Kumiya Sugiyama

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.

FceRI-mediated thymic stromal lymphopoietin production by interleukin-4- primed human mast cells

A significant increase of mRNA expression of thymic stromal lymphopoietin (TSLP) has been reported in the bronchial mast cells (MCs) of asthmatic subjects; however, the mechanism underlying the upregulation of TSLP mRNA and protein remains unknown. FcϵRI-mediated activation of human MCs upregulated TSLP mRNA expression by 5.2±2.9-fold, while activation of the MCs using lipopolysaccharide and polyriboinosinic:polyribocytidylic acid failed to upregulate TSLP. Stimulation of MCs with interleukin (IL)-4 alone did not affect the TSLP mRNA expression, while pre-incubation of MCs with IL-4 for 48 h significantly enhanced the FcϵRI-mediated TSLP mRNA expression (by 53.7±15.9-fold; p<0.05) and the amount of TSLP in the cell pellets increased significantly from 23.4±4.3 pg·mL−1 to 121.5±3.7 pg·mL−1 (p<0.0001). However, the released TSLP was rapidly degraded by proteases that were released by MCs. We identified the population of cells expressing TSLP in the lungs of 16 asthmatic and 11 control subjects by immunohistochemistry. The percentage of TSLP-positive MCs in the total population of MCs was significantly increased in asthmatic airways (p<0.0001). Thus, MCs are able to store TSLP intracellularly and to produce TSLP following aggregation of FcϵRI in the presence of IL-4.

Effects of aging on surfactant forms in rats

Surfactant present in the alveolar space exists in two major forms: functional large aggregate forms (LA) and nonfunctional small aggregate forms (SA), but there is no information about the changes of surfactant forms and the rate of conversion of LA to SA in the aged lungs. The purpose of the present study was to investigate the developmental aspects of surfactant forms in newborn, young, middle-aged and aged rats, LA and SA were recovered from alveolar lavages of rats. The rate of conversion from LA to SA was then analysed using a surface-area cycling technique. Age-related changes of saturated phosphatidylcholine (Sat-PC) and surfactant protein A (SP-A) pool sizes were also evaluated in alveolar lavages. The alveolar lavages recovered from aged rats contained a significantly higher proportion of LA than did those obtained from young or newborn rats. There was also an age-related decrease in the rate of conversion from LA to SA in vitro. The Sat-PC pool sizes in the alveolar lavages decreased with age, but the SP-A contents were similar between young and aged rats. These results suggested that decreased form conversion may contribute to maintaining functional surfactant pool sizes in the lungs of aged rats.

Over-expression of the LTC4 synthase gene in mice reproduces human aspirin-induced asthma.

Background The pathogenesis of aspirin‐induced asthma (AIA) is presumed to involve the aspirin/non‐steroidal anti‐inflammatory drug (NSAID)‐induced abnormal metabolism of arachidonic acid, resulting in an increase in 5‐lipoxygenase (5‐LO) metabolites, particularly leukotriene C4 (LTC4). However, the role of LTC4 in the development of AIA has yet to be conclusively demonstrated.

Interleukin-10 Regulates Transforming Growth Factor-β Signaling in Cultured Human Bronchial Epithelial Cells

Background: The basic pathological features of bronchial asthma can be explained on the basis of chronic airway inflammation, involving inflammatory cells such as T cells (particularly type 2 helper T, Th2, cells) and mast cells, and airway remodeling. Many aspects of airway remodeling remain unclear at the molecular level. Recent attention has focused on the role of transforming growth factor (TGF)-β, a fibrogenic cytokine, in airway remodeling. Currently available evidence suggests that airway remodeling is caused by an imbalance in regulatory mechanisms mediated by Smads, a family of signal-transducing molecules. Objectives: We studied the effects of the Th2 cytokines interleukin (IL)-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the regulatory cytokine IL-10 on the expression of inhibitory Smad7 protein in bronchial epithelial cells. Methods: Real-time reverse-transcriptase polymerase chain reaction was employed. Results: Stimulation with IL-10 upregulated the expression of Smad7 compared with control. Neither IL-5 nor GM-CSF induced Smad7 expression. Smad7 expression was upregulated by IL-10 plus either IL-5 or GM-CSF. IL-10 inhibited the expression of TGF-β-inducible early gene, which is known to downregulate Smad7 expression. Conclusions: Our results suggest that IL-10 acts as a regulatory cytokine in the inhibition of airway inflammation.

Measurement of Hymenoptera venom specific IgE by the IMMULITE 3gAllergy in subjects with negative or positive results by ImmunoCAP

Background Patients may receive negative results from a specific IgE (sIgE) test such as the ImmunoCAP (CAP) despite a documented history of systemic reaction to a Hymenoptera sting. Thus, further testing may be required using another serological method or venom skin prick tests to confirm allergy diagnosis and correct species. Objective To evaluate the sensitivity and the specificity of CAP and IMMULITE 3gAllergy (IMMULITE) for detecting sIgE to Paper wasp (WA) and Yellow Jacket (YJ) venoms using patient clinical history as the comparator. Methods Sera from 70 participants with a history of systemic reactions (SR) to WA and/or YJ stings were tested using CAP and IMMULITE. Fifty participants from this group had negative results on CAP. To assess specificity, sera from 71 participants who had never experienced either a WA or YJ sting were tested using CAP and IMMULITE. Fifty participants from this group tested positive using CAP. Results In participants with a history of systemic reaction to a Hymenoptera sting, yet who tested negative for WA and/or YJ sIgE according to CAP, the positivity rate according to IMMULITE was 20-42% using 0.10 IUA/mL as the limit of detection (LoD), per the manufacturers specification. When the LoD for CAP (0.35 IUA/mL) was applied to the IMMULITE results, positivity according to IMMULITE was 14-26%. Overall, sensitivity, specificity, and agreement with SR were greater for IMMULITE than for CAP. For YJ: sensitivity (IMMULITE:CAP), 42.8%:28.5%; specificity, 53.5%:39.4%; agreement, 48.2%:34%. For WA, sensitivity (IMMULITE:CAP), 58.6%:28.5%; specificity, 49.3%:47.8%; agreement, 43.9%:38.3%. Conclusion The IMMULITE performed well for detecting sIgE to Hymenoptera venom

Three Japanese patients (Mother and Two Children) with familial Mediterranean fever associated with compound heterozygosity for L110P/E148Q/M694I and an autosomal true dominant inheritance pattern

Familial Mediterranean fever (FMF) is characterized by repeated episodes of fever, peritonitis, pleuritis, and synovitis. We describe here 3 Japanese patients (a mother and 2 children) in whom FMF was diagnosed on analysis of MEFV. A 40-year-old woman presented with fever and abdominal pain. The patient had had these symptoms on and off since childhood and consulted many hospitals. A 38-year-old man had abdominal pain and fever since the age of 30 years. A 59-year-old woman had had episodes of fever, abdominal pain, and chest pain for more than 20 years. MEFV gene analysis showed compound heterozygosity for L110P, E148Q, and M694I in all three patients. In Japanese patients with FMF, this mode of autosomal true dominant inheritance has not yet been reported. FMF is difficult to diagnose unless it is included in the differential diagnosis by physicians. We hope that our valuable experience will promote increased awareness and understanding of FMF.

Anaphylaxis due to caffeine.

We report a rare case of anaphylaxis due to caffeine intake. A 27-year-old woman suffered her first episode of anaphylaxis and a positive skin prick test suggested that the anaphylaxis was due to an IgE-mediated hypersensitivity reaction to caffeine. She was diagnosed with caffeine allergy and has not had an allergic reaction after avoiding foods and drinks containing caffeine. Although caffeine is known to have antiallergic effects, this case shows that caffeine can be an allergen and cause anaphylaxis.

Epidemiologic Investigation of Hornet and Paper Wasp Stings in Forest Workers and Electrical Facility Field Workers in Japan

BACKGROUND Forestry and field workers who work outdoors are at high risk for Hymenoptera stings and may develop occupation-related allergies from being stung. However, clinical and immunological surveys of Hymenoptera stings in the occupational setting have rarely been reported. We surveyed the natural history of Hymenoptera stings in Japanese forestry workers (FWs) and electrical facility field workers (EFFWs), and we assessed the utility of measuring specific (s)IgE Ab to Hymenptera venom. METHODS Questionnaires on hornet and paper wasp stings were completed by 999 FWs, 354 EFFWs, and 365 office workers as controls between July and November 2009. Sera from these participants were tested for sIgE Ab levels to Hymenptera venom with a CAP system using a fluoroenzyme immunoassay. RESULTS Of the participants who had experienced Hymenoptera stings, 914 (91.5%) were FWs, 293 (82.8%) were EFFWs, and 295 (80.8%) were controls. Of the participants who had experienced systemic reactions, 210 (21.0%) were FWs, 51 (14.4%) were EFFWs, and 39 (10.7%) were controls. sIgE Ab in response to hornet and wasp venom was positive (≥ class 2) in 42.4% and 41.4% of FWs, 30.1% and 31.4% of EFFWs, and 15.1% and 18.1% of controls, respectively. The likelihood of being sIgE-positive to wasp and hornet venom was significantly higher in FWs and EFFWs than in controls (P < 0.05). CONCLUSIONS 21% of FWs and 14% of EFFWs had experienced systemic reactions to Hymenoptera stings with a higher frequency compared with office workers in the same area. 40% of FWs and 30% of EFFWs had sera that were sIgE positive to Hymenoptera venom.BACKGROUND Forestry and field workers who work outdoors are at high risk for Hymenoptera stings and may develop occupation-related allergies from being stung. However, clinical and immunological surveys of Hymenoptera stings in the occupational setting have rarely been reported. We surveyed the natural history of Hymenoptera stings in Japanese forestry workers (FWs) and electrical facility field workers (EFFWs), and we assessed the utility of measuring specific (s)IgE Ab to Hymenptera venom. METHODS Questionnaires on hornet and paper wasp stings were completed by 999 FWs, 354 EFFWs, and 365 office workers as controls between July and November 2009. Sera from these participants were tested for sIgE Ab levels to Hymenptera venom with a CAP system using a fluoroenzyme immunoassay. RESULTS Of the participants who had experienced Hymenoptera stings, 914 (91.5%) were FWs, 293 (82.8%) were EFFWs, and 295 (80.8%) were controls. Of the participants who had experienced systemic reactions, 210 (21.0%) were FWs, 51 (14.4%) were EFFWs, and 39 (10.7%) were controls. sIgE Ab in response to hornet and wasp venom was positive (≥ class 2) in 42.4% and 41.4% of FWs, 30.1% and 31.4% of EFFWs, and 15.1% and 18.1% of controls, respectively. The likelihood of being sIgE-positive to wasp and hornet venom was significantly higher in FWs and EFFWs than in controls (P < 0.05). CONCLUSIONS 21% of FWs and 14% of EFFWs had experienced systemic reactions to Hymenoptera stings with a higher frequency compared with office workers in the same area. 40% of FWs and 30% of EFFWs had sera that were sIgE positive to Hymenoptera venom.

Leukotriene C4 aggravates bleomycin-induced pulmonary fibrosis in mice.

Synthesis of cysteinyl leukotrienes (cys‐LT) is thought to cause inflammatory disorders such as bronchial asthma and allergic rhinitis. Recent reports have suggested that leukotriene C4 (LTC4) is an important regulator of pulmonary fibrosis. This study examined the effect of LTC4 in LTC4 synthase‐overexpressed transgenic mice with bleomycin‐induced pulmonary fibrosis. The function of lung‐derived fibroblasts from transgenic mice was also investigated.