Katsunori Masaki

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.

Periodontal disease and atherosclerosis from the viewpoint of the relationship between community periodontal index of treatment needs and brachial-ankle pulse wave velocity

BackgroundIt has been suggested that periodontal disease may be an independent risk factor for the development of atherosclerosis. However, the relationship between periodontal disease and atherosclerosis has not been fully elucidated. This study aimed to assess the effects of periodontal disease on atherosclerosis.MethodsThe study design was a cross-sectional study. Subjects were 291 healthy male workers in Japan. We used the Community Periodontal Index of Treatment Needs (CPITN) score, average probing depth and gingival bleeding index (rate of bleeding gums) to assess the severity of periodontal disease. We also used the Brachial-Ankle Pulse Wave Velocity (baPWV) as the index for the development of atherosclerosis.ResultsThe unadjusted odds ratio (OR) of atherosclerosis in relation to the CPITN score was 1.41 [95% CI: 1.16–1.73]. However, after adjustment for age, systolic blood pressure and smoking, the CPITN score had no relationship with atherosclerosis (adjusted OR: 0.91 [0.68–1.20]).ConclusionOur results show no relationship between mild periodontal disease and atherosclerosis after appropriate adjustments.

Association between a polymorphism of aminolevulinate dehydrogenase (ALAD) gene and blood lead levels in Japanese subjects.

This cross-sectional study investigated the relationship between the aminolevulinate dehydrogenase (ALAD) genotype and blood lead levels among 101 Japanese workers. Blood lead concentration measurement, biomarkers, and genotyping were performed. The minor allele frequency (MAF) for ALAD (ALAD2) was 0.08. Although the blood lead level in the subjects with heterozygous GC genotype was significantly higher than those with homozygous GG genotype, there were no significant differences for hemoglobin, hematocrit, serum and urinary ALA levels among genotypes. ALAD2 genotype was significantly associated with the blood lead concentration, even in the environmental lead exposed subjects. Further confirmation with a large sample size is needed.

Dual Role of Interleukin-23 in Epicutaneously-Sensitized Asthma in Mice

BACKGROUND Interleukin (IL)-23/Th17 axis plays an important role in the pathophysiology of asthma and eczema, however, there are some conflicting data about the effects of this system on allergic airway inflammation. In the present study, we aim to dissect the spatiotemporal differences in the roles of IL-23 in an epicutaneously-sensitized asthma model of mice. METHODS C57BL/6 mice were sensitized to ovalbumin (OVA) by patch application on the skin, followed by airway exposure to aerosolized OVA. During sensitization and/or challenge phase, either a specific neutralizing antibody (Ab) against IL-23 or control IgG was injected intraperitoneally. On days 1 and 8 after the final OVA exposure, airway inflammation and responsiveness to methacholine, immunoglobulin levels in serum, and cytokine release from splenocytes were evaluated. Skin Il23a mRNA levels were evaluated with quantitative RT-PCR. RESULTS Patch application time-dependently increased the expression of Il23a mRNA expression in the skin. Treatment with the anti-IL-23 Ab during sensitization phase alone significantly reduced the number of eosinophils in bronchoalveolar lavage fluids and peribronchial spaces after allergen challenge compared with treatment with control IgG. Anti-IL-23 Ab also reduced serum levels of OVA-specific IgG1. In contrast, treatment with the anti-IL-23 Ab during the challenge phase alone rather exacerbated airway hyperresponsiveness to methacholine with little effects on airway eosinophilia or serum IgG1 levels. CONCLUSIONS IL-23 expressed in the skin during the sensitization phase plays an essential role in the development of allergic phenotypes, whereas IL-23 in the airways during the challenge phase suppresses airway hyperresponsiveness.

Determinants of long-term persistence with tiotropium bromide for chronic obstructive pulmonary disease

Abstract Tiotropium bromide, a long-acting anticholinergic agent, improves pulmonary function and quality of life of patients suffering from chronic obstructive pulmonary disease (COPD). We retrospectively examined the factors that determine the long-term persistence with tiotropium bromide. Among 6,301 patients who underwent pulmonary function tests in our pulmonary clinic between 2006 and 2009, 644 met the following criteria: 1) age > 40 years, 2) ≥ 20 pack-years smoking history, and 3) forced expiratory volume in 1 sec / forced vital capacity ratio < 0.7. The clinical information, including the prescription of tiotropium, was obtained from the patients’ records. Tiotropium was administered to 255 patients (40%), of whom 48 (19%) discontinued treatment within 1 year, and 65 (25%) discontinued treatment within the median observation period of 32 months. The drug was discontinued because of ineffectiveness in 35 patients (73%), and because of adverse drug effects in 13 patients (27%). Young age, current smoking, absence of respiratory symptoms alleviation, and less severe disease characterized by a) mild airflow limitation, b) mild to moderate emphysema, or c) no exacerbation of COPD during the 1st year of treatment were predictors of drug discontinuation.

Distinct effects of endogenous interleukin-23 on eosinophilic airway inflammation in response to different antigens

BACKGROUND The role of interleukin (IL)-23 in asthma pathophysiology is still controversial. We examined its role in allergic airway inflammation in response to two distinct antigens using IL-23-deficient mice. METHODS Allergic airway inflammation was evaluated in wild-type and IL-23p19(-/-) mice. Mice were sensitized to ovalbumin (OVA) or house dust mite (HDM) by intraperitoneal injection of antigen and their airways were then exposed to the same antigen. Levels of antigen-specific immunoglobulins in serum as well as cytokines in bronchoalveolar or peritoneal lavage fluid and lung tissue were determined by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. RESULTS Deficiency of IL-23p19 decreased eosinophils and Th2 cytokines in bronchoalveolar lavage fluid (BALF) of OVA-treated mice, while it increased BALF eosinophils of HDM-treated mice. Peritoneal injection of OVA with alum, but not of HDM, induced local synthesis of IL-6, IL-10, and IL-23. Systemic production of antigen-specific IgG1 was partially dependent on IL-23. In contrast, airway exposure to HDM, but not to OVA, induced IL-23p19 mRNA expression in the lungs. In IL-23p19-deficient mice, HDM-exposed lungs did not exhibit the induction of IL-17A, which negatively regulates eosinophilic inflammation. CONCLUSIONS Different antigens induced IL-23 at different part of the body in our similar asthma models. Endogenous IL-23 production at the site of antigen sensitization facilitates type-2 immune responses, whereas IL-23 production and subsequent IL-17A synthesis in the airways suppresses allergic inflammation.

12‐OH‐17,18‐epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs

Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega‐6 fatty acid, is metabolized into cysteinyl leukotriene with pro‐inflammatory properties for allergic inflammation, whereas the omega‐3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti‐inflammatory effects. In this study, we investigated the mechanism underlying the counter‐regulatory roles of EPA in inflamed lungs.

Intraoral ulcer due to non-invasive positive pressure ventilation: an overlooked complication

A male patient aged 81 years reported with dyspnoea and loss of consciousness, at our emergency department. His respiratory rate was 30 breaths/min, and his level of consciousness determined using the Glasgow Coma Scale was eye (1), verbal (1) and motor (4). Despite oxygen administration via a bag valve mask, his percutaneous oxygen saturation level was measured as only 81%. Physical examination revealed weak vesicular sound on auscultation, suggesting he had severe emphysema. Arterial blood gas analysis after …

Fatal Fulminant Pneumonia Caused by Methicillin-Sensitive Staphylococcus aureus Negative for Major High-Virulence Factors Following Influenza B Virus Infection

Patient: Male, 32 Final Diagnosis: MSSA pneumonia Symptoms: Cough • dyspnea • fever Medication: Meropenem • levofloxacin • vancomycin • peramivir Clinical Procedure: Diagnosed based on CT images • sputum culture • PCR Specialty: Infectious Diseases Objective: Rare disease Background: Increasing evidence has indicated that Staphylococcus aureus pneumonia complicated with influenza virus infection is often fatal. In these cases, disease severity is typically determined by susceptibility to antimicrobial agents and the presence of high-virulence factors that are produced by Staphylococcus aureus, such as Panton-Valentine leukocidin (PVL). Case Report: We describe a rare case of fatal community-acquired pneumonia caused by methicillin-sensitive Staphylococcus aureus (MSSA), which did not secrete major high-virulence factors and coexisted with influenza type B infection. The 32-year-old previously healthy male patient presented with dyspnea, high fever, and cough. His roommate had been diagnosed with influenza B virus infection 3 days earlier. Gram-positive clusters of cocci were detected in the patient’s sputum; therefore, he was diagnosed with severe pneumonia and septic shock, and was admitted to the intensive care unit. Despite intensive antibiotic and antiviral treatment, he died of multiple organ failure 5 days after admission. His blood culture from the admission was positive for MSSA, and further analysis revealed that the strain was negative for major high-virulence factors, including PVL and enterotoxins, although influenza B virus RNA was detected by PCR. Conclusions: Physicians should pay special attention to patients with pneumonia following influenza and Staphylococcus aureus infection, as it may be fatal, even if the Staphylococcus aureus strain is PVL-negative and sensitive to antimicrobial agents.