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Background: Asthma often coexists with chronic rhinosinusitis (CRS). Recent studies revealed that sinus inflammation in asthmatic patients was related to eosinophilic inflammation. However, the relationship between the severity of CRS and four different sputum inflammatory phenotypes as defined by the proportion of eosinophils and neutrophils is unknown. The aim of this study was to examine the impact of the severity of CRS on lower airway and systemic inflammation in asthmatic patients. Methods: We enrolled 57 adult asthmatic patients who underwent sinus computed tomography (CT). The severity of CRS was evaluated by the Lund-Mackay score (LMS). The induced sputum inflammatory phenotype was defined by eosinophils (≥/

Background: Several cross-sectional studies have suggested an association between obesity and asthma. However, few studies have investigated this relationship longitudinally, especially in middle-aged subjects. Although metabolic syndrome is a well-known risk factor for many non-communicable diseases, its contribution to asthma remains controversial. Methods: From 2008, specific health checkups for metabolic syndrome have been conducted throughout Japan. To seek relationships of obesity and metabolic syndrome with late-onset asthma in Japan, we analyzed data collected from health insurance claims and specific health checkups for metabolic syndrome at three large health insurance societies. Among subjects aged 40–64 years (n = 9888), multivariate logistic regression analyses were performed to investigate the relationships of obesity and metabolic syndrome in fiscal year 2012 (from April 2012 to March 2013) with the incidence of late-onset asthma in the following two years (from April 2013 to March 2015). Results: In women, BMI 25–29.9 kg/m2 or ≥30 kg/m2, waist circumference ≥90 cm, and waist-to-height ratio ≥0.5 were shown to be significant risk factors for asthma, with adjusted odds ratios (95% CI) of 1.92 (1.35–2.75), 2.24 (1.23–4.09), 1.89 (1.30–2.75), and 1.53 (1.15–2.03), respectively. Significance was retained even after adjustment for metabolic syndrome, and there were no significant relationships between metabolic syndrome itself and the incidence of asthma in men or women. Conclusions: Only the obesity measures, not metabolic syndrome, were shown to be significant risk factors for the incidence of late-onset asthma but only in middle-aged Japanese women, and not in men. Keywords: Health insurance claims, Late-onset asthma, Metabolic syndrome, Obesity, Specific health checkups

Background: The correlation between inflammatory cells and airway smooth muscle plays fundamental roles in the pathophysiology of asthma. This study was designed to determine whether pre-exposure of airway smooth muscle to sphingosine-1-phosphate (S1P), which is released from mast cells by allergic reactions, causes a deterioration of β-adrenoceptor function. Methods: Isometric tension and the ratio of fluorescence intensities at 340 and 380 nm (F340/F380), an indicator of intracellular Ca2+ levels, were simultaneously measured using fura-2 loaded guinea-pig tracheal tissues. Intracellular cAMP levels were also measured. Results: Pre-exposure to S1P caused a reduction in the inhibitory effects of 0.3 μM isoprenaline, a β-adrenoceptor agonist, and 10 μM forskolin, a direct activator of adenylyl cyclase, against 1 μM methacholine-induced contraction in concentration- and time- dependent manners. In contrast, the values of F340/F380 were not augmented under this experimental condition. After incubation with S1P in the presence of 0.001-1 μM Y-27632, a Rho-kinase inhibitor, the reduced responsiveness to forskolin induced by S1P was reversed in a concentration-dependent manner. Moreover, pre-treatment with pertussis toxin (PTX), an inhibitor of Gi, suppressed the loss of forskolin-induced relaxation induced by S1P. Pre-exposure to S1P markedly inhibited the augmentation of cAMP accumulation induced by forskolin. However, addition of Y-27632 and pre-exposure to PTX returned forsokin-induced cAMP accumulation to the control level. Conclusions: Pre-exposure to S1P causes heterologus desensitization of β-adrenoceptors by increasing the sensitivity of airway smooth muscle to intracellular Ca2+. Ca2+ sensitization regulated by Gi and Rho-kinase is involved in this phenomenon.

Background: Sphingosine-1-phosphate (S1P), a lysophospholipid released from inflammatory cells, causes cell migration by increasing cytokines and chemokines. This study was designed to determine whether S1P causes adherence of eosinophils to pulmonary endothelial cells via enhancement of adhesion molecule expression. Methods: Expression of VCAM-1 and ICAM-1 was assessed by RT-PCR and Western blot analysis in human pulmonary microvasucular endothelial cells (HPMVECs). The number of adherent eosinophils to HPMVECs was calculated according to adhesion assay. Results: Pre-treatment of HPMVECs with S1P increased mRNA and protein expression of VCAM-1, in contrast, did not dramatically increase those expression of ICAM-1. The maximal expression of these adhesion molecules in mRNA and protein was observed 4 and 8 h after exposure to S1P, respectively. Pre-treatment with S1P also activated RhoA, a monomeric G protein; the ability of S1P to enhance the expression of VCAM-1 was attenuated by RhoA related inhibitors such as Y-27632, C3 exoenzyme, and GGTI-286. The effects of S1P on VCAM-1 were attenuated by pre-incubation with pertussis toxin, which catalyzes the ADP-ribosylation of Gi, a heterotrimeric G protein. After HPMVECs were treated with S1P, adhesion of human eosinophilic leukemic cell line (EoL-1) cells to HPMVECs was enhanced in a concentration-dependent manner. Augmented adherence of EoL-1 cells by S1P was also attenuated by Y-27632 and pertussis toxin. S1P causes adherence of eosinophils to pulmonary endothelium via RhoA activation. Conclusions: S1P may act as a lipid mediator in asthma. The RhoA/Rho-kinase pathway may be a therapeutic target for preventing eosinophil infiltration to the airway.

Background: Autoimmune pancreatitis is characterized by diffuse swelling of the pancreas and a high serum immunoglobulin (Ig) G4 concentration. Histopathologically, dense infiltration of lymphocytes and IgG4-positive plasma cells with fibrosis are seen in the pancreas. Although allergic diseases complicating autoimmune pancreatitis have been reported, the clinical features of bronchial asthma complicated by autoimmune pancreatitis remain unclear. Case Summary: We report three cases of bronchial asthma preceding the onset of type 1 autoimmune pancreatitis by 3 months to 30 years. All three cases were males with high serum IgG, IgG4, and IgE concentrations. The radioallergosorbent tests were positive for common allergens such as mites and house dust. One case had a pulmonary manifestation that proved to be an inflammatory pseudotumor of the lung with an accumulation of IgG4-positive plasma cells. The asthma symptom was ameliorated by oral prednisolone therapy for autoimmune pancreatitis, and when the corticosteroid doses were reduced, asthma became worse in all three cases. Discussion: It is possible that atopy and increased Th2 cell activity are related to a higher coincidence of IgG4-related diseases such as type 1 autoimmune pancreatitis. Because the present cases are few in number, further studies are necessary.