Asthma exacerbations in patients with asthma and rhinitis: Factors associated with asthma exacerbation and its effect on QOL in patients with asthma and rhinitis.

BACKGROUND: The comorbidity of asthma and allergic rhinitis is remarkably high, but not much is known about the effects of this combined condition on the quality of life. We aimed to evaluate the factors associated with asthma exacerbations and the effect of the exacerbations on the quality of life (QOL) through a one-year, large-scale, observational study in Japanese patients with asthma and rhinitis. METHODS: A case survey by attending physicians and a patient survey was conducted at each assessment timepoint over a period of one year. Patients were divided into two groups according to the presence or absence of asthmatic attacks after enrollment and were matched using propensity scores to evaluate the factors associated with asthma exacerbations and the effect of the exacerbation on QOL. RESULTS: Potential factors associated with asthma exacerbations included high body mass index value, low forced expiratory flow 75% of forced vital capacity (FEF75%), severe rhinitis as determined based on ARIA (Allergic Rhinitis and its Impact on Asthma). Although patients with asthma exacerbations had significantly impaired quality of life at baseline as evidenced by the economic aspects, in addition to physical, mental, and social activities, no further reduction with the attacks was observed. CONCLUSIONS: This study suggested that higher body mass index (BMI) and severe asthma as well as severe rhinitis were factors associated with asthma exacerbations. Although patients with asthma exacerbations had impaired QOL, attacks caused no further reduction.

ICAM-1 upregulation is not required for retinoic acid-induced human eosinophil survival.

Active metabolites of vitamin A, retinoic acids (RAs), are known to play critical roles in mucosal immune responses and dramatically inhibit human eosinophil apoptosis, but the detailed mechanisms have not been elucidated. We previously screened for ICAM-1 (CD54) upregulation in RA-stimulated human eosinophils by gene microarray analysis. As ICAM-1 induction and activation were observed to have a role in maintenance of eosinophil survival, we tested the hypothesis that RAs prolong eosinophil survival through ICAM-1 outside-in signaling. Blood-derived isolated eosinophils cultured with 9-cis RA and all-trans RA showed significant upregulation of ICAM-1 mRNA and cell surface expression. TTNPB, a retinoic acid receptor agonist, also induced ICAM-1 expression, while HX630, a retinoid X receptor agonist, did not. Furthermore, an RAR antagonist, HX531, completely inhibited the effect of RAs. Upregulated ICAM-1 was associated with altered kinetics of Akt, ERK, and p38 MAP kinase phosphorylation through ICAM-1 cross-linking, but an ICAM-1-blocking antibody did not affect RA-mediated cell survival. These findings indicate that RAs induce functional ICAM-1 expression through RARs, but the induced ICAM-1 does not contribute to prolongation of eosinophil survival.

G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10.

Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ERαß), G-protein-coupled estrogen receptor (GPER) was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA-sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13) in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3+CD4+ regulatory T cells and IL-10-producing GPER+CD4+ T cells was significantly increased in G-1-treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.

Expression and functional roles of G-protein-coupled estrogen receptor (GPER) in human eosinophils.

Sexual dimorphism in asthma links the estrogen and allergic immune responses. The function of estrogen was classically believed to be mediated through its nuclear receptors, i.e., estrogen receptors (ERs). However, recent studies established the important roles of G-protein-coupled estrogen receptor (GPER/GPR30) as a novel membrane receptor for estrogen. To date, the role of GPER in allergic inflammation is poorly understood. The purpose of this study was to examine whether GPER might affect the functions of eosinophils, which play an important role in the pathogenesis of asthma. Here, we demonstrated that GPER was expressed in purified human peripheral blood eosinophils both at the mRNA and protein levels. Although GPER agonist G-1 did not induce eosinophil chemotaxis or chemokinesis, preincubation with G-1 enhanced eotaxin (CCL11)-directed eosinophil chemotaxis. G-1 inhibited eosinophil spontaneous apoptosis and caspase-3 activities. The anti-apoptotic effect was not affected by the cAMP-phospodiesterase inhibitor rolipram or phosphoinositide 3-kinase inhibitors. In contrast to resting eosinophils, G-1 induced apoptosis and increased caspase-3 activities when eosinophils were co-stimulated with IL-5. No effect of G-1 was observed on eosinophil degranulation in terms of release of eosinophil-derived neurotoxin (EDN). The current study indicates the functional capacities of GPER on human eosinophils and also provides the previously unrecognized mechanisms of interaction between estrogen and allergic inflammation.

The effect of pharmacological PI3Kγ inhibitor on eotaxin-induced human eosinophil functions.

BACKGROUND: Asthma is characterized by chronic inflammation caused by activation of immune cells including Th2 lymphocytes and eosinophils. Phosphoinositide 3-kinase (PI3K) γ deficient asthmatic mice did not develop lung eosinophilia, although the detailed mechanisms are not well known. A CC chemokine eotaxin (CCL11) plays a prominent role in developing eosinophilic inflammation through CCR3. In this study, we tested the roles of PI3Kγ in eotaxin-induced eosinophil functions using a pharmacological inhibitor. METHOD: Human peripheral blood eosinophils were isolated by CD16-negative selection method. The effect of AS605240, synthetic PI3Kγ inhibitor on eotaxin-induced adhesion, chemotaxis, and degranulation were studied using intracellular adhesion molecule-1 (ICAM-1)-coated plates, Boyden chamber system, ELISA for eosinophil-derived neurotoxin (EDN) levels in the culture supernatant, respectively. CCR3 expression levels and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were assessed by flowcytometry. Involvement of PI3Kγ in spontaneous apoptosis was studied using flowcytometry. RESULTS: Although AS605240 did not affect the eosinophil spontaneous apoptosis, eotaxin-induced chemotaxis, adhesion to ICAM-1 coated plate, and EDN release were inhibited by AS605240. AS605240 also inhibited the eotaxin-induced ERK1/2 phosphorylation without down-regulation of surface CCR3 expression. CONCLUSION: These results indicate that PI3Kγ inhibitor attenuates eotaxin-induced eosinophil functions by suppressing the downstream signaling of CCR3 without significant cytotoxicity. PI3Kγ plays an important role in the development of eosinophilic inflammation and blockade of PI3Kγ might be a therapeutic strategy for treatment of eosinophil-related diseases including asthma.

Adiponectin attenuates human eosinophil adhesion and chemotaxis: implications in allergic inflammation.

OBJECTIVE: Growing evidence has shown an association between obesity and asthma. Adiponectin, an adipocyte-derived cytokine, is known to have anti-inflammatory effects with reduced concentrations in obese subjects. Recent findings raised the intriguing possibility that adiponectin might play a role in allergic inflammation, although the mechanistic basis for their relationship remains unclear. The purpose of this study was to examine whether adiponectin might affect functions of eosinophils, which play an important role in the pathogenesis of asthma. METHODS: Human peripheral blood eosinophils were purified to study expression of adiponectin receptors AdipoR1 and AdipoR2 using RT-PCR and flow cytometry. The effect of adiponectin on eosinophil survival was investigated using annexin V and propidium iodide staining. Eotaxin-induced cell adhesion was investigated using ICAM-1-coated plates. A Boyden chamber and real-time horizontal migration system were used for eotaxin-directed chemotaxis assay. Expression of eotaxin receptor CCR3 and intracellular calcium influx were assessed by flow cytometry. RESULTS: AdipoR1 and AdipoR2 were expressed in human eosinophils. Adiponectin did not affect eosinophil survival or CCR3 expression; however, eotaxin-enhanced adhesion was inhibited by pretreatment with adiponectin. Adiponectin also diminished eotaxin-directed chemotactic responses by disturbing both velocity and directionality. Calcium influx in response to eotaxin was attenuated by adiponectin. CONCLUSIONS: These results indicate that adiponectin attenuates the eosinophil functions induced by eotaxin without affecting cell viability. The inhibitory effect was associated with diminished calcium signaling rather than altering of surface receptor expression. Increasing circulating adiponectin might be a novel therapeutic modality for treatment of asthma, especially in obese asthmatics.

Gender difference in allergic airway remodelling and immunoglobulin production in mouse model of asthma.

BACKGROUND AND OBJECTIVE: Epidemiological studies have shown that the prevalence of adult asthma and severe asthma is higher in women. It has also been reported that female mice are more susceptible than males to the development of allergic airway inflammation and airway hyperresponsiveness (AHR). The influence of gender difference in the pathogenesis of severe asthma, especially airway remodelling in an animal model, has been studied rarely. We investigated gender difference in the development of airway remodelling using a long-term antigen-challenged mouse 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 differences in AHR, airway inflammation and airway remodelling between the sexes were investigated. RESULTS: In OVA-sensitized and OVA-challenged (OVA/OVA) female mice, eosinophils, lymphocytes, T-helper type 2 cytokines and growth factors in bronchoalveolar lavage fluid were increased compared with OVA/OVA male mice. Histological features of airway remodelling were also increased in OVA/OVA female mice. Serum total and OVA-specific immunoglobulin E (IgE) and serum IgA were significantly elevated in OVA/OVA female mice. CONCLUSIONS: These results indicate that female mice experience more airway remodelling compared with male mice. These results suggest the involvement of sex hormones and gender differences in cellular functions in airway remodelling.

Lung metastasis from perineal leiomyosarcoma: a case report and a review of the Japanese literature.

Pulmonary metastasis from leiomyosarcoma is rare and its clinical management is challenging. A single lung metastasis from a perineal leiomyosarcoma occurred in a 79-year-old woman. Five months after resection of the lung metastasis, a new metastatic tumor developed in the contralateral lung. Since the patient did not desire to receive hospitalized treatment, TS-1 (an oral agent consisting of a combination of tegafur, gimeracil, and oteracil potassium) therapy was started on an outpatient basis. The lung metastasis has been successfully controlled for at least 17 months with excellent tolerability. The clinical features and the treatment of this case are discussed.

Obesity and eosinophilic inflammation: does leptin play a role.

It has been pointed out that obesity is a risk factor for, and is involved in the exacerbation of asthma. Mounting evidence about adipose tissue-derived proteins (adipokines) gave rise to the current understanding of obesity as a systemic inflammatory disorder. In this review, we summarized the involvement of leptin, focusing on eosinophil functions. Several studies have indicated that leptin can restrain eosinophil apoptosis, enhance migration, increase adhesion molecules and induce cytokine production. Since leptin also acts on a variety of immune cells related to allergic response, increased leptin in obese individuals potentially explains the mechanism by which obesity leads to an exacerbation of asthma. Further studies targeting adipokines will delineate the association between obesity and eosinophil-associated diseases.

Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD.

The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

Docosahexaenoic acid exerts anti-inflammatory action on human eosinophils through peroxisome proliferator-activated receptor-independent mechanisms.

BACKGROUND: Despite the fact that previous studies have indicated the significant roles of polyunsaturated fatty acids (PUFAs) in the immune system through peroxisome proliferator-activated receptor alpha (PPARα) and PPARγ, the biological functions and the mechanisms of action in eosinophils are poorly understood. METHODS: We investigated the functional effects of docosahexaenoic acid (DHA, n-3 PUFA) on human peripheral blood eosinophils, using in vitro systems to test the hypothesis that DHA negatively regulates eosinophil mechanisms through PPARα and PPARγ. RESULTS: Eosinophil apoptosis that spontaneously occurs under normal culture conditions was accelerated in the presence of DHA. In addition, eotaxin-directed eosinophil chemotactic responses were inhibited by pretreatment with DHA, disturbing both the velocity and the directionality of the cell movement. Pharmacological manipulations with specific antagonists indicated that the effects of DHA were not mediated through PPARα and PPARγ, despite the presence of these nuclear receptors. DHA also induced Fas receptor expression and caspase-3 activation that appears to be associated with a proapoptotic effect of DHA. Further, DHA rapidly inhibited the expression of eotaxin receptor C-C chemokine receptor 3 and eotaxin-induced calcium influx and phosphorylation of extracellular signal-regulated kinase. Interestingly, these inhibitory effects were not observed with linoleic acid (n-6 PUFA). CONCLUSIONS: The data might explain one of the mechanisms found in previous research showing the favorable effects of n-3 PUFA supplementation on allergic diseases, and provide novel therapeutic strategies to treat eosinophilic disorders.

Detection of Mycobacterium abscessus from blood cultures during treatment of interstitial pneumonia: a case study.

A 76-year-old male diagnosed with interstitial pneumonia in December 2002 was treated with a steroid in a nearby hospital. Exacerbation of infectious pneumonitis and interstitial pneumonia required complementary inpatient treatment in August 2007. Although polymerase chain reaction examination of expectorated sputa revealed the absence of Mycobacterium tuberculosis, M. avium, and M. intracellulare on admission, nontuberculous M. abscessus was detected in the routine blood cultures. Taken together with clinical findings, M. abscessus was most likely the primary causative organism. Diagnosis of mycobaterium-induced septicemia generally involves the use of mycobacterium-designated bottles, MGIT method, and Ogawa medium; however, we used microbe cultures with routine blood-culture bottles in the present case. Of the 24 mycobacterium-induced septicemia cases reported in the past 10 years, only eight cases were detected from routine blood-culture bottles; they were all rapidly growing bacteria. Mycobacteria other than the rapidly growing mycobacteria display delayed culture proliferation, therefore it is possible that non-detected microbes were probably present in the patients despite the fact that they were suffering from septicemia. In cases suspected to have severe infections, particularly those with a depressed immunodefense system, blood-culture testing for mycobacteria would be highly helpful for diagnosis.

The opposing role of two prostaglandin D2 receptors, DP and CRTH2, in human eosinophil migration.

BACKGROUND: Prostaglandin D2 (PGD2) regulates various immunological responses via two distinct PGD2 receptors, prostaglandin D receptor (DP), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Recent studies have demonstrated that PGD2 induces the migration of eosinophils through CRTH2. Although human eosinophils express both DP and CRTH2, it is unclear whether the function of DP is involved in eosinophil migration. OBJECTIVE: In this study, we investigated the roles of DP and CRTH2 in eosinophil migration by using selective agonists and antagonists. METHODS: Eosinophils were isolated from human subjects with mild eosinophilia by modified CD16-negative selection. After stimulation with or without DP receptor agonist, eosinophil migration was measured by Boyden chamber. The effect of DP agonists on CRTH2-induced eosinophil migration was studied in terms of CRTH2 expression, Ca2+ mobilization, ERK/MAPK phosphorylation, and cyclic AMP (cAMP) production. RESULTS: Treatment with DP agonists inhibited CRTH2-induced chemotaxis of eosinophils. Furthermore, we showed that DP agonists enhanced cAMP production in CRTH2 agonist stimulation without increasing CRTH2 expression. DP mediates eosinophils through the elevation of intracellular cAMP production but does not change CRTH2 expression. CONCLUSION: Taken together, the balance between DP and CRTH2 could influence the degree of PGD2-induced eosinophil migration and DP agonist might regulate eosinophil activation.

[Development of a microbiology data warehouse (Akita-ReNICS) for networking hospitals in a medical region].

The active involvement of hospital laboratory in surveillance is crucial to the success of nosocomial infection control. The recent dramatic increase of antimicrobial-resistant organisms and their spread into the community suggest that the infection control strategy of independent medical institutions is insufficient. To share the clinical data and surveillance in our local medical region, we developed a microbiology data warehouse for networking hospital laboratories in Akita prefecture. This system, named Akita-ReNICS, is an easy-to-use information management system designed to compare, track, and report the occurrence of antimicrobial-resistant organisms. Participating laboratories routinely transfer their coded and formatted microbiology data to ReNICS server located at Akita University Hospital from their health care system's clinical computer applications over the internet. We established the system to automate the statistical processes, so that the participants can access the server to monitor graphical data in the manner they prefer, using their own computer's browser. Furthermore, our system also provides the documents server, microbiology and antimicrobiotic database, and space for long-term storage of microbiological samples. Akita-ReNICS could be a next generation network for quality improvement of infection control.

Peroxisome proliferator-activated receptor-γ is expressed in eosinophils in nasal polyps.

BACKGROUND: Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptors, which regulate fatty acid metabolites. One of the natural ligands for PPARγ is 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), a major metabolite of prostaglandin D(2) (PGD(2)). Recently, PPARγ has been shown to play an important role in anti-inflammatory reactions, including within-airway allergic diseases, in a mouse model. Our aim was to clarify the expression and localization of PPARγ and PGD(2) synthase, which produces ligands of PPARγ, in nasal polyps by immunohistochemical analysis. METHODS: Nasal polyps of chronic rhinosinusitis patients (6 asthmatic patients and 6 nonasthmatic patients) were obtained during surgery. May-Grünwald-Giemsa staining was performed to evaluate the eosinophil infiltration of the polyps. To identify the cells expressing PPARγ protein and PGD(2) synthase, double immunostaining was performed using anti-PPARγ antibody, monoclonal antileukocyte antibodies, and PGD(2) synthase antibody. RESULTS: The number of eosinophils and the number of PPARγ-positive cells in the nasal polyps of the asthmatic patients were significantly higher than those in the nonasthmatic patients. PPARγ was expressed on eosinophils and T cells of the infiltrating cells in the nasal polyps. PGD(2) synthase was also expressed on PPARγ-positive cells. CONCLUSION: PPARγ is involved in nasal polyposis pathogenesis, acting on eosinophils and T cells.

Thioredoxin in allergic inflammation.

Thioredoxin (TRX) is a redox-active protein that regulates reactive oxidative metabolism and plays a crucial role in the antioxidant system in regulating the reduction/oxidation balance by scavenging reactive oxygen species, which is implicated in the mechanism of asthma. As for the mechanisms by which TRX exerts its beneficial effects, some studies have shown that TRX suppresses allergic inflammation in animal models of asthma. Recently, we reported that TRX directly modulated the chemotaxis of eosinophils, which have been shown to play a pivotal role in the mechanism of allergic airway inflammation, in the absence of T helper (Th)1 or Th2 cytokines. Further, serum TRX levels in patients with asthma were significantly increased in patients with attacks compared with those in the asymptomatic period. This review focuses on TRX in allergic reactions and discusses the physiological role of TRX.