Yukio Kawagishi

Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma

Background: Although there is increasing evidence of the importance of cysteinyl leukotrienes (LT) as mediators of aspirin‐induced bronchoconstriction in aspirin‐sensitive asthma, the cellular origin of the LT is not yet clear.

Nationwide Cross-Sectional Population-Based Study on the Prevalences of Asthma and Asthma Symptoms among Japanese Adults

Background: Asthma is a common respiratory disease worldwide. However, few reports are available on the prevalences of asthma and asthma symptoms among Asian subjects. Methods: To determine the prevalences of asthma and asthma symptoms among Japanese subjects, we performed a nationwide cross-sectional, population-based study on Japanese adults aged 20–79 years. Ten areas spread throughout the country were randomly selected. Door-to-door or postal surveys were performed using a translated version of the European Community Respiratory Health Survey questionnaire. Results: The survey was completed by 23,483 participants. The overall response rate was 70.6%. The prevalences of wheeze and current asthma among all participants aged 20–79 years were 10.1% (95% CI: 9.7–10.5%) and 4.2% (95% CI: 4.0–4.5%), respectively. The prevalences among young adults aged 20–44 years were 9.3% (95% CI: 8.7–9.9%) and 5.3% (95% CI: 4.8–5.8%), respectively. The prevalence of current asthma was highest in females aged 30–39 years in comparison with the other gender and age groups. Conclusions: This nationwide study determined the prevalences of asthma and asthma symptoms among Japanese adults. The results provide fundamental information on the respiratory health of Japanese adults.

Association of the polymorphisms in the 5′-untranslated region of PTEN gene with type 2 diabetes in a Japanese population

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known to act as a lipid phosphatase hydrolyzing phosphatidylinositol (PI)(3,4,5)P3 to PI(4,5)P2. Since the PI3‐kinase product, PI(3,4,5)P3, is an important second messenger leading to the metabolic action of insulin, PTEN functions as a potent negative regulator of insulin signaling and its gene is one of the possible candidates involved in susceptibility to the development of type 2 (non‐insulin‐dependent) diabetes. In the present study, we investigated the polymorphisms of the PTEN gene in Japanese patients with type 2 diabetes and non‐diabetic control subjects. We identified three mutations of the gene in the type 2 diabetes patients. Among these mutations, the frequency of the substitution of C with G at position −9 (−9C→G) (SNP1), located in the untranslated region of exon 1, was significantly higher in type 2 diabetic patients than in control subjects. In addition, transfection of the PTEN gene with SNP1 resulted in a significantly higher expression level of PTEN protein compared with that of the wild‐type PTEN gene in Cos1 and Rat1 cells. Furthermore, insulin‐induced phosphorylation of Akt in HIRc cells was decreased more greatly by transfection of SNP1 PTEN gene than that of wild‐type PTEN gene. These findings suggest that the change of C to G at position −9 of the PTEN gene is associated with the insulin resistance of type 2 diabetes due possibly to a potentiated hydrolysis of the PI3‐kinase product.

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway.

Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance‐associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI‐H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c‐jun N‐terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX‐induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c‐jun to the MRP1 promoter containing the AP‐1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction.

The prevalence of rhinitis and its association with smoking and obesity in a nationwide survey of Japanese adults

Rhinitis is a common disease, and its prevalence is increasing worldwide. Several studies have provided evidence of a strong association between asthma and rhinitis. Although smoking and obesity have been extensively analyzed as risk factors of asthma, associations with rhinitis are less clear.

Interstitial pneumonitis associated with infliximab therapy without methotrexate treatment

Tumor necrosis factor (TNF)-α inhibitors are increasingly being used to treat rheumatoid arthritis. Infliximab (INF) is a TNF-α inhibitor that is usually used in combination with methotrexate (MTX). Interstitial lung disease (ILD) during combination therapy has been attributed to MTX rather than INF. However, INF-associated ILD without combination with MTX has recently been reported. We describe herein a case of severe ILD secondary to INF without MTX therapy.

Association between Body Mass Index and Asthma among Japanese Adults: Risk within the Normal Weight Range

Background: Increasing amounts of data have shown that some Asian populations are more susceptible to increased weight and development of noncommunicable disease than Western populations. However, little is known about the association between increased weight, particularly within the normal range, and the development of asthma among Asian populations. Methods: To examine the association between increased body mass index (BMI) and asthma among Japanese adults, data from a nationwide population-based cross-sectional survey of asthma prevalence in Japan were analyzed (n = 22,962; age range 20–79 years). BMIs were classified into 7 categories considering WHO recommendations (cutoff points: 17.00, 18.50, 23.00, 25.00, 27.50 and 30.00), and the association between BMI and the prevalences of asthma as well as asthma symptoms were assessed by multivariate logistic regression. Results: The prevalences of obesity (BMI ≧30.00) in this population were relatively low (males 3.0%, females 2.3%). BMI categories of 25.00 or higher in both genders were significantly associated with an increased risk of asthma compared with the reference category (BMI 18.50–22.99). Even in females with a BMI of 23.00–24.99, the prevalence of asthma significantly increased (adjusted odds ratio 1.49, 95% confidence interval 1.16–1.92) compared with that in the reference category. Conclusions: An increase in the prevalence of asthma among Japanese females starts at a BMI of 23.00, which was relatively lower than those reported from Western countries. This finding suggests that the Japanese population is likely to have asthma with a lesser degree of obesity than Western populations.

Association of serum adiponectin with asthma and pulmonary function in the Japanese population.

Conflicting findings have been reported regarding the role of adiponectin in asthma. The aim of this study was to evaluate the association of adiponectin with pulmonary functions and asthma in the Japanese population. First, among a general population that participated in a previous study (group 1), we selected 329 subjects after excluding those with asthma, chronic obstructive pulmonary disease, and a smoking history and examined the associations of the serum total adiponectin levels with pulmonary functions. In a second cohort (group 2) consisting of 61 asthmatic patients and 175 control non-asthmatic subjects, we examined the associations between asthma and the levels of total, high (HMW), middle (MMW) and low (LMW) molecular weight adiponectin isoforms as well as the ratio of each isoform to total adiponectin level. Although the total adiponectin levels were not significantly different between the asthmatic and control subjects in group 2, the levels were significantly and positively associated with the forced expiratory volume in 1 s after adjustments for confounding factors (P < 0.05) in women in group 1. In group 2, the LMW adiponectin level was significantly higher and the MMW/total adiponectin ratio was significantly lower among the asthmatic subjects than among the control subjects after adjustments for confounding factors in both sexes (P < 0.05). The present study showed that a low total adiponectin level may lead to airway narrowing compatible with asthmatic airways in women, and higher LMW adiponectin levels and lower MMW/total adiponectin ratio are significantly associated with current asthma in both sexes.

Visceral adipose tissue level, as estimated by the bioimpedance analysis method, is associated with impaired lung function

Aims/Introduction:  It has been reported that metabolic syndrome is associated with impaired lung function, and abdominal obesity is regarded as the most important determinant of this association. We evaluated the association between a component of metabolic syndrome, indices of body composition, including the total adipose tissue content, lean bodyweight and visceral adipose tissue content, as assessed by bioimpedance analysis, and lung function.

Ionizing radiation suppresses FAP-1 mRNA level in A549 cells via p53 activation

Ionizing radiation (IR) is known to upregulate cell surface Fas through p53 activation in various cells. However, the signaling pathway intermediating between p53 activation and cell surface Fas upregulation remains to be elucidated. Recently, Fas‐associated phosphatase‐1 (FAP‐1) has been reported to associate with Fas and inhibit cell surface Fas expression. We evaluated the expression of FAP‐1 mRNA following IR in A549 cells. Ionizing radiation inhibited the expression of FAP‐1 mRNA. Pretreatment with p53 inhibitor pifithrin α cancelled the IR‐induced downregulation of FAP‐1 mRNA. These results suggest that IR‐induced p53 activation may upregulate cell surface Fas via the down‐modulation of FAP‐1.