Shunsuke Shoji

Experimental hypersensitivity pneumonitis in the mouse: Histologic and immunologic features and their modulation with cyclosporin A☆

A murine model of hypersensitivity pneumonitis (HP) was established with transnasally administered Thermoactinomyces vulgaris (Tv) bacilli. Bronchoalveolar lavage (BAL) of experimental animals revealed marked increase in the total cell, lymphocyte, and macrophage numbers; the findings were similar to those in human HP. The BAL lymphocytes were mostly Thy 1.2 positive. Lyt-1 positive cells predominated Lyt-2 positive cells. Anti-Tv IgG antibodies and delayed-type hypersensitivity footpad reactions against Tv were detected in animals with HP. Cyclosporin A (CyA), a potent immunosuppressive drug, had marked effects on the development of HP in this model. When CyA was administered throughout the course of Tv inoculations, the granulomatous pneumonitis was markedly suppressed, and an increase in BAL lymphocytes, Thy 1.2 positive cells, was suppressed. When CyA was administered only during the first half period of the Tv treatment, suppression of the disease was minimal; when CyA was administered in the latter half, both the HP lesions and the increase in BAL cell lymphocyte numbers were significantly suppressed. These results indicate that a series of transnasal administration of Tv in mice may provide a good model for human HP.

Leptin enhances ICAM-1 expression, induces migration and cytokine synthesis, and prolongs survival of human airway epithelial cells.

There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and a human airway epithelial cell line, BEAS-2B. Flow cytometry showed enhanced ICAM-1 expression by both of those cells in response to leptin, and that effect was abrogated by dexamethasone or NF-κB inhibitor. Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself. Multiplex cytokine analysis demonstrated enhanced production of CCL11, G-CSF, VEGF, and IL-6 by BEAS-2B cells stimulated with leptin. Furthermore, transfection of Ob-R small interference RNA decreased the effect of leptin on CCL11 production as assessed by quantitative PCR. Finally, leptin induced migration of primary airway epithelial cells toward leptin, suppressed BEAS-2B apoptosis induced with TNF-α and IFN-γ, and enhanced proliferation of primary airway epithelial cells. In summary, leptin was able to directly activate human airway epithelial cells by binding to Ob-R and by NF-κB activation, resulting in upregulation of ICAM-1 expression, induction of CCL11, VEGF, G-CSF, and IL-6 synthesis, induction of migration, inhibition of apoptosis, and enhancement of proliferation.

A Case of Acute Eosinophilic Pneumonia Following Short-Term Passive Smoking : An Evidence of Very High Level of Urinary Cotinine

Acute eosinophilic pneumonia (AEP) is characterized by febrile illness, diffuse pulmonary infiltrates with eosinophilia. The pathogenesis is not well understood. We report a case of 22-year-old men who never smoke presented with AEP 2 days after acute passive smoke exposure. He developed acute respiratory failure despite having no history of the disease. Computed tomography of the lung revealed diffuse bilateral pulmonary infiltrates. Lung biopsy specimens revealed marked eosinophil infiltration in the alveolar septa without signs of vasculitis. Two days prior to the disease, he was exposed to cigarette smoke for 2 hours in a closed area. In the absence of other causes, passive smoking may cause lung inflammatory responses. The level of urinary cotinine, which is a biomarker of smoke exposure, was considerably higher (0.198 μg/ml [201 ng/mg Creatinine]) than that in nonsmokers, but never detected following period. This case suggests that short-term passive smoking may cause AEP.

Involvement of fibronectin and matrix metalloproteinases in airway smooth muscle cell migration for the process of airway remodeling.

BACKGROUND Airway remodeling is a repair process occurring after airway injury; its primary histopathological features are subepithelial fibrosis and smooth muscle thickening of the bronchi. These histopathological changes are considered to occur due to bronchial smooth muscle cells (bSMC) that secrete extracellular matrix (ECM) proteins, which work as chemoattractants and influence cell migration. Therefore, we examined the interaction between bSMCs and ECM proteins in vitro for understanding the remodeling process in the bronchi. METHODS bSMCs were cultured to collect a bSMC-conditioned medium. Using the bSMC-conditioned medium thus obtained, we performed a cell migration assay, characterized beta integrin expression, and identified ECM proteins and matrix metalloproteinases by western blotting and gelatin zymography, respectively. RESULTS The response of bSMC migration to bSMC-conditioned medium increased with time in culture, and fibronectin (FIB) was detected as a chemoattractant for bSMCs in bSMC-conditioned medium by western blot analysis and a cell migration assay using anti-FIB antibodies. The involvement of beta1 integrin in the migration of bSMCs toward FIB contained in bSMC-conditioned medium was demonstrated by inhibition of cell migration using anti-beta1 integrin antibodies. Expression of beta1 integrin on bSMCs was confirmed by using a beta-integrin-mediated cell adhesion array. In addition, metalloproteinases detected in bSMC-conditioned medium by gelatin zymography were suggested to be matrix metalloproteinase-1 and 2 by western blotting and amino acid sequencing. CONCLUSIONS Our results suggest that FIB and matrix metalloproteinases secreted from bSMCs might play major roles in bSMC migration in the process of airway remodeling.

Addition of Leukotriene Receptor Antagonists to Inhaled Corticosteroids Improved QOL of Patients with Bronchial Asthma Surveyed in Suburban Tokyo, Japan

BACKGROUND Bronchial asthma is a chronic inflammatory disease that has a severe impact on health worldwide. METHODS A survey of 10,771 patients with bronchial asthma in the Tama region, Tokyo was conducted for 5 years to examine treatment and quality of life (QOL). Subjects were patients aged ≥ 16 years and their physicians who replied to a questionnaire sent in November from 2002 to 2006. Symptoms of bronchial asthma, visits to an emergency room, use of drugs, and severity of asthma were investigated. RESULTS Asthmatic symptoms improved over the 5 years, with a reduction in the number of emergency room visits. Since inhaled corticosteroids (ICS) were used by >80% of patients in 2002, we suspected that increased use of concomitant leukotriene receptor antagonists (LTRA) and long-acting β(2) agonists (LABA) might have contributed to these findings. The effects of these drugs were compared between ICS + LTRA (n = 45) and ICS + LABA (n = 54) groups of patients. There was no significant difference in the ICS dose between these groups. In the ICS + LABA group, 18.5% and 22.2% of patients visited an emergency room before and after initiation of combination therapy, respectively, with no statistically significant difference. In contrast, the rate of emergency room visits in the ICS + LTRA group decreased from 24.4% to 6.6% after addition of LTRA. CONCLUSIONS These results suggest that the frequency of visits to an emergency room was decreased by complementing the anti-inflammatory effect of ICS with further treatment of inflammation, particularly with LTRA.

The relationship between the number of patients with cedar fever and the dosage of medication during cedar pollination season in Fukuoka City, Japan

Abstract Rationale Japanese cedar pollen is the most important cause of seasonal rhinoconjunctivitis in Japan. More than 10% of Japanese people suffer from cedar early spring. To prove the importance of pollen counting and forecast, we tried to correlate the number of patients seeking, medications for rhinitis by prescription and OTC products with pollen counting. Methods We performed cedar pollen counting, using the volumetric and the gravitational methods. We gathered the information on the number of cedar pollinosis patients seen at the ENT clinics and the type and amount of the rhinitis medications purchased at the drugstores in Fukuoka City. We performed statistical analysis of the data. In addition, we analyzed the results of daily symptom logs of patients with cedar pollinosis during pollen season. Results The analysis indicated a significant positive correlation between the pollen counts during previous week and the dosage of medications. Conclusions Our data indicate that cedar pollen counts are useful for estimating the subsequent symptoms and medication use for cedar pollinosis. This correlation may be useful in reducing the morbidity and cost of treating cedar pollinosis in this region.