Kenji Mano

Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: Essential role of GM-CSF

BACKGROUND Inhaled pollutants were recently shown to be responsible for an increased incidence of airway allergic diseases, including asthma. A common feature of all forms of asthma is airway hyperresponsiveness. OBJECTIVE Our purpose was to elucidate the effects of diesel exhaust particulate (DEP), one of the most prevalent inhaled pollutants, on airway responsiveness. METHODS A/J and C57Bl/6 mice were used; the former are genetically predisposed to be hyperresponsive to acetylcholine, whereas the latter are not. DEP was administered intranasally for 2 weeks, after which pulmonary function was analyzed by whole-body plethysmography. RESULTS Intranasal administration of DEP increased airway responsiveness to acetylcholine in both A/J and C57Bl/6 mice and induced displacement of ciliated epithelial cells by mucus-secreting Clara cells. The effect was mediated by M(3) muscarinic receptors. Acetylcholine-evoked bronchial constriction was reversed by administration of terbutaline, a beta(2)-adrenergic antagonist, which is also characteristic of human asthma. Intranasal administration of antibody raised against GM-CSF abolished DEP-evoked increases in airway responsiveness and Clara cell hyperplasia. The antibody raised against IL-4 also inhibited DEP-evoked increases in airway responsiveness. However, it was to a lesser extent compared with antibody against GM-CSF. In addition, DEP stimulated GM-CSF messenger RNA expression in the lung. CONCLUSION DEP induces airway hyperresponsiveness by stimulating GM-CSF synthesis.

Nuclear factor kappa B mediates interleukin-8 production in eosinophils.

Background: Recent reports indicate that in response to various stimuli, eosinophils produce a variety of cytokines (e.g. IL–8) which play pivotal roles in allergic inflammation. In that regard, the transcription factor, nuclear factor, Kappa B (NF–κB), is an important activator of tumor–necrosis–factor–alpha (TNF–α)–induced IL–8 gene expression in monocytes, lymphocytes and neutrophils. We therefore investigated the role played by NF–κB in cytokine production induced by stimulation of eosinophils with the proinflammatory cytokines, granulocyte–monocyte colony–stimulating factor (GM–CSF) and TNF–α. Methods: Peripheral blood samples were obtained from human subjects with slight to moderate eosinophilia. NF–κB activation elicited by exposing cells to GM–CSF and/or TNF–α was investigated using immunohistochemistry and gel shift assays. To functionally assess the effects of NF–κB translocation, IL–8 production was also examined using an enzyme–linked immunosorbent assay. Results: Stimulation of eosinophils with GM–CSF + TNF–α induced significant increases in the synthesis and secretion of IL–8 which were associated with translocation of NF–κB p50 into the nucleus. The binding of NF–κB to the DNA was verified by the gel shift assays. IL–8 production was significantly inhibited by N–acetyl–L–cysteine, FK506 and MG–132, inhibitors of NF–κB activation and translocation. Conclusion: On the basis of our findings, we conclude that activation and translocation of NF–κB plays a crucial role in the signal–transduction pathway leading to the synthesis and release of IL–8 by eosinophils.

A double‐blind, placebo‐controlled dose–response study with budesonide Turbuhaler in Japanese asthma patients

The aim of this study was to investigate the dose–response for inhaled budesonide via Turbuhaler® in Japanese patients with mild to moderate asthma.

Aminophlline is effective on acute exacerbations of asthma in adults–objective improvements in peak flow, spirogram, arterial blood gas measurements and lung sounds

Second Department of Medicine, Teikyo University School of Medicine, *Clinical Research Center for Allergy and Rheumatology. National Sagamihara Ho.spital. f Section of Allergy and Respiratory Medicine. Doai Memorial Hospital IMat.sunwra Clinic and Research institute for Asthma and Imtnunological Diseases, l^Fourth Department of Medicine, Nippon Medical School, and ^International Medical Center of Japan, Tokyo, Japan

A double-blind, placebo-controlled steroid-sparing study with budesonide Turbuhaler in Japanese oral steroid-dependent asthma patients

The aim of this study was to evaluate the oral steroid‐sparing capacity of budesonide Turbuhaler®.

THE DISTRIBUTION OF POLYMORPHIC TRAITS IN ATOPIC ASTHMATIC PATIENTS

The phenotypic distribution and gene frequencies of haptoglobin (Hp), transferrin (Tf), group specific component (Gc), cholinesterase (Cho E2), and alpha1-antitrypsin (Pi) in plasma proteins, and phosphoglucomutase (PGM), 6-phosphogluconate dehydrogenase ((6-PGD), esterase D (Es D), phosphohexose isomerase (PHI), adenosine deaminase (ADA) and acid phosphatase (AcP) in red cells were studied in 127 atopic, asthmatic patients. The gene frequencies were compared with normal groups. The phenotypic distribution of the Pi system in atopic patients was somewhat different from the normal. No significant differences were found between the two groups in protein systems or in enzyme systems, except Pi systems. In conclusion, except for the Pi system, no definite association between polymorphic traits and atopic asthma was found in this study.

Efficacy of budesonide Turbuhaler compared with that of beclomethasone dipropionate pMDI in Japanese patients with moderately persistent asthma.

Objective: The aim of the study was to compare the efficacy and safety of budesonide Turbuhaler® with that of beclomethasone dipropionate (BDP) pMDI.

Effect of Thromboxane A2 Synthetase Inhibitor on Immediate-Type Hypersensitivity Reactions

The effect of the thromboxane (TX) A2 synthetase inhibitor, OKY-046, on human leukocyte histamine release and bronchial hypersensitivity in asthmatic subjects was evaluated. It was found that OKY-046 inhibited IgE- and Ca2+ ionophore A23187-mediated leukocyte histamine release in a dose-dependent fashion (IC50: 1.0 and 3.0 X 10(-3) M, respectively) and that OKY-046 could diminish bronchial hypersensitivity, determined by leukotriene D4 inhalation, following a 2-week oral medication. These data suggest that the TXA2 synthetase inhibitor can produce favorable effects upon the course of immediate-type hypersensitivity reactions.