Hisato Hiranuma

Myeloid differentiation-2 is a potential biomarker for the amplification process of allergic airway sensitization in mice

BACKGROUND Allergic sensitization is a key step in the pathogenesis of asthma. However, little is known about the molecules that are critical regulators for establishing allergic sensitization of the airway. Thus, we conducted global gene expression profiling to identify candidate genes and signaling pathways involved in house dust mite (HDM)-induced allergic sensitization in the murine airway. METHODS We sensitized and challenged mice with HDM or saline as a control through the airway on days 1 and 8. We evaluated eosinophilia in bronchoalveolar lavage fluid (BALF), airway inflammation, and mucus production on days 7 and 14. We extracted total RNA from lung tissues of HDM- and saline-sensitized mice on days 7 and 14. Microarray analyses were performed to identify up-regulated genes in the lungs of HDM-sensitized mice compared to the control mice. Data analyses were performed using GeneSpring software and gene networks were generated using Ingenuity Pathways Analysis (IPA). RESULTS We identified 50 HDM-mediated, stepwise up-regulated genes in response to allergic sensitization and amplification of allergic airway inflammation. The highest expressed gene was myeloid differentiation-2 (MD-2), a lipopolysaccharide (LPS)-binding component of Toll-like receptor (TLR) 4 signaling complex. MD-2 protein was expressed in lung vascular endothelial cells and was increased in the serum of HDM-sensitized mice, but not in the control mice. CONCLUSIONS Our data suggest MD-2 is a critical regulator of the establishment of allergic airway sensitization to HDM in mice. Serum MD-2 may represent a potential biomarker for the amplification of allergic sensitization and allergic inflammation.

Utility of serum YKL-40 levels for identification of patients with asthma and COPD

Eosinophil (no.) 283.2 ± 23.6 309.2 ± 41.4 264.1 ± 26.2 248.1 ± 31.3 0.5119 (%) 4.55 ± 0.30 4.86 ± 0.49 4.57 ± 0.58 3.90 ± 0.39 0.4216 CRP (mg/dL) 0.40 ± 0.15 0.54 ± 0.28 0.18 ± 0.03 0.31 ± 0.09 0.5983 YKL40 (ng/ml) 125.3 ± 7.23 75.8 ± 7.68 157.4 ± 13.6 197.1 ± 13.1 <0.0001* (percentile) 65.4 ± 2.43 49.9 ± 3.26 79.4 ± 4.09 84.1 ± 3.42 <0.0001* log total IgE (IU/ml) 2.25 ± 0.06 2.28 ± 0.08 2.40 ± 0.10 2.04 ± 0.11 0.0680

Serum eosinophil-derived neurotoxin: Correlation with persistent airflow limitation in adults with house-dust mite allergic asthma.

BACKGROUND The serum level of eosinophil-derived neurotoxin (EDN), a protein present in eosinophil granules, correlates with the severity of childhood asthma. However, the relationship between the serum EDN level and the severity of adult asthma has not been sufficiently investigated. OBJECTIVE This study aimed to elucidate the correlation between the serum EDN level and markers of severity in adult asthma. METHODS The subjects comprised 83 adult patients who had asthma and who were undergoing treatment. Of these patients, 40 were positive for house-dust-specific immunoglobulin E (IgE) antibodies; 9 patients with severe adult asthma who were treated with omalizumab were included in the study. We measured the blood eosinophil count, serum EDN, and eosinophil cationic protein levels before investigating the correlations of these parameters with lung function and symptom score. RESULTS There were no significant correlations between the blood eosinophil count or serum EDN or eosinophil cationic protein level with lung function and the symptom score in patients with asthma. However, serum EDN level was inversely correlated with the decrease percentage forced expiratory volume in 1 second (%FEV1) in patients positive for house-dust-specific IgE antibody (R = -0.54; p < 0.05), whereas no such correlation was observed in patients with negative results for house-dust-specific IgE antibody (R = 0.11; p = 0.468). A significant correlation was observed between a decrease in serum EDN level from baseline and lung function improvement after 8 weeks of omalizumab therapy (R = -0.77; p = 0.015). CONCLUSION Serum EDN level may be a useful marker for monitoring persistent airflow limitation in adult patients with asthma who had positive results for house-dust-specific IgE antibodies.

Serum free IgE guided dose reduction of omalizumab: a case report

BackgroundOmalizumab is a human IgG1 antibody against IgE used as a therapy for sever asthmatic patients with asthma. According to the guidelines of the Global Initiative for Asthma, omalizumab is an add-on drug at treatment step 5 that is used for severe asthma patients who are allergic to perennial allergens. The effects of omalizumab for severe asthma therapy have been validated in multiple clinical studies. However, the long-term effects of omalizumab on IgE production and possibility of resetting of administration dose of omalizumab remain unknown.Case PresentationThe serum total and free IgE levels were measured over time in a 63-year-old female patient with allergic asthma who was administered 375 mg omalizumab biweekly for 36 months. Her symptoms did not worsen and clinical course remained favorable after reducing the dose to 375 mg per month. The serum free IgE levels temporarily increased following a dose reduction of omalizumab. The serum free IgE trough level temporarily increased at 4 weeks after capable to reduce the dosage; however, thereafter, the serum free IgE level decreased to desired levels (below 30 ng/mL).ConclusionsThe present case shows the possibility of reducing the dose following the long-term use of omalizumab. Considering the high medical cost of omalizumab, the dose reduction may be a viable option. It may be useful to measure the serum free IgE level to appropriately identify patients in whom the dose can be reduced, and to carefully monitor the clinical course.

Long-term course of serum total and free IgE levels in severe asthma patients treated with omalizumab

Omalizumab, a human immunoglobulin G1 antibody to immunoglobulin E (IgE), is an antibody drug indicated for the treatment of asthma. It can improve symptoms in patients with intractable atopic asthma and reduce the risk of exacerbation and is one of the few drugs that improve the quality of life of patients. As omalizumab improves airway inflammation and causes IgE level depression, there is a possibility that IgE production levels will be reduced after long-term omalizumab administration. The reduction in IgE production in such patients would be advantageous for the management of atopic asthma. However, not enough research has been conducted on the long-term effects of omalizumab administration on IgE production. In general, serum total IgE revels are believed to reflect IgE production levels in the body. However, the traditional methods of measuring IgE levels, such as the ImmunoCAPmethod for measurement of total serum IgE (Thermo Fisher Scientific, Waltham, MA, USA), cannot distinguish between omalizumab-binding IgE and free IgE. Hence, these methods cannot evaluate IgE production levels in omalizumab-administered patients. On the other hand, it is conceivable that serum free IgE levels are associated with IgE production levels in omalizumab-administered patients. Using a mathematical model, Lowe et al. simulated changes in total blood IgE after several years of continued treatment with omalizumab, based on data on total blood IgE from 10 clinical trials, and predicted that total blood IgE levels would gradually decline with the long-term use of omalizumab. They further predicted that this long-term decline in IgE level would be more marked as the duration of omalizumab treatment extended.1 However, this was merely a prediction based on a mathematical model. At present, several methods are available for measuring free IgE after omalizumab administration.2,3 No reports have actually directly measured changes in serum free IgE levels as an indicator of IgE production during long-term omalizumab treatment. As we previously reported, the method that we established involves measuring IgE by Enzyme-Linked ImmunoSorbent Assay (ELISA) using antibodies refined from human FcεRI recombinant proteins.4 In our previous report, we showed the term course of serum free IgE levels at baseline and at 4 weeks in four cases.4 In the short term, two cases of them did not reach the target concentration of free IgE (below 25 ng/ml). Here we presented data from 8 patients in whomwe measured fluctuations in total serum IgE and

Evaluation of airway resistance in primary small cell carcinoma of the trachea by MostGraph: a case study

The case subject was a 58-year-old woman who presented to our hospital with a chief complaint of respiratory discomfort. Wheezing could be heard in both lungs; treatment was initiated with inhaled steroids for suspected bronchial asthma. However, 1 week later, the respiratory discomfort had not improved and the wheezing sound had progressed to the neck area. Upper airway obstruction was suspected; therefore, chest computed tomography (CT) was performed, revealing tracheal stenosis caused by a tumor in the upper airway. Because of the high risk of airway obstruction, tracheotomy and tracheal tumor resection were performed. Histopathological examination of the resected tumor revealed small cell lung cancer (SCLC); the stage was determined to be clinical stage IIIB (cT4N2M0), for which chemotherapy with two cycles of cisplatin plus etoposide followed by radiation therapy were administered. Pulmonary function testing revealed no change in the forced expiratory volume in 1 sec and flow volume (FV) curve before and after tumor resection, whereas airway resistance measured by MostGraph-01 showed a marked decrease following treatment. We believe that MostGraph-01 may be useful for measuring airway resistance and evaluating a tracheal tumor, and report a case using MostGraph-01.