Katsuyoshi Tomomatsu

Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma

BACKGROUND Protectin D1 (PD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3 fatty acid docosahexaenoic acid (DHA). Exogenous PD1 conferred protection against eosinophilic inflammation in animals with experimental asthma, although its endogenous cellular source and functions in human airways are of interest. OBJECTIVE We sought to investigate the synthesizing capacity of PD1 in eosinophils from healthy subjects and patients with severe asthma and its direct effects on eosinophil functions. METHODS Human eosinophil-derived metabolites of arachidonic acid and DHA were analyzed with liquid chromatography-tandem mass spectrometry-based lipidomic analysis. The biological activities of PD1 on the function of human eosinophils, including chemotaxis, adhesion molecule expressions, degranulation, superoxide anion generation, or survival, were examined. RESULTS We identified PD1 as one of the main anti-inflammatory and proresolving molecules synthesized in human eosinophils. PD1, in nanomolar concentrations, suppressed the chemotaxis induced by CCL11/eotaxin-1 or 5-oxo-eicosatetraenoic acid and modulated the expression of the adhesion molecules CD11b and L-selectin, although it had no effects on the degranulation, superoxide anion generation, or survival of the eosinophils. Compared with the cells harvested from healthy subjects, we observed a prominent decrease in the biosynthesis of PD1 by eosinophils from patients with severe asthma, even in presence of DHA. CONCLUSION These observations are a first indication that activated human eosinophils represent a major source of PD1, which can act as a self-resolving machinery in eosinophilic inflammation, whereas the production of PD1 is impaired in patients with severe asthma.

Predictors of Osteoporosis and Vertebral Fractures in Patients Presenting with Moderate-to-Severe Chronic Obstructive Lung Disease

Abstract Bone mineral density (BMD) alone does not reliably predict osteoporotic fractures. The Fracture Risk Assessment Tool (FRAX) was developed to estimate the risk of fracture in the general population. This study was designed to identify predictors of osteoporosis and vertebral fractures in patients presenting with chronic obstructive pulmonary disease (COPD). We studied 85 patients (mean age = 75 years; 92% men) with moderate to very severe COPD. Osteoporosis and vertebral fractures were diagnosed with dual energy X-ray absorptiometric scan and vertebral X-rays, respectively. Patient characteristics, including age, gender, body mass index (BMI), and results of pulmonary function tests, chest computed tomography scan, blood and urinary biomarkers of bone turnover were recorded, and a FRAX score was calculated by a computer-based algorithm. Osteoporosis, defined as a T score < –2.5, found in 20 patients (24%), was associated with female gender, BMI, dyspnea scale, long-term oxygen therapy (LTOT), vital capacity (VC), emphysema score on computed tomography, measurements of serum and urinary biomarkers of bone turnover. Vertebral fractures, diagnosed in 29 patients (35%), were strongly correlated with age, LTOT, VC, and forced expiratory volume in 1 sec, treatment with oral corticosteroid or warfarin, and weakly associated with the presence of osteoporosis. There was no correlation between FRAX score and prevalence of vertebral fractures, suggesting that neither BMD alone nor FRAX score would predict the presence of vertebral fractures in COPD patients. A disease-specific algorithm to predict osteoporotic fractures is needed to improve the management of patients suffering from COPD.

Induction of Mucin and MUC5AC Expression by the Protease Activity of Aspergillus fumigatus in Airway Epithelial Cells

Allergic bronchopulmonary mycosis, characterized by excessive mucus secretion, airflow limitation, bronchiectasis, and peripheral blood eosinophilia, is predominantly caused by a fungal pathogen, Aspergillus fumigatus. Using DNA microarray analysis of NCI-H292 cells, a human bronchial epithelial cell line, stimulated with fungal extracts from A. fumigatus, Alternaria alternata, or Penicillium notatum, we identified a mucin-related MUC5AC as one of the genes, the expression of which was selectively induced by A. fumigatus. Quantitative RT-PCR, ELISA, and histochemical analyses confirmed an induction of mucin and MUC5AC expression by A. fumigatus extracts or the culture supernatant of live microorganisms in NCI-H292 cells and primary cultures of airway epithelial cells. The expression of MUC5AC induced by A. fumigatus extracts diminished in the presence of neutralizing Abs or of inhibitors of the epidermal growth factor receptor or its ligand, TGF-α. We also found that A. fumigatus extracts activated the TNF-α–converting enzyme (TACE), critical for the cleavage of membrane-bound pro–TGF-α, and its inhibition with low-molecular weight inhibitors or small interfering RNA suppressed the expression of MUC5AC. The protease activity of A. fumigatus extracts was greater than that of other fungal extracts, and treatment with a serine protease inhibitor, but not with a cysteine protease inhibitor, eliminated its ability to activate TACE or induce the expression of MUC5AC mRNA in NCI-H292. In conclusion, the prominent serine protease activity of A. fumigatus, which caused the overproduction of mucus by the bronchial epithelium via the activation of the TACE/TGF-α/epidermal growth factor receptor pathway, may be a pathogenetic mechanism of allergic bronchopulmonary mycosis.

Strain-Specific Phenotypes of Airway Inflammation and Bronchial Hyperresponsiveness Induced by Epicutaneous Allergen Sensitization in BALB/c and C57BL/6 Mice

Background: Allergen sensitization through a disrupted skin barrier appears to play a prominent role in the development of atopic diseases, including allergic asthma. The role of the genetic background in immunological and physiological phenotypes induced by epicutaneous sensitization is undetermined. Methods: BALB/c and C57BL/6 mice were sensitized either epicutaneously by patch application of ovalbumin (OVA) or systemically by intraperitoneal injection of OVA with alum before exposure to aerosolized OVA. The concentrations of OVA-specific immunoglobulin in serum and cytokines in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay. The severity of airway inflammation was evaluated by cell counts in BALF, and bronchial responsiveness to methacholine was measured by the flexiVent system. Results: The production of OVA-specific IgG1 and IgE was greater in the epicutaneously sensitized BALB/c than C57BL/6 mice. In contrast, both eosinophilic airway inflammation and bronchial responsiveness to methacholine were more prominent in the C57BL/6 than in the BALB/c mice. The concentrations of interleukin-4 increased significantly in the BALF from C57BL/6 mice only. No between-strain differences were observed after intraperitoneal sensitization. Conclusions: The C57BL/6 mouse is a more appropriate model than the BALB/c mouse to study the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.

High-flow nasal cannula oxygen therapy for acute exacerbation of interstitial pneumonia: A case series

We report 3 cases (all men, age: 69-81 years) of acute exacerbation of interstitial pneumonia (AEIP) that were successfully treated with a high-flow nasal cannula (HFNC), which delivers heated, humidified gas at a fraction of inspired oxygen (FIO2) up to 1.0 (100%). Oxygenation was insufficient under non-rebreathing face masks; however, the introduction of HFNC with an FIO2 of 0.7-1.0 (flow rate: 40 L/min) improved oxygenation and was well-tolerated until the partial pressure of oxygen in blood/FIO2 ratio increased (between 21 and 26 days). Thus, HFNC might be an effective and well-tolerated therapeutic addition to the management of AEIP.

Clinical contributions of exhaled volatile organic compounds in the diagnosis of lung cancer

Background Exhaled volatile organic compounds (VOC) are being considered as biomarkers for various lungs diseases, including cancer. However, the accurate measurement of extremely low concentrations of VOC in expired air is technically challenging. We evaluated the clinical contribution of exhaled VOC measured with a new, double cold-trap method in the diagnosis of lung cancer. Methods Breath samples were collected from 116 patients with histologically confirmed lung cancer and 37 healthy volunteers (controls) after inspiration of purified air, synthesized through a cold-trap system. The exhaled VOC, trapped in the same system, were heat extracted. We analyzed 14 VOC with gas chromatography. Results The concentrations of exhaled cyclohexane and xylene were significantly higher in patients with lung cancer than in controls (p = 0.002 and 0.0001, respectively), increased significantly with the progression of the clinical stage of cancer (both p < 0.001), and decreased significantly after successful treatment of 6 patients with small cell lung cancer (p = 0.06 and 0.03, respectively). Conclusion Measurements of exhaled VOCs by a double cold-trap method may help diagnose lung cancer and monitor its progression and regression.

Prospective analyses of volatile organic compounds in obstructive sleep apnea patients.

Various volatile organic compounds (VOCs) are known to be toxic. Although exhaled VOC patterns change in obstructive sleep apnea (OSA) patients, individual VOC profiles are not fully determined. The primary outcome was VOC characterizations; secondary outcomes included their relationships with sleep and clinical parameters in OSA patients. We prospectively examined 32 OSA patients with an apnea-hypopnea index (AHI) ≥ 15 by full polysomnography, and 33 age- and sex-matched controls without obvious OSA symptoms. Nine severe OSA patients were examined before and after continuous positive airway pressure (CPAP) treatment. By applying a method which eliminates environmental VOC influences, exhaled VOCs were identified by gas chromatography (GC)-mass spectrometry, and their concentrations were determined by GC. Exhaled aromatic hydrocarbon concentrations (toluene, ethylbenzene, p-xylene, and phenylacetic acid) in the severe OSA groups (AHI ≥ 30) and exhaled saturated hydrocarbon concentrations (hexane, heptane, octane, nonane, and decane) in the most severe OSA group (AHI ≥ 60) were higher than those in the control group. Exhaled isoprene concentrations were increased in all OSA groups (AHI ≥ 15); acetone concentration was increased in the most severe OSA group. Ethylbenzene, p-xylene, phenylacetic acid, and nonane concentrations were increased according to OSA severity, and correlated with AHI, arousal index, and duration of percutaneous oxygen saturation (SpO2) ≤ 90%. Multiple regression analyses revealed these 4 VOC levels were associated with the duration of SpO2 ≤ 90%. Isoprene and acetone decreased after CPAP treatment. OSA increased some toxic VOCs, and some correlated with OSA severity. CPAP treatment possibly ameliorates these productions.

Endobronchial Hamartoma as a Cause of Pneumonia

Patient: Male, 66 Final Diagnosis: Endobronchial hamartoma Symptoms: Fever Medication: — Clinical Procedure: Flexible bronchoscopy • surgical resection Specialty: Pulmonology Objective: Unusual clinical course Background: Post-obstructive pneumonia occurs in the presence of airway obstruction, usually caused by lung cancer. However, there are cases of bronchial obstruction due to benign origin such as foreign bodies and benign endobronchial tumors, which are often misdiagnosed. Case Report: A 66-year-old man was referred to our hospital due to high fever with abnormal shadow in the right lung. Chest computed tomography after a course of antibiotic treatment showed an intra-bronchial tumor obstructing the right upper bronchus. Part of the tumor was removed with flexible bronchoscopy, and histopathological examination revealed cartilage tissue but not fat or other components. Lobectomy of the right upper lobe of the lung was performed to make a definite diagnosis and prevent recurrent obstructive pneumonia. The resected tumor contained mature cartilage and fat tissues, and was diagnosed as endobronchial hamartoma. Conclusions: Benign endobronchial tumors such as hamartomas should be considered in the differential diagnosis of post-obstructive pneumonia.

Concordance between Aspergillus-specific precipitating antibody and IgG in allergic bronchopulmonary aspergillosis.

BACKGROUND Several serological tests for specific precipitin or IgG are available to demonstrate type III hypersensitivity reactions to Aspergillus species and are essential for infectious fungal disease diagnosis. These assays are also important for allergic bronchopulmonary aspergillosis (ABPA) diagnosis; however, their concordance in ABPA was not well studied. METHODS Fifty-two ABPA patients diagnosed based on ISHAM criteria were enrolled. Precipitins and IgG specific to Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, or Aspergillus terreus were measured using Ouchterlony double immunodiffusion tests and ImmunoCAP method, respectively. A. fumigatus-specific IgG was also determined using complement-fixation (CF) method. RESULTS Forty-eight percent of cases were double-positive for A. fumigatus-specific precipitin and IgG (ImmunoCAP), whereas 3 (6%) and 14 (28%) cases were positive for precipitin or IgG alone, respectively. Kappa coefficient between these measurements was 0.32, suggesting poor concordance. Double-positive cases were more likely to present: Aspergillus sp. in sputum culture, lower pulmonary functions, peripheral blood eosinophilia, higher total IgE and A. fumigatus-specific IgG titer than precipitin-negative cases. A. fumigatus-specific IgG (CF) was positive only in 8 (15%) cases. The presence of A. fumigatus-specific precipitin or IgG was associated with antibodies specific for other Aspergillus spp., suggesting cross-reactivity. CONCLUSIONS Positive rate of A. fumigatus-specific precipitin or IgG (ImmunoCAP) was superior to IgG (CF), but relatively poor concordance was noted between precipitin and IgG (ImmunoCAP). Positive precipitin for A. fumigatus suggests more active diseases. Cross-reactivity may exist between antibodies to different Aspergillus spp. Therefore, the type III hypersensitivity results in ABPA diagnosis should be carefully evaluated.

Lung Cancer Associated with Seronegative Myasthenia Gravis

A 64-year-old man presented with diplopia, muscle weakness, a pulmonary nodule and mediastinal widening on a chest radiograph. He was diagnosed with clinical stage IIIA (T2aN2M0) lung cancer. His neurological symptoms worsened following the initiation of thoracic radiation therapy (60 Gy) and chemotherapy. A diagnosis of myasthenia gravis (MG) was confirmed with a repetitive nerve stimulation test that showed a waning pattern, and a positive edrophonium test, although neither anti-acetylcholine receptor antibodies nor anti-muscle-specific tyrosine kinase antibodies were detected. The ptosis and limb muscle weakness improved with prednisolone and acetylcholinesterase inhibitor treatment, and a partial response of the lung cancer to chemoradiotherapy was obtained. However, the ptosis and limb muscle weakness worsened again following a recurrence of the lung cancer. The herein described case, in which lung cancer and MG occurred and recurred simultaneously, suggests that MG can develop as a paraneoplastic syndrome of lung cancer.