory responses vary depending on the causative virus. The purpose of this study was to compare the inflammatory responses in the airways of acute exacerbations of asthma induced by respiratory syncytial virus (RSV) and influenza A virus. Methods: Sputum induction was performed in asthmatic patients with acute exacerbations induced by RSV (n = 6), influenza A (n = 7), and non-upper respiratory infection (URI)-related factors (n = 8). Sputum concentrations of cysteinyl leukotrienes (cysLTs), TNF-α and IFN-γ were measured. Results: Sputum cysLTs were significantly higher in RSV-induced exacerbations than in influenza A- and non-URI-induced exacerbations. Sputum TNF-α was significantly higher in influenza A-induced exacerbations than in RSV- and non-URI-induced exacerbations. Sputum IFN-γ was significantly lower in RSV-induced exacerbations than in the others. Conclusions: RSV and influenza A cause acute exacerbations and have different effects on airway inflammation in asthmatic patients. RSV significantly increased cysLTs, while influenza A significantly increased TNF-α in the airway. The underlying mechanism in virus-induced asthma might depend on the viral species.

Aspergillus fumigatus regulates mite allergen‐pulsed dendritic cells in the development of asthma

Background The role in allergic asthma development of the immune response against fungi with concomitant exposure to other common aeroallergens has yet to be determined. In particular, there is little understanding of how inhaled fungi affect the host response to mite allergens.

Observational study of the additive effects of pranlukast on inflammatory markers of clinically stable asthma with inhaled corticosteroids and long-acting beta 2 agonists.

Background: Little is understood about the additive effects of leukotriene receptor antagonists (LTRA) on asthmatics currently medicated with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA). Objectives: The present study examines the anti-inflammatory effects of the LTRA pranlukast in addition to ICS and LABA, among asthmatic patients with normal pulmonary function and unremarkable clinical symptoms. Methods: Fifteen adult asthmatics participated in a 2-month, open-label, uncontrolled, prospective, multicenter, observational trial. Patients stabilized (predicted forced expiratory volume in 1 s >80%) by medication with ICS and LABA were also given pranlukast (450 mg daily). Asthma-related symptoms, pulmonary function, blood eosinophil counts and several inflammatory markers in sputum were monitored at week 0, as well as at 4 and 8 weeks after starting therapy with pranlukast. Results: Adding pranlukast did not further improve blood eosinophil counts, pulmonary function and symptoms, but significantly attenuated sputum cysteinyl leukotrienes, tumor necrosis factor-α and interleukin-5 concentrations. Conclusions: Although the clinical relevance remains obscure, adding an LTRA attenuates allergic airway inflammation in some asthmatics undergoing treatment with ICS and LABA.

Effects of a Short Course of Pranlukast Combined with Systemic Corticosteroid on Acute Asthma Exacerbation Induced by Upper Respiratory Tract Infection

Background. Upper respiratory tract infections (URIs) represent the most frequent cause of acute asthma exacerbation. Systemic corticosteroid (CS) is presently recommended for URI-induced asthma exacerbation, although it might inhibit cellular immunity against respiratory virus infection. Objectives. To determine the effects of adding a short course (2 weeks) of a leukotriene receptor antagonist (LTRA) to systemic CS on URI-induced acute asthma exacerbation. Methods. Twenty-three adult asthmatics (mean age, 42.8 ± 9.8 y; Male:Female, 10:13) with URI-induced acute asthma exacerbation confirmed by a questionnaire and physical findings were randomly assigned to receive either oral prednisolone (PSL) alone or oral PSL plus the LTRA pranlukast (PRL) for 2 weeks (PSL + PRL). The cumulative doses of PSL and the amount of time required to clear asthma-related symptoms were determined. Levels of respiratory syncytial virus (RSV) RNA and influenza viral (IV) antigen in nasopharyngeal swabs were also determined. Results. Adding PRL significantly reduced the cumulative dose of PSL and tended to reduce the time required to clear asthma-related symptoms. Either RSV or IV was detected in about one-third of the patients. Conclusion. The combination of an LTRA and CS might be more useful than CS alone for treating URI-induced acute exacerbation of asthma and reducing the cumulative CS dose.

Cysteinyl leukotriene receptor antagonist regulates allergic airway inflammation in an organ- and cytokine-specific manner.

Background Cysteinyl leukotrienes (cys-LTs) are very important factors in the pathophysiology of bronchial asthma. Cys-LT receptor antagonists (LTRAs) decrease allergic airway inflammation. The aim of the present study was to determine the differential effects of LTRAs and corticosteroids on allergic airway inflammation and allergen-specific cytokine production from lymphoid tissues using a murine model of asthma. Material/Methods Four groups of female BALB/c mice [control (Cont); Dermatophagoides farinae allergen-sensitized (AS); pranlukast (Prl), an LTRA-treated AS; and dexamethasone (Dex)-treated AS] were examined. Lung pathology and cytokine production by prepared mononuclear cells isolated from mediastinal lymph nodes (MLNs) and spleen were compared among these groups. Results AS mice exhibited allergic airway inflammation and significant increases in allergen-specific Th1 and Th2 cytokines in MLNs and spleen. Prl-treated mice showed significant attenuation of allergic airway inflammation concomitant with reduction of Th2 cytokines and IFN-γ in MLNs but not in spleen. In contrast, Dex significantly decreased Th1 and Th2 cytokines in MLNs and also decreased them (except IL-13 and IL-2) in spleen. Conclusions The inflammatory effects of cys-LTs could differ in lymphoid organs. LTRAs potentially regulate allergic airway inflammation in an organ- and cytokine-specific manner, while systemic corticosteroid shows nonspecific effects.

Clearance of Aspergillus fumigatus is impaired in the airway in allergic inflammation

BACKGROUND Aspergillus fumigatus (Af) sometimes colonizes and persists within the respiratory tree in some patients with asthma. To date, the precise reasons why the clearance of Af is impaired in patients with asthma remain unknown. OBJECTIVE To characterize the effects of allergic airway inflammation on clearance of Af. METHODS Control and Dermatophagoides farinae (Df) allergen-sensitized BALB/c mice were intranasally infected with Af. After 2 and 9 days of infection, the pathology, fungal burden, and cytokine profile in lung tissue were compared. In a different set of experiments, the phagocytotic activity of alveolar macrophages and the expression of their pathogen recognition receptors also were determined. RESULTS The Af conidia and neutrophilic airway inflammation disappeared by day 9 after infection in control mice. In Df-sensitized mice, Af conidia and neutrophilic and eosinophilic airway inflammation persisted at day 9 after infection. Compared with control mice, Df allergen-sensitized mice showed significant increases in interleukin (IL)-5 and decreases in IL-12 and interferon-γ in lung tissues at day 2 after infection. Most importantly, compared with Af-infected non-Df-sensitized mice, IL-17 in lung tissues was significantly decreased in Df allergen-sensitized Af-infected mice at day 2 after infection but was significantly increased at day 9. Alveolar macrophages isolated from Df allergen-sensitized mice exhibited significant decreases in phagocytotic activity and expression of Toll-like receptor-4 and dectin-1 compared with those from control mice. CONCLUSION In the airway of patients with allergy, T-helper cell type 2-dominant immunity potentially affects the expression of pathogen recognition receptors and attenuates cellular defense against Af. Prolonged IL-17 production also could play an important role.