Miyoshi Fujita

C-reactive protein levels in the serum of asthmatic patients.

BACKGROUND Asthma is a chronic airway inflammatory disease caused by immune cells such as T lymphocytes and eosinophils. Recently, highly sensitive C-reactive protein (hs-CRP) assays have become available for detecting small changes in CRP levels within the reference range, allowing for the evaluation of clinical inflammation. OBJECTIVE To investigate the relationship between hs-CRP levels and bronchial asthma. METHODS We collected blood samples from 109 patients with bronchial asthma, with or without attacks, and measured serum eosinophil cationic protein levels, pulmonary function, and serum CRP levels using an hs-CRP assay. RESULTS Mean serum hs-CRP levels were significantly higher in patients without attacks (0.473 mg/L) and with attacks (0.908 mg/L) (P < .001 for both) than in controls (0.262 mg/L). Serum hs-CRP levels were inversely correlated with forced expiratory volume in 1 second/forced vital capacity in asthmatic patients (r = -0.4915; P < .01). CONCLUSION Serum hs-CRP levels may be related to the state of asthma exacerbation and allergic inflammation.

Theophylline and Dexamethasone Induce Peroxisome Proliferator-Activated Receptor-γ Expression in Human Eosinophils

Eosinophils are major effector cells in allergic diseases including asthma. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor that regulates immune reaction. We have previously demonstrated that human eosinophils express PPARγ and that stimulation with a synthetic agonist for PPARγ attenuated the factor-induced eosinophil survival and chemotaxis. However, the modulator of the eosinophil PPARγ expression has not yet been studied. In this study, we investigated the effect of theophylline and dexamethasone (widely used drugs in the treatment of asthma) on PPARγ expression in eosinophils. Purified human peripheral blood eosinophils were cultured, and therapeutic concentrations of theophylline and dexamethasone were added. Subsequently, PPARγ was measured using quantitative real-time RT-PCR and flow cytometry. Theophylline and dexamethasone markedly enhanced both mRNA and protein levels of PPARγ. These findings suggest that the increase in PPARγ expression on eosinophils may play a role in the anti-inflammatory effects of theophylline and dexamethasone.

The Synthetic PPARγ Agonist Troglitazone Inhibits Eotaxin-Enhanced Eosinophil Adhesion to ICAM-1-Coated Plates

Accumulation and activation of eosinophils in tissue are critical events in the allergic inflammatory response and adhesion molecules play important roles in this process. We previously demonstrated that human eosinophils expressed a nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), and that stimulation with a PPARγ agonist attenuated cytokine/chemokine-induced eosinophil activation, such as survival, chemotaxis and degranulation. In the present study, we investigated the effect of troglitazone, a synthetic PPARγ agonist, on adherence to intercellular adhesion molecule-1 (ICAM-1). Eosinophils were purified from human peripheral blood, and the functional adherence to recombinant soluble ICAM-1-coated plates was examined. We found that in the presence of eotaxin, troglitazone inhibited eosinophil adherence in a concentration-dependent manner. This novel activity appears to be associated with modulation of qualitative change of integrins in response to eotaxin, because quantitative reduction of CD11a, CD11b and CD18 expression by troglitazone was not observed using flow cytometry. The PPARγ agonist troglitazone has a potent inhibitory effect on eosinophil adhesion to ICAM-1, and this may be a therapeutic modality for the treatment of eosinophil-related diseases including bronchial asthma.

Red blood cells regulate eosinophil chemotaxis by scavenging RANTES secreted from endothelial cells

Background Eosinophils play a critical role in the pathogenesis of allergic diseases. CC chemokines, such as regulated on activation, normal, T cell expressed, and secreted (RANTES), are key regulators of eosinophil locomotion. Although eosinophils migrate from the bloodstream into tissues, mechanisms that generate a chemogradient across the endothelium remain to be fully elucidated.

Hepatocyte Growth Factor Suppresses Production of Reactive Oxygen Species and Release of Eosinophil-Derived Neurotoxin from Human Eosinophils

Background:Reactive oxygen species (ROS) and eosinophilic granule proteins such as eosinophil-derived neurotoxin (EDN) are known to damage bronchial tissue and cause airway hyperresponsiveness (AHR) in asthma. Hepatocyte growth factor (HGF) regulates various biological activities and is known to be a multifunctional factor. In our previous study, we found that HGF suppressed allergic airway inflammation and AHR in a murine model of asthma. However, there have been few reports regarding the detailed mechanism of the anti-allergic effect of HGF in asthma. In this study, we investigated the potential of recombinant HGF to regulate the production of ROS and the release of EDN from human eosinophils. Methods:Eosinophils were isolated from subjects with mild eosinophilia by modified CD16-negative selection. We investigated the expression of CD69, an activation marker of eosinophils, on eosinophils, using flow cytometry. Further, ROS production from eosinophils was analyzed using luminol-dependent chemiluminescence, and EDN release was measured by ELISA. Results:Treatment with HGF suppressed interleukin-5-induced upregulation of CD69 expression, ROS production and EDN release from human eosinophils. Conclusion:Taken together, these data suggest that in asthma, HGF attenuates allergic airway inflammation and AHR through at least the suppression of ROS production and EDN release from eosinophils.

120 The Features of Airway Remodeling Are More Severe in Female Mice

Background Epidemiological studies have already shown that females are dominant in terms of the sex ratio of adult asthma prevalence and severe asthma. It has also been reported that female mice are more susceptible to the development of allergic airway inflammation and airway hyperresponsiveness (AHR) than males. However, there have been few reports of studies on sex difference in the pathogenesis of severe asthma, especially airway remodeling in an animal model. In this study, we investigated sex difference in formation of airway remodeling using a long-term antigen challenged asthma model. Methods Following ovalbumin (OVA)/alum intraperitoneal injection, male or female mice (BALB/c) were challenged with aerosolized 1% OVA on 3 days/week for 5 weeks, and we investigated the sex difference in AHR, airway inflammation, as well as airway remodeling. Results In OVA-sensitized and -challenged (OVA/OVA) female mice, AHR, the number of eosinophils and lymphocytes, as well as Th2 cytokines and growth factors in BAL fluid were increased compared with OVA/OVA male mice. On the other hand, there is no significant difference in the level of eotaxin in BAL fluid. The histological features of airway remodeling, including goblet cell hyperplasia, subepithelial fibrosis and myofibroblast hypertrophy, were also increased in OVA/OVA female mice. Moreover, serum total and OVA-specific IgE were significantly elevated in OVA/OVA female mice. Conclusions These results indicate that female mice are dominant in terms of forming airway remodeling as compared with male mice. The involvement of sex difference for sensitization and growth factor release in lung tissue based on inflammatory cell infiltration is indicated for the mechanism of sex difference of airway remodeling.