Important things in the treatment of asthma

Bronchial asthma is a chronic airway disease characterized by allergic inflammation. Inhaled corticosteroids are most effective drugs to control asthma. According to an increase in inhaled corticosteroids usage, asthma mortality in Japan decreased over ２ decades. Asthma is characterized by variable symptoms such as dyspnea, cough, wheezes, and chest tightness. Airway inflammation that leads to airway hyperresponsiveness is associated with these symptoms. Diagnosis of asthma is based on the following factors （１） repetitive symptoms, such as paroxysmal dyspnea, wheezing, chest tightness, and cough ; （２） reversible airflow limitation ; （３） airway hyperresponsiveness ; and （６） exclusion of other cardiopulmonary diseases.（４）An atopic state and （５） airway inflammation, which are usually indicative of eosinophilia, supports a diagnosis of asthma. Diagnosing mild asthma in the absence of either wheezes or dyspnea can be difficult. Anti-asthmatic agents consist of two types of drugs, long-term controller agents and reliever agents. Although inhaled corticosteroids is a key drug of long-term controller, but poor adherence to treatment or incorrect inhalation technique leads to poor asthma control. Therefore patient education and instruction of inhalation technique are most important for asthma treatment

Lysophosphatidic Acid Induces Allergic Inflammation

Background: Lysophosphatidic acid (LPA), a prototypic member of a large family of lysophospholipids, has been recently shown to play a role in immune responses to respiratory diseases. The involvement of LPA in allergic airway inflammation has been reported, but the mechanism remains unclear. Object: We analyzed the biological activity of LPA in vitro and in vivo and investigated its role in allergic inflammation in mice using an LPA receptor 2 (LPA2) antagonist. Methods: We used a murine model with acute allergic inflammation, in which mice are sensitized and challenged with house dust mite, and analyzed airway hyperresponsiveness (AHR), pathological findings, Th2 cytokines, and IL-33 in bronchoalveolar lavage fluid (BALF) and lung homogenates. The effect of LPA on Th2 differentiation and cytokine production was examined in vitro using naive CD4+ T cells isolated from splenocytes. We also investigated in vivo the effects of LPA on intranasal administration in mice. Results: The LPA2 antagonist suppressed the increase of AHR, the number of total cells, and eosinophils in BALF and lung tissue. It also decreased the production of IL-13 in BALF and IL-33 and CCL2 in the lung. LPA promoted Th2 cell differentiation and IL-13 production by Th2 cells in vitro. Nasal administration of LPA significantly increased the number of total cells and IL-13 in BALF via regulating the production of IL-33 and CCL-2-derived infiltrating macrophages. Conclusion: These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma

Numerical analysis and measurement of glass flow in a small melting furnace

Control of glass flow in a glass tank is a key technology in the glass melting process. The flow and temperature distributions of the glass melt greatly affect the quality of glass products. However, these phenomena have not been well understood due to the difficulty involved in the measurement as a result of the high temperature of the glass melt. Α small melting furnace was developed that was heated by electrodes. The glass flow was measured and analyzed by 3-D computer simulation. The numerical results show good agreement with the experimentally measured values. It is shown that it is possible to control the glass convection using a variety of the electric boosting conditions, the heat loss through walls and the charged glass batch. The quality of glass melt was evaluated by analyzing the temperature histories of virtual particles the furnace was charged with. It is found that the temperature of the particles is high and stable near the throat, as shown by the experimental data

Singlet oxygen -derived nerve growth factor exacerbates airway hyperresponsiveness in a mouse model of asthma with mixed inflammation

Background: Refractory asthma, which is caused by several factors including neutrophil infiltration is a serious complication of bronchial asthma. We previously reported that nerve growth factor (NGF) is involved in AHR. NGF-derived induction of hyperalgesia is dependent on neutrophils; however, this relationship remains unclear in respiratory disease. In this study, we examined the roles of neutrophils and NGF in refractory asthma. Methods: Using intranasal house dust mite sensitization, we established a mouse model of asthma with mixed inflammation (Mix-in). AHR, NGF production and hyperinnervation of the lungs were examined with or without different inhibitory treatments. The levels of the singlet oxygen markers, 10- and 12-(Z,E)-hydroxyoctadecadienoic acids (HODE) in the lungs, were measured by liquid chromatography-tandem mass spectrometry. An in vitro experiment was also performed to evaluate the direct effect of singlet oxygen on NGF production. Results: NGF production and hyperinnervation were higher in Mix-in mice than in conventional eosinophilic-asthmatic mice and were positively correlated with AHR. Asthmatic parameters were inhibited by NGF neutralizing Abs and myeloperoxidase (MPO) inhibition. The 10- and 12-(Z,E)-HODEs levels were increased in the lungs and were positively correlated with MPO activity and NGF production. NGF was produced by bronchial epithelial cells in vitro upon stimulation with singlet oxygen. Conclusions: Our findings suggest that neutrophil MPO-derived singlet oxygen induces increased NGF production, leading to AHR and 10- and 12-(Z,E)-HODEs production. These findings may help to develop new therapies targeting this mechanism and to establish a new biomarker for non-type 2 and refractory asthma

Alfacalcidol enhances collagen quality in ovariectomized rat bones: VITAMIN D IMPROVES BONE COLLAGEN QUALITY

The aim of this study was to investigate the effects of alfacalcidol (1α(OH)D3 : ALF) on bone collagen employing an ovariectomized rat model. Thirty-five 16-week-old female Sprague-Dawley rats were divided into five groups: SHAM (sham-operated + vehicle), OVX (ovariectomy + vehicle), and three ALF-treated groups, that is, ovariectomy + 0.022 µg/kg/day ALF, ovariectomy + 0.067 µg/kg/day ALF, and ovariectomy + 0.2 µg/kg/day ALF. After 12 weeks of treatment, tibiae were subjected to histological, biochemical and immunohistochemical analyses. Collagen matrices in OVX bone appeared as immature and poorly organized; however, with the ALF treatment, it was improved in a dose-dependent manner. Contents of collagen and pyridinoline cross-link were decreased in OVX compared with SHAM, but they increased to the level comparable to SHAM in ALF-treated groups. The total aldehyde, that is, a sum of free and those involved cross-links, in the highest dose of ALF was significantly higher than the rest of the groups (p < 0.05). In addition, the expression of lysyl oxidase was increased in the all ALF-treated groups compared with OVX (p < 0.05). In conclusion, ALF increases not only the amount of collagen but also enhances the maturation of collagen in ovariectomy-induced osteoporotic bones, which likely contributes to the improvement of bone quality

CD40 and IFN-γ dependent T cell activation by human bronchial epithelial cells

We examined whether freshly isolated human bronchial cells (HBEC) and bronchial epithelial cell line/ BEAS-2B cells expressed surface molecules required for APC function. These cells expressed CD40 and ICAM-1, but not B7-1, B7-2 or HLA-DR molecules. Treatment of these cells with IFN-γ resulted in enhanced expression of CD40 and ICAM-1 as well as induction of HLA-DR expression. Th2 cytokines such as IL-4 and IL-5, proinflammatory cytokine of GM-CSF and nonspecific activator endotoxin had no effect on these phenotypic expressions. Functional examinations showed that allogeneic lymphocytes purified from peripheral blood strongly proliferated in response to BEAS-2B cells cultured with IFN-γ, but only weakly compared with those without IFN-γ. When allogeneic lymphocytes were purified to CD4+ cells, the proliferative response against BEAS-2B cells was abolished. Blockade of CD40-CD40L interaction by anti-CD40 antibody also inhibited the proliferation of lymphocytes to BEAS-2B cells, although this treatment showed a minimum effect on the response to allogeneic MNC. Thus, bronchial epithelial cells have the ability to present allogeneic antigens to T cells in both CD40- and IFN-γ- dependent manners under the presence of third party cells that transduce co-stimulatory signals

Alfacalcidol enhances collagen quality in ovariectomized rat bones

The aim of this study was to investigate the effects of alfacalcidol (1α(OH)D3: ALF) on bone collagen employing an ovariectomized rat model. Thirty-five 16-week-old female Sprague-Dawley rats were divided into five groups: SHAM (sham-operated-+-vehicle), OVX (ovariectomy-+-vehicle), and three ALF-treated groups, that is, ovariectomy-+-0.022-μg/kg/day ALF, ovariectomy-+-0.067-μg/kg/day ALF, and ovariectomy-+-0.2-μg/kg/day ALF. After 12 weeks of treatment, tibiae were subjected to histological, biochemical and immunohistochemical analyses. Collagen matrices in OVX bone appeared as immature and poorly organized; however, with the ALF treatment, it was improved in a dose-dependent manner. Contents of collagen and pyridinoline cross-link were decreased in OVX compared with SHAM, but they increased to the level comparable to SHAM in ALF-treated groups. The total aldehyde, that is, a sum of free and those involved cross-links, in the highest dose of ALF was significantly higher than the rest of the groups (p-<-0.05). In addition, the expression of lysyl oxidase was increased in the all ALF-treated groups compared with OVX (p-<-0.05). In conclusion, ALF increases not only the amount of collagen but also enhances the maturation of collagen in ovariectomy-induced osteoporotic bones, which likely contributes to the improvement of bone quality

COPD・肺がんの予防

Chronic obstructive pulmonary disease (COPD) is a long-standing, crippling disease characterized by the accelerated decline of lung function, commonly brought by aging and long-time inhalation of toxic chemicals such as tobacco smoking. Consequently, most COPD patients suffer from chronic cough, sputum and dyspnea on exertion. Moreover, in addition to the decline of lung function due to the destruction of the alveolar structure, COPD is closely related to other diseases such as osteoporosis, cardiovascular diseases, diabetes, muscle dysfuncion, and lung cancer. Therefore, COPD is currently recognized as a systemic disease that the comprehensive management and care are necessary. Although COPD represents an increasing burden throughout the world and is one of the major causes of death word-wide, the issue has been arisen that the recognition of COPD in the general society is still low, especially in Japan. On the other hand, lung cancer is a life-threatening disease with the leading cause of malignancy-related death world-wide, the etiology of which is also closely related to tobacco smoking. Because the pathogenesis and the mortality of COPD and lung cancer are closely related each other, the action to prevent these diseases could be made simultaneously, primarily by the smoking cessation and the detection survey. In this article, we describe the present situation of COPD and lung cancer, the importance of smoking cessation, and the effort of Tokushima City Medical Association to manage COPD in Tokushima

Interleukin (IL)-12 gene transduction and its functional expression into human bronchial epithelial cells (BEAS-2B) by adenovirus vector

Interleukin (IL)-12 is known as a cytokine that augments the Th1 type response. Especially in allergic diseases such as a bronchial asthma, IL-12 induced restoration of the balance of the Th1/Th2 type immune response is an attractive strategy. In this study, the functional properties of the human bronchial epithelial cell line (BEAS-2B) transduced by an adenoviral vector encoding the human IL-12 gene were examined. Adenovirus vectors, AxCAegfp and Ax1CIhp40ip35 were transduced into BEAS -2B cells. Wild and gene-transduced BEAS -2B cells were incubated and the concentrations of IL-12and IFN-γ produced by co-cultured lymphocytes in the supernatant were measured using ELISA. The expressions of surface adhesion molecules, such as CD54 and CD106 were analyzed using flow cytometry. The efficiency of transgene expression of BEAS-2B cells was in a multiplicity of infection(MOI)-dependent manner and at an MOI of 30, the efficiency was approximately 80%. The gene-modified BEAS-2B cells produced biologically active IL-12 in dose - and time-dependent manners. IL-12 gene transduction did not significantly affect the expression of adhesion molecules (CD 54, CD106 and HLA-A,B,C) by BEAS-2B cells. These results suggest that the IL-12 gene may be successfully transduced into human bronchial epithelial cells by adenoviral vector to express IL-12 activity in vivo