Liposomal Amphotericin B Fosters the Corticosteroids' Anti-inflammatory Effect on Murine Allergic Bronchopulmonary Aspergillosis Model Airways.

Fungus is an antigen for bronchial asthma causing allergic bronchopulmonary mycosis (ABPM). As a therapy other than corticosteroids, itraconazole (ITCZ) is known to suppress the allergic inflammation induced by Aspergillus fumigatus (Af). However, the efficacy of liposomal amphotericin B (LAMB) with/without corticosteroid on ABPM is unknown. Mice sensitized to Dermatophagoides farinae (Df) allergen were intranasally infected with Af (DfAf group). After the infection, corticosteroid (dexamethasone (Dex)) was administered for 5 days (DfAf/Dex group). The effects of ITCZ or LAMB with/without Dex were also evaluated. Pathologically, Dex and LAMB combination treatment decreased the allergic inflammation evidently. The bronchoalveolar lavage fluid (BALF) concentrations of IL-5, IL-13, and MIP-2 were significantly elevated in DfAf mice compared with control mice (p < 0.05, each). In DfAf mice, ITCZ and LAMB significantly decreased the elevation of MIP-2 (p < 0.05 vs the DfAf group). The addition of both Dex and LAMB suppressed the MIP-2 elevation in DfAf mice (p < 0.05 vs the Df/Af/Dex/LAMB group), but the addition of Dex and ITCZ did not (DfAf/Dex/ITCZ group). None of Dex, ITCZ, or LAMB decreased pulmonary IL-13 concentration. It was suggested that combination of antifungal drugs and corticosteroid enhanced the suppressing effect of airway inflammations. This finding will give a hope for the treatment of severe fungus-related asthma.

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.

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 AND 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-g 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.

Dissociation between sensitizing and colonizing fungi in patients with allergic bronchopulmonary aspergillosis.

BACKGROUND: Because allergic bronchopulmonary aspergillosis (ABPA) does not require the presence of Aspergillus fumigatus for diagnosis, serological and radiological findings without cultures usually confirm this condition. OBJECTIVE: To determine which fungi colonize the airways of patients with definitive ABPA. METHODS: We enrolled 11 patients (ages 57.5 ± 17.1 years; male: female, 4:7) with ABPA diagnosed by serological and radiological criteria. Fungi colonizing the airway were identified from mucous plugs that were naturally expectorated or obtained by fiberoptic bronchoscopy. RESULTS: Aspergillus spp. (n = 8) was the most frequently isolated, followed by Schizophyllum commune (n = 4), Candida albicans (n = 2), Rhizopus oryzae (n = 1), and Penicillium spp. (n = 1). Among the Aspergillus spp., A. niger, A. terreus, and A. sydowii were more frequently isolated (total, n = 6) than A. fumigatus (n = 2). Many patients were sensitized with several fungi in addition to Aspergillus, which were dissociated with airway-colonizing fungi. CONCLUSION: Multiple fungal species can colonize the airway, and dissociation between colonizing and sensitizing species frequently occurs in definitive ABPA. Considering the increased prevalence of azole-resistant Aspergillus spp., administering antifungal drugs that target A. fumigatus without identifying which fungal species colonize the airway might be problematic.

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.

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.

Severe, but manageable hypoxia caused by bronchospasm induced by bevacizumab.

Bevacizumab has a lower risk of treatment-related infusion reactions than other humanized monoclonal antibodies, and bronchospasm induced by bevacizumab has not been reported. We administered bevacizumab 15 mg/kg over 90 min infusion to a 34 year-old man with lung adenocarcinoma and childhood asthma. Then, grade 3 hypoxia developed and improved spontaneously. This reversible obstructive lung disorder was confirmed using a flow-volume loop, and the patient was diagnosed as having a bronchospasm due to infusion reaction of bevacizumab. This bronchospasm was easily manageable and preventable using an oral bronchodilator and an inhalant combination product, and the patient continued with bevacizumab therapy until the disease progression.

Retrospective cohort study of leukotriene receptor antagonist therapy for preventing upper respiratory infection-induced acute asthma exacerbations.

Upper respiratory tract infections (URIs) represent the most frequent cause of acute asthma exacerbations. It has yet to be determined whether leukotriene receptor antagonist (LTRA) treatment prevents URI-induced acute asthma exacerbations in adults. The objective of the present study was to evaluate the preventive effects of LTRA treatment on URI-induced acute asthma exacerbations. The incidences of URI alone, acute asthma exacerbation without URI, and URI-induced acute asthma exacerbation were determined retrospectively by analyzing diary and medical records of 321 adult asthmatic patients (mean age, 56.3 ± 17.2 years; male/female ratio, 117:204) over 1 year. Results were compared between patients who had been taking an LTRA (n = 137) and those who had never taken any LTRA (n = 184) during the study periods. Significantly fewer URIs alone and acute asthma exacerbations without URI occurred in patients with than in those without prophylactic daily use of LTRA. LTRA treatment significantly reduced the durations of URIs alone and of total acute asthma exacerbations, as well as the incidence of mild exacerbations of asthma. In contrast, in patients with URI-induced acute asthma exacerbations, LTRA treatment failed to significantly reduce the interval between URI onset and acute asthma exacerbation, as well as the duration and severity of both URIs and acute asthma exacerbations. Use of an LTRA for adult asthmatic patients appears to reduce the incidences of URIs alone and acute asthma exacerbations without URI, but it failed to prevent URI-induced acute asthma exacerbations once a URI occurred.

Pathologically confirmed, early-onset, severe chronic obstructive pulmonary disease.

A 27-year-old man who had been a smoker since 14 years of age presented with exertional dyspnea. Approximately three years earlier, he had been occupationally been exposed to an organic solvent and felt dyspnea during its use. He later developed severe dyspnea and received treatment for asthma. He had no relevant family history. Chest auscultation revealed decreased breath sounds without rales. Spirometry and high-resolution computed tomography scans suggested a diagnosis of chronic obstructive pulmonary disease (COPD). Video-assisted thoracoscopic surgery performed to obtain a pathological diagnosis confirmed the presence of centrilobular emphysema. High susceptibility, smoking from an early age and organic solvent exposure may have caused early-onset COPD in this case.

Regulation of dendritic cell functions against harmful respiratory pathogens by a cysteinyl leukotrienes receptor antagonist.

Cysteinyl leukotriene receptor antagonist (LTRA) is a widely used medicine for asthma. Cysteinyl leukotrienes (cysLTs) are involved in the regulation of dendritic cell (DC) function. However, the effects of LTRA on DC-related antimicrobial immunity against harmful respiratory pathogens remain unknown. The purpose of this study was to examine the effects of LTRA administered in vivo on DC function against representative respiratory pathogens in vitro. Pulmonary DCs were isolated from four groups of mice: control, mite allergen sensitized (AS), and AS mice treated with the corticosteroid dexamethasone (Dex) or with the LTRA pranlukast (Prl). These DCs were incubated with mite allergen, lipopolysaccharide (LPS), Aspergillus fumigatus, or respiratory syncytial virus (RSV). IL-10 and IL-12 production was then determined. Dex treatment significantly inhibited lipopolysaccharide (LPS)-induced IL-10 and IL-12 production as well as baseline IL-12 production in AS mice. The Prl did not significantly inhibit LPS-induced IL-10 and IL-12 production in AS mice. More importantly, Prl significantly increased IL-10 and IL-12 in AS mice after RSV infection. This study shows that LTRA that is used for asthma potentially up-regulates antimicrobial immunity through modulation of DC function against some respiratory infections without immunosuppression.

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.

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.

The YABBY gene TONGARI-BOUSHI1 is involved in lateral organ development and maintenance of meristem organization in the rice spikelet.

The meristem initiates lateral organs in a regular manner, and proper communication between the meristem and the lateral organs ensures the normal development of plants. Here, we show that mutation of the rice (Oryza sativa) gene TONGARI-BOUSHI1 (TOB1) results in pleiotropic phenotypes in spikelets, such as the formation of a cone-shaped organ instead of the lemma or palea, the development of two florets in a spikelet, or premature termination of the floret meristem, in addition to reduced growth of the lemma or palea and elongation of the awn. These phenotypes seem to result from not only failure in growth of the lateral organs, but also defects in maintenance and organization of the meristem. For example, the cone-shaped organ develops as a ring-like primordium from an initial stage, suggesting that regulation of organ initiation in the meristem may be compromised. TOB1 encodes a YABBY protein, which is closely related to FILAMENTOUS FLOWER in Arabidopsis thaliana, and is expressed in the lateral organ primordia without any patterns of polarization. No TOB1 expression is detected in the meristem, so TOB1 may act non-cell autonomously to maintain proper meristem organization and is therefore likely to play an important role in rice spikelet development.

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 (T(reg)) 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 T(reg) and IL-10 and increasing mDCs. CONCLUSIONS: In asthmatic airways, pDCs mediate tolerance to inhaled allergens through the regulation of T(reg), IL-10 and mDCs. RSV infection of pDCs potentially inhibits their immunotolerogenic effects and thus exacerbates allergic airway inflammation.

Bronchoscopic observation of unusual deformities of bronchial cartilage and subsequent airway narrowing in respiratory relapsing polychondritis.

BACKGROUND: Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent chondritis and inflammation of other proteoglycan-rich tissues. An RP patient with co-existing respiratory tract problems could have a poor prognosis. CASE REPORT: We reported a case of RP died with recurrent suffocation. At the early stage in this case, unusual deformities of bronchial cartilage were observed. Following systemic corticosteroid therapy, these deformities disappeared, and typical diffuse mucosal edema and dynamic collapse of airways developed. CONCLUSIONS: These bronchoscopic abnormalities could be the early stage of RP.

Body mass index correlated with forced expiratory volume in 1 second/forced vital capacity in a population with a relatively low prevalence of obesity.

BACKGROUND: Obesity is the most common metabolic disease in the world. However, the relationship between obesity and lung function is not fully understood. Although several longitudinal studies have shown that increases in body weight can lead to reductions in pulmonary function, whether this is the case with the Japanese population and whether high body mass index (BMI) status alone represents an appropriate predictor of obstructive lung dysfunction remains unclear. The purpose of present study was to estimate the effect of BMI on lung function measured by spirometry of Japanese patients in general clinics. We measured BMI and performed spirometry on screening patients who had consulted general clinics. METHODS: Subjects comprised 1231 patients ≥ 40 years of age (mean age (65.0 ± 12.0) years, 525 men, 706 women) who had consulted clinics in Nagasaki Prefecture, Japan, for non-respiratory disease. BMI was calculated and lung function was measured by spirometry. RESULTS: BMI was found to be positively correlated with forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) in men and with maximum mid-expiratory flow (MMF) in all subjects. Following adjustment for relevant factors, a significant positive correlation between BMI and FEV(1)/FVC was identified for all subjects. Comparison between subjects with normal BMI (18.5 - 25.0) and higher BMI (25.1 - 30.0) also demonstrated that FEV(1)/FVC and percentage of predicted maximum mid-expiratory flow (%MMF) were significantly higher in the latter subjects. CONCLUSIONS: In a population without marked respiratory disease, higher BMI subjects showed less obstructive pulmonary dysfunction compared to normal BMI subjects. High BMI status alone may be inappropriate as a predictor of obstructive lung dysfunction, particularly in populations with a low prevalence of obesity.

Aspergillus fumigatus synergistically enhances mite-induced allergic airway inflammation.

BACKGROUND: Infection is an important trigger of exacerbation of bronchial asthma. The fact that Aspergillus fumigatus (Af) causes a distinct clinical syndrome, allergic bronchopulmonary aspergillosis (ABPA), suggests unique immunological properties in allergic asthma. The present study aimed to determine how Af enhances preexisting allergic airway inflammation and colonizes the airway in asthma. MATERIAL/METHODS: Six groups of BALB/c mice were prepared: Control; live or dead Af-infected (Live Af or Dead Af); Dermatophagoides farinae (Df) allergen-sensitized (Df); and Df-sensitized plus live or dead Af-infected (Df-live Af or Df-dead Af). Pulmonary pathology, cytokine profiles and mucous production in the airway were evaluated in these groups. RESULTS: Af infection significantly enhanced Df allergen-induced eosinophilic inflammation via enhancement of Th2-like response. Live, but not dead, Af significantly exacerbated neutrophilic inflammation. Induction of IL-13 and Muc5ac proteins by Df allergen sensitization was significantly enhanced by both live and dead Af infection, resulting in mucous hypersecretion. CONCLUSIONS: Collectively, the present study showed that mite allergen sensitization concomitant with Af infection enhanced Th2-dominant immune response in the airway, which induced mucous hypersecretion and potentially permitted further colonization by Af spores. It is likely that Af enhances allergic airway inflammation as an allergen, while it enhances neutrophilic airway inflammation as a pathogen. Future studies on pharmacological intervention in the present murine model utilizing glucocorticoid, and anti-fungal drugs are thus promising.

[Two cases of chronic pulmonary thromboembolism diagnosed clinically as chronic obstructive pulmonary disease].

Two cases of chronic pulmonary thromboembolism accidentally diagnosed in the clinical evaluation of COPD are reported. Case 1, a 69-year-old woman who had never smoked, was given a diagnosis of COPD since she had exertional dyspnea with obstructive pulmonary dysfunction and multiple low attenuation areas on her chest CT. Pulmonary ventilation and perfusion scintigram showed mismatched defects and as chronic pulmonary thromboembolism (CPTE) was finally diagnosed. Case 2, a 70-year-old former smoking man had also been previously given a diagnosis of COPD. He had exertional dyspnea, hypoxemia and multiple low attenuation areas in chest CT. Nonetheless his pulmonary function was normal. Pulmonary ventilation and perfusion scintigram showed mismatched defects and pulmonary angiography identified a floating thrombus in the pulmonary artery. Thus he CPTE was diagnosed. The diagnosis of CPTE in COPD is not easy. Physicians should recognize that CPTE can be associated with COPD and perform further examinations including pulmonary ventilation and perfusion scintigram when patients do not show typical results and/or adequately respond to conventional therapy for COPD.