The Effect of PPAR Agonists on the Migration of Mature and Immature Eosinophils

PPARγ agonists can either enhance or inhibit eosinophil migration, which is a sum of directional migration (chemotaxis) and random cell movement (chemokinesis). To date, the effects of PPAR agonists on chemokinesis have not been examined. This study investigates the effects of PPARα, δ, and γ agonists on eosinophil migration and chemokinesis. Eosinophils purified from blood of atopic donors were preincubated with rosiglitazone (PPARγ agonist), GW9578 (PPARα agonist), GW501516 (PPARδ agonist), or diluent. The effects of PPAR agonists were examined on eosinophil chemokinesis, eotaxin-induced migration of eosinophils, and migration of IL-5Rα+ CD34+ cells. Expressions of CCR3, phospho-p38, phospho-ERK, and calcium release were also measured in eosinophils after rosiglitazone treatment. Low concentrations of rosiglitazone, but not GW9578 or GW501516, increased chemokinesis of eosinophils (P=0.0038), and SDF-1α-induced migration of immature eosinophils (P=0.0538). Rosiglitazone had an effect on eosinophil calcium flux but had no effect on expression of CCR3 or phosphorylation of p38 or ERK. In contrast, high concentrations of rosiglitazone inhibited eosinophil migration (P=0.0042). The effect of rosiglitazone on eosinophil migration and chemokinesis appears to be through modification of calcium signaling, which alludes to a novel PPAR-mediated mechanism to modulate eosinophil function

Overexpression of Chitinase 3-Like 1/YKL-40 in Lung-Specific IL-18-Transgenic Mice, Smokers and COPD

We analyzed the lung mRNA expression profiles of a murine model of COPD developed using a lung-specific IL-18-transgenic mouse. In this transgenic mouse, the expression of 608 genes was found to vary more than 2-fold in comparison with control WT mice, and was clustered into 4 groups. The expression of 140 genes was constitutively increased at all ages, 215 genes increased gradually with aging, 171 genes decreased gradually with aging, and 82 genes decreased temporarily at 9 weeks of age. Interestingly, the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. However, IL-13 gene deletion did not reduce the level of Chi3l1 protein in the lungs of IL-18 transgenic mice. Based on our murine model gene expression data, we analyzed the protein level of YKL-40, the human homolog of Chi3l1, in sera of smokers and COPD patients. Sixteen COPD patients had undergone high resolution computed tomography (HRCT) examination. Emphysema was assessed by using a density mask with a cutoff of −950 Hounsfield units to calculate the low-attenuation area percentage (LAA%). We observed significantly higher serum levels in samples from 28 smokers and 45 COPD patients compared to 30 non-smokers. In COPD patients, there was a significant negative correlation between serum level of YKL-40 and %FEV1. Moreover, there was a significant positive correlation between the serum levels of YKL-40 and LAA% in COPD patients. Thus our results suggest that chitinase-related genes may play an important role in establishing pulmonary inflammation and emphysematous changes in smokers and COPD patients

ニュータウンに居住する専業主婦の外出頻度および主観的健康感との関係

専業主婦については、活動量や運動量の制限などが報告されている一方、若年期からの地域とのつながりにより外出頻度は維持されやすいと考えられる. そこで高齢者で報告されている外出頻度と主観的健康感との関連が専業主婦でもみられるのか、年齢による影響を明らかにすることを目的とした. 研究は大阪府堺市南区の一地区内の全世帯(3,069世帯)に無記名自記式の質問紙調査を行い、回答数1,820(回収率58.0%)の中から専業主婦701名を分析対象とした. 質問項目は最近1週間の外出頻度、主観的健康感について尋ねた. その結果、外出頻度は60代、70代後半、80代以上と段階的に減少した. 主観的健康感は加齢とともに不安あり群が増加した. 外出頻度と主観的健康感の関連は50代以上で外出頻度が減少するとともに主観的健康感が低下する傾向を認めた. 以上より、健康維持、増進のためには50代から年代ごとの取り組みが必要であることが示唆された.Physical activity levels and the amount of exercise in housewives are reportedly low; however, a high frequency of outings is likely to be maintained due to connection with local residents. This study aimed to identify the relationship between the frequency of outings and self-rated health in housewives, and investigate age-related effects. Anonymous self-administered questionnaires were distributed to 3,069 households in one district of Minami-ku, Sakai-shi, Osaka, and, of the 1,820 responses (response rate: 58.0%), 701 housewives were analyzed. Questionnaire items included the frequency of outings and self-rated health over the past one week. As the results of the questionnaire, the frequency of outings gradually decreased as the age advanced from their 60s to 80s or over. Regarding self-rated health, the number of subjects with anxiety increased with age. Among the subjects aged 50 or over, there was a decreasing trend in the frequency of outings and self-rated health. The findings suggest the need to take appropriate measures to maintain and promote the health of housewives aged 50 and over according to their age group

Endogenous and Exogenous Thioredoxin 1 Prevents Goblet Cell Hyperplasia in a Chronic Antigen Exposure Asthma Model

Background: Goblet cell hyperplasia with mucus hypersecretion contribute to increased morbidity and mortality in bronchial asthma. We have reported that thioredoxin 1 (TRX1), a redox (reduction/oxidation)-active protein acting as a strong antioxidant, inhibits pulmonary eosinophilic inflammation and production of chemoki- nes and Th2 cytokines in the lungs, thus decreasing airway hyperresponsiveness (AHR) and airway remodeling in mouse asthma models. In the present study, we investigated whether endogenous or exogenous TRX1 inhibits goblet cell hyperplasia in a mouse asthma model involving chronic exposure to antigen. Methods: We used wild-type Balb/c mice and Balb/c background human TRX1-transgenic mice constitutively overproducing human TRX1 protein in the lungs. Mice were sensitized 7 times (days 0 to 12) and then challenged 9 times with ovalbumin (OVA) (days 19 to 45). Every second day from days 18 to 44 (14 times) or days 35 to 45 (6 times), Balb/c mice were treated with 40 μg recombinant human TRX1 (rhTRX1) protein. Goblet cells in the lungs were examined quantitatively on day 34 or 45. Results: Goblet cell hyperplasia was significantly prevented in TRX1-transgenic mice in comparison with TRX1 transgene-negative mice. rhTRX1 administration during OVA challenge (days 18 to 44) significantly inhibited goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice. Moreover, rhTRX1 administration after the establishment of goblet cell hyperplasia (days 35 to 45) also significantly ameliorated goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice. Conclusions: Our results suggest that TRX1 prevents the development of goblet cell hyperplasia, and also ameliorates established goblet cell hyperplasia