Chronic Pulmonary Aspergillosis Caused by Aspergillus tubingensis Diagnosed by a Bronchoscopic Biopsy.

We herein report a case of chronic pulmonary aspergillosis (CPA) caused by Aspergillus tubingensis diagnosed by a bronchoscopic biopsy with negative serological and sputum culture findings. A 66-year-old man was referred for the assessment of a pulmonary cavity. Computed tomography showed a thick-walled cavity in the upper right pulmonary lobe. Serum ß-D glucan, Aspergillus galactomannan, and Aspergillus antibody tests were negative. Aspergillus species were not detected in the sputum. Culture and pathological specimens were obtained from the mass by bronchoscopy. Microscopic examination findings were consistent with Aspergillus niger complex morphologically and identified as Aspergillus tubingensis through DNA sequencing. The patient was diagnosed with chronic pulmonary aspergillosis.

Positive correlation between voriconazole trough concentrations and C-reactive protein levels in patients with chronic pulmonary aspergillosis: A retrospective cohort study.

BACKGROUND: Voriconazole (VRCZ) is the first-line treatment for chronic pulmonary aspergillosis (CPA). VRCZ trough concentration monitoring is recommended for adequate therapy because VRCZ concentrations vary widely. However, factors associated with variations in VRCZ concentrations, especially in the same patient at different time points, have not been identified. The objective of this study was to identify factors influencing VRCZ trough concentrations. PATIENTS AND METHODS: This single-center retrospective study conducted at our institute between April 2014 and August 2016 included patients with CPA who received VRCZ. Patient trough concentrations were measured more than twice while the patients received the same dose using the same administration route (defined as one series). A step-wise method and multiple regression analysis were used to test the effects of patient characteristics on VRCZ trough concentrations. RESULTS: Sixty-nine series in 49 patients were analyzed. VRCZ was administered orally in 59 series, intravenously in 7 series, and by dry syrup in 3 series. The median VRCZ trough concentration and the median variation in VRCZ concentrations were 1.68 and 0.99 µg/ml, respectively. In the simple regression analysis, creatinine, alkaline phosphatase, C-reactive protein (CRP), and creatinine clearance significantly correlated with VRCZ concentrations. Multiple regression analysis demonstrated a significant positive correlation between CRP and VRCZ concentration (P < 0.0001). CONCLUSION: In patients with CPA, VRCZ concentration correlated with CRP levels in the same patients receiving the same dose of VRCZ at different time points.

The accuracy and clinical impact of the morphological identification of Aspergillus species in the age of cryptic species: A single-centre study.

BACKGROUND: Aspergillus spp. is identified morphologically without antifungal susceptibility tests (ASTs) in most clinical laboratories. The aim of this study was to examine the clinical impact of the morphological identification of Aspergillus spp. to ensure the adequate clinical management of Aspergillus infections. PATIENTS/METHODS: Aspergillus isolates (n = 126) from distinct antifungal treatment-naïve patients with aspergillosis were first identified morphologically, followed by species-level identification via DNA sequencing. An AST for itraconazole (ITC) and voriconazole (VRC) was performed on each Aspergillus isolate. RESULTS: Based on the genetic test results, morphology-based identification was accurate for >95% of the isolates at the species sensu lato level although the test concordance of Aspergillus spp. with low detection rates was low. The rates of cryptic species were found to be 1.2% among the isolates of A. fumigatus complex and 96.8% in the A. niger complex. Cryptic species with lower susceptibilities to antifungal drugs than sensu stricto species among the same Aspergillus section were as follows: The A. lentulus (n = 1) isolates had low susceptibilities to azoles among the A. fumigatus complex species (n = 86), and A. tubingensis isolates (n = 18) exhibited lower susceptibility to azoles among the A. niger complex species (n = 31). CONCLUSION: Diagnostic accuracy was high at the A. fumigatus and A. niger complex level. However, in the presence of cryptic species, a solely morphological identification was insufficient. Particularly, ITC and VRC might be inappropriate for aspergillosis treatment when the A. niger complex is identified morphologically because it is possible that the Aspergillus isolate is A. tubingensis.

Non-fumigatus Aspergillus Infection Associated with a Negative Aspergillus Precipitin Test in Patients with Chronic Pulmonary Aspergillosis.

Aspergillus antibody testing is key for the clinical diagnosis of chronic pulmonary aspergillosis (CPA) with high sensitivity. However, false-negative results in patients with CPA might be obtained, depending on the Aspergillus species. The aim of this study was to investigate which factors are associated with false-negative results in Aspergillus precipitin tests and whether the sensitivity of precipitin tests in CPA is influenced by Aspergillus fumigatus and non-fumigatus Aspergillus species. Between February 2012 and December 2020, 116 consecutive antifungal treatment-naive patients with CPA were identified and included in this retrospective chart review. Aspergillus species isolated from the respiratory tract of patients were identified by DNA sequencing. Characteristics of patients with positive and negative results for Aspergillus precipitin tests were compared. The sensitivity of the Aspergillus precipitin tests was compared between patients with A. fumigatus-associated CPA and non-fumigatus Aspergillus-associated CPA. A non-fumigatus Aspergillus species was the only factor significantly associated with negative Aspergillus precipitin test results in patients with CPA in the multivariate analysis (hazard ratio, 8.3; 95% confidence interval, 3.2 to 22.1; P < 0.0001). The positivity of the Aspergillus precipitin test for patients with non-fumigatus Aspergillus-associated CPA was lower than that for patients with A. fumigatus-associated CPA (84.8% versus 37.9%; P < 0.0001). These results revealed that the presence of non-fumigatus Aspergillus-associated CPA should be considered with a negative Aspergillus precipitin test; this finding may prevent diagnostic delay or misdiagnosis for CPA.

Diaphragmatic hernia during treatment of lung cancer harboring an EGFR mutation.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line treatment for patients with nonsmall-cell lung cancer harboring EGFR mutations. We report a 65-year-old Japanese woman with nonsmall-cell lung cancer taking an EGFR-TKI who visited the emergency department with acute nausea and vomiting. Imaging studies demonstrated an incarcerated diaphragmatic hernia. Urgent diagnostic surgery revealed a gap in the diaphragm acting as a hernial orifice, where a metastatic tumor was detected. We consider that regression of the diaphragmatic metastasis by EGFR-TKI therapy resulted in perforation of the diaphragm, causing the diaphragmatic hernia. Gastrointestinal adverse events, e.g. nausea, vomiting and diarrhea, are common during EGFR-TKI treatment. However, this case suggests that in patients with diaphragmatic metastasis, we should consider the rare possibility of diaphragmatic perforation and a subsequent hernia.

High detection rate of azole-resistant Aspergillus fumigatus after treatment with azole antifungal drugs among patients with chronic pulmonary aspergillosis in a single hospital setting with low azole resistance.

The prevalence of azole-resistant Aspergillus fumigatus (ARAF) among chronic pulmonary aspergillosis (CPA) patients treated with azoles in Japan is unknown. The aim of this study was to determine the detection rate of ARAF in isolates from CPA patients who were treated with azoles for varying durations. The potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104) between February 2012 and February 2019, at National Hospital Organization Tokyo National Hospital. The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF among all isolates was 8.3% (n = 10). Of the 10 resistant isolates, eight were ITCZ-resistant and five were VRCZ-resistant. Among 47 isolates obtained from 36 CPA patients who were treated with ITCZ (for an average of 256 days) and/or VRCZ (for an average of 29 days), the resistance rates were 17.0% and 10.6%, respectively. In addition, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients, particularly in those with ongoing long-term azole treatment, at the time of azole antifungal therapy failure.

Aspergillus fumigatus can acquire azole resistance during long-term treatment with azole drugs in patients with chronic pulmonary aspergillosis (CPA). The aim of this study was to determine the detection rate of azole-resistant A. fumigatus (ARAF) in isolates from CPA patients who had been treated with azoles. In addition, a potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104). The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF from all isolates was 8.3% (n = 10). Greater than 10% of the 47 isolates obtained from 36 CPA patients who had been treated with azoles exhibited resistance. Furthermore, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients undergoing long-term azole treatment at the time of antifungal therapy failure.

Long-Term Outcomes of Bronchial Artery Embolization for Patients with Non-Mycobacterial Non-Fungal Infection Bronchiectasis.

BACKGROUND: There is no study on the predictive factors of recurrent haemoptysis after bronchial artery embolization (BAE) with the long-term outcomes in patients with bronchiectasis (BE). OBJECTIVES: To evaluate the long-term outcomes of BAE in BE patients without accompanying refractory active infection of mycobacteriosis and aspergillosis with analysis for the predictive factors of recurrent haemoptysis. METHODS: Data of 106 patients with BE who underwent BAE using coils between January 2011 and December 2018 were retrospectively reviewed. The cumulative haemoptysis control rate was estimated using Kaplan-Meier methods with log-rank tests to analyze differences in recurrence-free rate between groups based on technical success and failure, bacterial colonization status, number of BE lesions, and vessels embolized to bronchial arteries (BAs) or BAs + non-bronchial systemic arteries (NBSAs). RESULTS: Bacterial colonization was detected in approximately 60% of patients. Computed tomography showed bronchiectatic lesions with 2.9 ± 1.4 lobes. In the first series of BAE, embolization was performed in the BAs alone and BAs + NBSAs in 65.1 and 34.9% of patients, respectively, with 2.4 ± 1.4 embolized vessels in total. The median follow-up period was 1,000 (7-2,790) days. The cumulative haemoptysis control rates were 91.3, 84.2, 81.5, and 78.9% at 1, 2, 3, and 5 years, respectively. The haemoptysis control rates were higher in the technical success group than in the technical failure group (p = 0.029). CONCLUSIONS: High haemoptysis control rates for long-term periods were obtained by embolization for all visualized abnormal arteries, regardless of the colonization status, number of bronchiectatic lobes, and target vessels, irrespective of NBSAs.

Comparison of QuantiFERON-TB Gold Plus, QuantiFERON-TB Gold In-Tube, and T-SPOT.TB among patients with tuberculosis.

OBJECTIVES: This study evaluated the efficacy of the following interferon (IFN)-γ release assays (IGRAs): QuantiFERON-TB Gold Plus (QFT-Plus), QFT-Gold In-Tube (QFT-GIT), and T-SPOT. TB (T-SPOT) with the quantitative values of IFN-γ response. METHODS: Blood samples were collected from patients with active tuberculosis (TB), latent TB infection (LTBI), individuals with previous TB infection, and healthy volunteers enrolled between May 2017 and June 2018. RESULTS: IGRAs results were analyzed in 175 subjects (76 had active TB, 14 had LTBI, 35 had prior TB infection, and 50 were healthy). QFT-Plus and QFT-GIT revealed equal efficacy for IFN-γ values, and the IFN-γ response in QFTs tended to increase with the spot counts in T-SPOT, with similar high sensitivities (approximately 90%) in the active TB group. The test concordance of two of three IGRAs was optimal among all subjects (κ coefficients: 0.82-0.96). Additionally, the median quantitative values of IFN-γ with QFT-Plus and QFT-GIT were higher in the active TB group than in the LTBI and previous TB groups. CONCLUSION: Three IGRAs showed equivalent efficacy with high sensitivities and higher IFN-γ response in active TB group than that in non-active TB group.

The benefit of stool mycobacterial examination to diagnose pulmonary tuberculosis for adult and elderly patients.

BACKGROUND: In patients with suspected pulmonary tuberculosis, who have difficulty in expectorating sputum, alternative specimens by invasive procedures, gastric aspirate or sputum suction, are not always available in the feeble elderly. Several studies report the benefit of stool test for pediatric or HIV infected patients, but few in adult patients. OBJECTIVE: To evaluate the benefit of stool examination as non-invasive alternative test to detect Mycobacterium tuberculosis (MTB) infection. METHODS: Stool specimens were examined for mycobacteria in 187 cases of microbiologically-diagnosed pulmonary tuberculosis between September 2013 and August 2017. We retrospectively reviewed the medical records to determine the positive detection rate of MTB with stool specimens and investigated factors related to MTB detection. RESULTS: Among 187 patients included, positive rate of MTB in stool was 12.8% (24/187) by stool acid-fast bacilli smear, 68.1% (98/144) by TRC Rapid®, and 40.6% (76/187) by culture. Multivariate logistic regression analysis revealed two contributing factors to MTB detection in stool; cavitation and male. The adjusted odds ratio with 95% confidence interval (CI) for cavitation was 2.9 (95%CI 1.48-5.69) and 2.1 (95%CI 1.08-3.93) for male. CONCLUSION: We recommend stool examination for those who are unable to give sputum and have risks for invasive procedures.

Utility of bronchoscopy in the definitive diagnosis of patients with haematological malignancies presenting with radiological abnormalities.

INTRODUCTION: Patients with haematological malignancies usually have a plethora of respiratory complications. Bronchoscopy is one of the most important procedures used to diagnose respiratory complications. Despite enormous benefit, patients should be carefully selected for bronchoscopy as the process is invasive; however, there are only few reports evaluating the contributing factors of bronchoscopy that result in the definitive diagnosis of respiratory complications in these patients. OBJECTIVE: This study aimed to elucidate and identify the contributing factors of bronchoscopy for definitive diagnosis in patients with haematological malignancies. METHODS: We retrospectively analysed 275 patients with haematological malignancies who later showed respiratory complications, requiring consultation with pulmonologists. We found that 62 patients underwent bronchoscopy. Our data analysis focused on this particular subset of patients to identify the factors crucial for definitive diagnosis via bronchoscopy. RESULTS: Bronchoscopy provided definitive diagnosis for 25 patients (diagnostic yield = 40.3%). We determined that nodular shadow was associated with high diagnostic yields by multivariate logistic regression [odds ratio (OR): 6.6 (2.1-23)]. Furthermore, in several bronchoscopic procedures, biopsy also contributed to definitive diagnosis of patients with nodular shadow [OR: 17 (1.5-180)]. Life-threatening complications were not observed due to bronchoscopy in our study. CONCLUSIONS: Our study demonstrated that patients with haematological malignancies who showed lung nodular shadows are more likely to be definitively diagnosed by bronchoscopy, whereas transbronchial biopsy may also be beneficial for these patients.

Acute Arterial Thrombosis during Postoperative Adjuvant Cisplatin-based Chemotherapy for Completely Resected Lung Adenocarcinoma.

A malignant tumor can cause hypercoagulation and it also often coexists with thrombosis. Cisplatin-based chemotherapy can also induce adverse vascular effects, including arterial thrombosis. We herein report a case of acute arterial thrombosis in a patient undergoing postoperative adjuvant cisplatin-based chemotherapy for completely resected lung cancer. The patient complained of acute leg pain after chemotherapy, and computed tomography revealed multiple thrombi from the thoracic to popliteal arteries. Arterial thrombosis during adjuvant chemotherapy is extremely rare; however, careful clinical observation of patients receiving cisplatin-based chemotherapy is important, because arterial thrombosis, even in the absence of the primary malignant tumor, is possible.

Successful treatment of pulmonary injury after nitrogen oxide exposure with corticosteroid therapy: A case report and review of the literature.

Nitrogen oxides are representative chemicals of occupational and environmental exposure, which can lead to fatal pulmonary injury. These oxides are also known to cause delayed occurrence of bronchiolitis obliterans (BO). Herein, we report a case of nitrogen oxide-induced lung injury. A 50-year-old man developed pulmonary edema after nitric acid exposure. Hypoxemia and respiratory failure were immediately improved after introduction of corticosteroid pulse therapy with supplemental oxygen. This was followed by administration of oral prednisolone, and delayed BO did not develop. This case supports the therapeutic efficacy of corticosteroids against pulmonary injury and late-onset BO after nitrogen oxide exposure. KEY CLINICAL MESSAGE: Prolonged oral prednisolone might be a potential therapy to prevent delayed onset of bronchiolitis obliterans after nitric acid exposure.

Development of Pulmonary Artery Aneurysms Due to Behçet's Disease and Resolution after Treatment.

We herein describe a patient with Behçet's disease in whom we followed the development and resolution of pulmonary artery aneurysms. He presented with intermittent hemoptysis, pulmonary thromboembolism was initially diagnosed, and anticoagulant therapy was started. Over the next several months, the expansion of pulmonary arteries was noted. Five months after his initial admission, he was readmitted for massive hemoptysis, and further examinations revealed that he had Behçet's disease. Corticosteroids and intravenous cyclophosphamide were started. Over the next five months, the pulmonary artery aneurysms and thrombosis resolved. The development of pulmonary artery aneurysms led to the diagnosis of Behçet's disease, and they resolved after immunosuppressive therapy.

A case of Meigs' syndrome with preceding pericardial effusion in advance of pleural effusion.

BACKGROUND: Meigs' syndrome is defined as the presence of a benign ovarian tumor with pleural effusion and ascites that resolve after removal of the tumor. The pathogenesis of the production of ascites and pleural effusion in this syndrome remains unknown. Aside from pleural effusion and ascites, pericardial effusion is rarely observed in Meigs' syndrome. Here, we report the first case of Meigs' syndrome with preceding pericardial effusion in advance of pleural effusion. CASE PRESENTATION: An 84-year-old Japanese non-smoking woman with a history of lung cancer, treated by surgery, was admitted due to gradual worsening of dyspnea that had occurred over the previous month. She had asymptomatic and unchanging pericardial effusion and a pelvic mass, which had been detected 3 and 11 years previously, respectively. The patient was radiologically followed-up without the need for treatment. Two months before admission, the patient underwent a right upper lobectomy for localized lung adenocarcinoma and intraoperative pericardial fenestration confirmed that the pericardial effusion was not malignant. However, she began to experience dyspnea on exertion leading to admission. A chest, abdomen, and pelvis computed tomography scan confirmed the presence of right-sided pleural and pericardial effusion and ascites with a left ovarian mass. Repeated thoracentesis produced cultures that were negative for any microorganism and no malignant cells were detected in the pleural effusions. Pleural fluid accumulation persisted despite a tube thoracostomy for pleural effusion drainage. With a suspicion of Meigs' syndrome, the patient underwent surgical resection of the ovarian mass and histopathological examination of the resected mass showed ovarian fibroma. Pleural and pericardial effusion as well as ascites resolved after tumor resection, confirming a diagnosis of Meigs' syndrome. This clinical course suggests a strong association between pericardial effusion and ovarian fibroma, as well as pleural and peritoneal fluid. CONCLUSIONS: In female patients with unexplained pericardial effusion and an ovarian tumor, clinicians should consider the possibility of Meigs' syndrome. Although a malignant disease should be suspected in all patients with undiagnosed pleural and/or pericardial effusion, Meigs' syndrome is curable by tumor resection and should be differentiated from malignancy.

Adult bronchial asthma, definition, cause and severity assessment.

Bronchial asthma is a serious global burden affecting 1 to 18 % of people in different countries and the number is increasing. Asthma is characterized by chronic airway inflam- mation, which leads to symptoms of wheeze, shortness of breath, chest tightness due to airflow limitation. Symptoms and degree of airflow limitation change over time, however usually persist. Asthma is also associated with airway hyper responsiveness to stimuli leading to repeated cough which deteriorate quality of life of asthma patients. Here I describe the definition of asthma, its cause, and assessment of severity in line with the Asthma Prevention and Management Guideline 2015, Japan.

Interleukin-17A and Toll-Like Receptor 3 Ligand Poly(I:C) Synergistically Induced Neutrophil Chemoattractant Production by Bronchial Epithelial Cells.

Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, are common respiratory disorders worldwide. Exacerbations of these diseases are frequent and worsen patients' respiratory condition and overall health. However, the mechanisms of exacerbation have not been fully elucidated. Recently, it was reported that interleukin (IL)-17A might play an important role in neutrophilic inflammation, which is characteristic of such exacerbations, through increased production of neutrophil chemoattractants. Therefore, we hypothesized that IL-17A was involved in the pathogenesis of acute exacerbation, due to viral infection in chronic inflammatory airway diseases. In this study, we assessed chemokine production by bronchial epithelial cells and investigated the underlying mechanisms. Comprehensive chemokine analysis showed that, compared with poly(I:C) alone, co-stimulation of BEAS-2B cells with IL-17A and poly(I:C) strongly induced production of such neutrophil chemoattractants as CXC chemokine ligand (CXCL)8, growth-related oncogene (GRO), and CXCL1. Co-stimulation synergistically induced CXCL8 and CXCL1 mRNA and protein production by BEAS-2B cells and normal human bronchial epithelial cells. Poly(I:C) induced chemokine expression by BEAS-2B cells mainly via Toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-ß-mediated signals. The co-stimulation with IL-17A and poly(I:C) markedly activated the p38 and extracellular-signal-regulated kinase 1/2 pathway, compared with poly(I:C), although there was little change in nuclear factor-κB translocation into the nucleus or the transcriptional activities of nuclear factor-κB and activator protein 1. IL-17A promoted stabilization of CXCL8 mRNA in BEAS-2B cells treated with poly(I:C). In conclusion, IL-17A appears to be involved in the pathogenesis of chronic inflammatory airway disease exacerbation, due to viral infection by promoting release of neutrophil chemoattractants from bronchial epithelial cells.

Lymphotoxin ß receptor signaling induces IL-8 production in human bronchial epithelial cells.

Asthma-related mortality has been decreasing due to inhaled corticosteroid use, but severe asthma remains a major clinical problem. One characteristic of severe asthma is resistance to steroid therapy, which is related to neutrophilic inflammation. Recently, the tumor necrosis factor superfamily member (TNFSF) 14/LIGHT has been recognized as a key mediator in severe asthmatic airway inflammation. However, the profiles and intracellular mechanisms of cytokine/chemokine production induced in cells by LIGHT are poorly understood. We aimed to elucidate the molecular mechanism of LIGHT-induced cytokine/chemokine production by bronchial epithelial cells. Human bronchial epithelial cells express lymphotoxin ß receptor (LTßR), but not herpesvirus entry mediator, which are receptors for LIGHT. LIGHT induced various cytokines/chemokines, such as interleukin (IL)-6, oncostatin M, monocyte chemotactic protein-1, growth-regulated protein α and IL-8. Specific siRNA for LTßR attenuated IL-6 and IL-8 production by BEAS-2B and normal human bronchial epithelial cells. LIGHT activated intracellular signaling, such as mitogen-activated protein kinase and nuclear factor-κB (NF-κB) signaling. LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element. Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTßR signaling induces IL-8 production via the Erk and NF-κB pathways. LIGHT, via LTßR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

Effect of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) on airway epithelial cells.

Acetylcholine (ACh) exerts various anti-inflammatory effects through α7 nicotinic ACh receptors (nAChRs). We have previously shown that secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of α7 nAChR signaling, is down-regulated both in an animal model of asthma and in human epithelial cells treated with an inflammatory cytokine related to asthma. Our aim of this study was to explore the effect of SLURP-1, signal through α7 nAChR, in the pathophysiology of airway inflammation. Cytokine production was examined using human epithelial cells. Ciliary beat frequency of murine trachea was measured using a high speed camera. The IL-6 and TNF-α production by human epithelial cells was augmented by siRNA of SLURP-1 and α7 nicotinic ACh receptor. The cytokine production was also dose-dependently suppressed by human recombinant SLURP-1 (rSLURP-1). The ciliary beat frequency and amplitude of murine epithelial cells were augmented by PNU282987, a selective α7 nAChR agonist. Those findings suggested that SLURP-1 and stimulus through α7 nicotinic ACh receptors actively controlled asthmatic condition by stimulating ciliary beating and also by suppressing airway inflammation.

Suppressive effects of a pyrazole derivative of curcumin on airway inflammation and remodeling.

To advance the control of airway epithelial cell function and asthma, we investigated the effects of a new curcumin derivative, CNB001, which possesses improved pharmacological properties. Normal human bronchial epithelial (NHBE) cells were stimulated with synthetic double-stranded RNA, Poly(I:C). CNB001 significantly suppressed IL-6, TNF-α, and GM-CSF production by NHBE cells, and did so more effectively than did curcumin or dexamethasone (DEX). CNB001 significantly inhibited the decrease of E-cadherin mRNA expression and increase of vimentin mRNA expression observed in NHBE cells induced by a combination of TGF-ß1 and TNF-α, which are markers of airway remodeling. In NHBE cells stimulated by TGF-ß1, CNB001 significantly downregulated the level of active serine peptidase inhibitor clade E member (SERPINE) 1, which is also reported to be related to airway remodeling. Whereas DEX alone significantly increased the active SERPINE1 level, the combination of DEX and CNB001 significantly suppressed active SERPINE1. In addition, CNB001 significantly suppressed neutrophil infiltration, IL-6, TNF-α, IL-13 and active SERPINE1 production in bronchoalveolar lavage fluid of the murine asthma model, which was not observed in the case of DEX. In conclusion, the curcumin derivative, CNB001, is a promising candidate to treat asthma associated with neutrophilic airway inflammation and remodeling.