RESUMEN
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.
Asunto(s)
Asma/complicaciones , Asma/epidemiología , Calidad de Vida , Rinitis/complicaciones , Rinitis/epidemiología , Adulto , Anciano , Atención Ambulatoria , Asma/diagnóstico , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Rinitis/diagnósticoRESUMEN
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.
Asunto(s)
Quimiocina CCL11/metabolismo , Eosinófilos/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinoxalinas/farmacología , Tiazolidinedionas/farmacología , Quimiotaxis/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Neurotoxina Derivada del Eosinófilo/metabolismo , Eosinófilos/metabolismo , Citometría de Flujo , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , FosforilaciónRESUMEN
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.
Asunto(s)
Adiponectina/inmunología , Asma/inmunología , Adhesión Celular/inmunología , Quimiotaxis/inmunología , Eosinófilos/inmunología , Señalización del Calcio/inmunología , Supervivencia Celular/inmunología , Eosinófilos/citología , Citometría de Flujo , Humanos , Neutrófilos/inmunología , ARN/química , ARN/genética , Receptores de Adiponectina/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
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.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Asma/metabolismo , Asma/fisiopatología , Inmunoglobulina A/metabolismo , Inmunoglobulina E/metabolismo , Inmunoglobulina G/metabolismo , Factores Sexuales , Animales , Asma/inducido químicamente , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hormonas Esteroides Gonadales/fisiología , Inyecciones Intraperitoneales , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/administración & dosificación , Ovalbúmina/efectos adversosRESUMEN
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.
Asunto(s)
Eosinofilia/inmunología , Leptina/inmunología , Obesidad/inmunología , Tejido Adiposo/inmunología , Humanos , Inflamación/inmunología , Leptina/sangreRESUMEN
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.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Eosinófilos/efectos de los fármacos , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Apoptosis/efectos de los fármacos , Calcio , Caspasa 3/metabolismo , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Ácidos Docosahexaenoicos/antagonistas & inhibidores , Eosinofilia/sangre , Eosinófilos/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Ácido Linoleico/farmacología , Masculino , Fosforilación , Receptores CCR3/biosíntesis , Índice de Severidad de la Enfermedad , Receptor fas/biosíntesisRESUMEN
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.
Asunto(s)
Eosinófilos/metabolismo , Pólipos Nasales/patología , PPAR gamma/metabolismo , Asma/complicaciones , Asma/patología , Recuento de Células , Eosinófilos/patología , Humanos , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/metabolismo , Pólipos Nasales/etiología , Pólipos Nasales/metabolismo , Rinitis/complicaciones , Rinitis/patología , Sinusitis/complicaciones , Sinusitis/patología , Linfocitos T/metabolismoRESUMEN
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.
Asunto(s)
Hipersensibilidad/metabolismo , Tiorredoxinas/fisiología , Animales , Antioxidantes/farmacología , Antioxidantes/fisiología , Humanos , Inflamación/metabolismo , Tiorredoxinas/farmacologíaRESUMEN
BACKGROUND: Tissue eosinophilia is one of the hallmarks of allergic diseases and Th2-type immune responses including asthma. Systemic inflammation caused by adipose tissue in obesity via production of adipokines such as leptin has been attracting attention recently as a contributor to exacerbation of allergic immune reactions. In this study, we examined whether leptin might affect eosinophil chemotactic responses. METHODS: Peripheral blood eosinophils were purified, and the effect of leptin on eosinophil migration was investigated using in vitro systems. RESULTS: High concentrations of leptin induced eosinophil chemotaxis and rapid phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase but not calcium mobilization. We also found that pretreatment of eosinophils with physiological concentrations of leptin amplified the chemotactic responses to eotaxin. This leptin-primed chemotaxis appears to be associated with increased calcium mobilization but not with ERK1/2 and p38 pathways. CONCLUSIONS: These results indicate that leptin has both direct and indirect effects on eosinophil chemotaxis and intracellular signaling. In physiological settings, leptin may maintain eosinophil accumulation at allergic inflammatory foci.
Asunto(s)
Quimiocina CCL11/inmunología , Quimiocina CCL11/farmacología , Quimiotaxis de Leucocito , Eosinófilos/inmunología , Leptina/farmacología , Leptina/fisiología , Femenino , Humanos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Proteínas Recombinantes/farmacología , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
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.
Asunto(s)
Quimiotaxis , Eosinófilos/inmunología , Receptores Inmunológicos/fisiología , Receptores de Prostaglandina/fisiología , Western Blotting , Calcio , Células Cultivadas , AMP Cíclico/metabolismo , Eosinofilia , Eosinófilos/fisiología , Humanos , Hipersensibilidad/inmunología , Inflamación/inmunología , Prostaglandina D2/metabolismo , Receptores Inmunológicos/agonistas , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/antagonistas & inhibidores , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
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.
Asunto(s)
Sangre/microbiología , Huésped Inmunocomprometido , Enfermedades Pulmonares Intersticiales/terapia , Infecciones por Mycobacterium/microbiología , Mycobacterium/aislamiento & purificación , Neumonía Bacteriana/microbiología , Sepsis/microbiología , Anciano , Antibacterianos/uso terapéutico , Técnicas de Cultivo , Quimioterapia Combinada , Resultado Fatal , Humanos , Masculino , Infecciones por Mycobacterium/tratamiento farmacológico , Terapia por Inhalación de Oxígeno , Neumonía Bacteriana/tratamiento farmacológico , Reacción en Cadena de la Polimerasa , Prednisolona/uso terapéutico , Sepsis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Redes Comunitarias , Bases de Datos Factuales , Hospitales , Control de Infecciones/métodos , Gestión de la Información/métodos , Microbiología , Técnicas Bacteriológicas , Infección Hospitalaria/microbiología , Infección Hospitalaria/prevención & control , Farmacorresistencia Bacteriana , Humanos , JapónRESUMEN
Hepatocyte growth factor (HGF) has multiple activities in a variety of tissues, and is known to prevent the onset and progression of various diseases, but the mechanisms by which HGF exert its beneficial effects remain to be elucidated, although many studies have shown that HGF exerts anti-inflammatory effects in multiple animal models of diseases of the liver, kidney, lung and other organs. Recently, we have reported that HGF also reduces allergic airway inflammation in a murine model of asthma by ovalbumin. Furthermore, HGF directly modulates various functions of eosinophils, which have been shown to play a pivotal role in the development of allergic airway inflammation. HGF influences a number of cell types, and regulates various biological activities, including cytokine production, cell migration, proliferation and survival. This review focuses on the effect of HGF on various inflammatory cells, e.g. eosinophils and dendritic cells, in allergic reactions.
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Células Sanguíneas/efectos de los fármacos , Factor de Crecimiento de Hepatocito/farmacología , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Animales , Células Sanguíneas/inmunología , Células Sanguíneas/fisiología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/fisiología , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Eosinófilos/fisiología , Factor de Crecimiento de Hepatocito/fisiología , Factor de Crecimiento de Hepatocito/uso terapéutico , Humanos , Hipersensibilidad/tratamiento farmacológicoRESUMEN
Phosphoinositide 3-kinases (PI3Ks) are known to be involved in a variety of cellular responses such as cell survival, proliferation, differentiation and cell migration. Recently, PI3Ks have been associated with the pathogenesis of asthma because various immune cells regulate allergic responses. Among the three classes of PI3Ks, the roles of PI3K gamma and PI3K delta in allergic responses have attracted particular attention. In a previous report, allergic airway hyperresponsiveness (AHR), inflammation and airway remodeling in an ovalbumin-induced asthma model were decreased in PI3K gamma-deficient mice compared with wild-type mice. In addition, AHR and inflammation were attenuated by administration of a selective PI3K delta inhibitor in a murine model of asthma. These results indicate that PI3K gamma and PI3K delta may be new therapeutic targets for asthma. However, PI3K gamma and PI3K delta may differ in terms of the mechanism of regulation. In this review, we focus on the roles of PI3K gamma and PI3K delta in the pathogenesis of asthma and discuss the mechanistic differences between PI3K gamma and PI3K delta.
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Asma/tratamiento farmacológico , Asma/enzimología , Inhibidores Enzimáticos/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Asma/fisiopatología , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Inflamación/fisiopatología , Ratones , Inhibidores de las Quinasa Fosfoinosítidos-3RESUMEN
Retinoic acids (RAs), which are active metabolites of vitamin A, are known to enhance Th2-type immune responses in vitro, but the role of RAs in allergic inflammatory cells remains unclear. In this study, we demonstrated that purified peripheral blood eosinophils expressed nuclear receptors for RAs at the mRNA and protein levels. Eosinophils cultured with all-trans RA (ATRA) and 9-cis-RA showed dramatically induced cell survival and nuclear hypersegmentation, and the efficacy of RAs (10(-6)M) was similar to that of IL-5 (1 ng/ml), the most critical cytokine for eosinophil activation. Pharmacological manipulation with receptor-specific agonists and antagonists indicated that the antiapoptotic effect of RAs was mediated through ligand-dependent activation of both retinoid acid receptors and retinoid X receptors (mainly retinoid acid receptors). Furthermore, using a gene microarray and a cytokine Ab array, we discovered that RAs induced vascular endothelial growth factor, M-CSF, and MCP-1 secretion, although they were not involved in eosinophil survival. RA-induced eosinophil survival appears to be associated with down-regulation of caspase 3 and inhibition of its enzymatic activity. These findings indicate an important role of RAs in homeostasis of granulocytes and provide further insight into the cellular and molecular pathogenesis of allergic reactions.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Eosinófilos/inmunología , Hipersensibilidad/inmunología , Tretinoina/farmacología , Antineoplásicos/inmunología , Apoptosis/genética , Apoptosis/inmunología , Caspasa 3/biosíntesis , Caspasa 3/genética , Caspasa 3/inmunología , Núcleo Celular/inmunología , Núcleo Celular/metabolismo , Núcleo Celular/patología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL2/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/inmunología , Factores de Crecimiento Endotelial/metabolismo , Eosinófilos/metabolismo , Eosinófilos/patología , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/genética , Regulación Enzimológica de la Expresión Génica/inmunología , Homeostasis/efectos de los fármacos , Homeostasis/genética , Homeostasis/inmunología , Humanos , Hipersensibilidad/genética , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-5/biosíntesis , Interleucina-5/inmunología , Interleucina-5/metabolismo , Factor Estimulante de Colonias de Macrófagos/genética , Factor Estimulante de Colonias de Macrófagos/inmunología , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Análisis por Matrices de Proteínas , Receptores X Retinoide/agonistas , Receptores X Retinoide/genética , Receptores X Retinoide/inmunología , Receptores X Retinoide/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Streptococcus pneumoniae is a common cause of respiratory tract infections (RTIs). The prevalence of Streptococcus pneumoniae strains with reduced susceptibility to antimicrobial agents has dramatically increased worldwide. Susceptibility to nine antimicrobial agents and serotypes were determined among 1,644 Streptococcus pneumoniae strains isolated from patients with RTIs in the Tohoku district of Japan from October to December every year from 1998 to 2007. The prevalence of penicillin G-nonsusceptible Streptococcus pneumoniae (PNSP) strains increased gradually from 48.5% in 1998, reached a statistical peak in 2004 (65.1%) and then decreased to 51.5% in 2007. Streptococcus pneumoniae strains with each serotype 3, 6, 19 and 23 were constantly detected, and the distribution of these serotypes in PNSP strains did not significantly change during the study period. A trend of Streptococcus pneumoniae strains nonsusceptible to other beta-lactams tested was similar to that of PNSP strains, except for cefditoren, to which the resistance rate was < 20% throughout the analysis period. The prevalence of strains nonsusceptible to erythromycin and minocycline were consistently > 60%. Almost all penicillin G-resistant Streptococcus pneumoniae (PRSP) strains were resistant to both erythromycin and minocycline throughout the analysis period. The prevalence of strains resistant to fluoroquinolones tested were < 3% over the study period. Our longitudinal surveillance demonstrated for the first time that decreased prevalence of both beta-lactam- and multidrug-resistant strains has been occurring since 2004 in a region of Japan. Careful monitoring of antimicrobial susceptibility of Streptococcus pneumoniae should be continued.
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Antibacterianos/farmacología , Streptococcus pneumoniae/efectos de los fármacos , Adolescente , Adulto , Distribución por Edad , Anciano , Técnicas de Tipificación Bacteriana , Niño , Preescolar , Demografía , Farmacorresistencia Bacteriana/efectos de los fármacos , Femenino , Humanos , Pacientes Internos , Japón , Estudios Longitudinales , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Pacientes Ambulatorios , Penicilina G/farmacología , Sistema Respiratorio/microbiología , Caracteres Sexuales , Streptococcus pneumoniae/clasificación , Streptococcus pneumoniae/aislamiento & purificación , Adulto JovenRESUMEN
BACKGROUND: Bronchial asthma is characterized by chronic airway inflammation caused by inflammatory cells. Phosphoinositide 3-kinases (PI3Ks) are known to play a prominent role in fundamental cellular responses of various inflammatory cells, including proliferation, differentiation, and cell migration. PI3Ks therefore are expected to have therapeutic potential for asthma. Although some investigations of the involvement between the pathogenesis of asthma and PI3K have been performed, it is unknown whether PI3Kgamma, a PI3K isoform, is involved in the pathogenesis of asthma. OBJECTIVE: We investigated the role of PI3Kgamma in allergen-induced allergic airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling with PI3Kgamma-deficient mice. METHODS: After ovalbumin (OVA) sensitization, wild-type (WT) and PI3Kgamma-deficient mice were exposed to aerosolized OVA 3 days per week for 5 weeks. RESULTS: In OVA-sensitized and OVA-challenged (OVA/OVA) PI3Kgamma-deficient mice, levels of airway inflammation, AHR, and airway remodeling were significantly decreased compared with those in OVA/OVA WT mice. On the other hand, no significant differences were detected in serum OVA-specific IgE and IgG1 levels and CD4/CD8 balance in bronchoalveolar lavage fluid between OVA/OVA WT mice and OVA/OVA PI3Kgamma-deficient mice. To determine in which phase of allergic responses PI3Kgamma plays a role, we transferred splenocytes from OVA-sensitized WT or PI3Kgamma-deficient mice to naive mice of either genotype. Similar increased levels of eosinophils were induced in both WT recipient mice but not in both PI3Kgamma-deficient recipient mice. CONCLUSION: PI3Kgamma might be involved in allergic airway inflammation, AHR, and airway remodeling by regulating the challenge/effector phase of allergic responses.
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Asma/etiología , Bronquios/patología , Hiperreactividad Bronquial/etiología , Fosfatidilinositol 3-Quinasas/fisiología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Fosfatidilinositol 3-Quinasa Clase Ib , Citocinas/análisis , Citocinas/fisiología , Femenino , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Inmunofenotipificación , Isoenzimas/fisiología , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Linfocitos T/inmunologíaRESUMEN
Education in laboratory medicine is important. However, many medical students and doctors cannot understand this importance. This problem may be caused by the unclear character of laboratory medicine in research as well as hospital work, resulting in a lack of staff in the Department of Laboratory Medicine. One of the characters of laboratory medicine is its all-inclusive actions unrestrained by medical specialty. Thus, we tell medical students that the staff of laboratory medicine are suitable members of the infection control team (ICT) and nutrition support team (NST) in lectures. Moreover, we also teach allergy, immunology, infection, and sex-specific medicine, which are some subjects the topics of research. Many students in Akita University recognize that the staff of the Department of Laboratory Medicine are specialists of infection and allergy. On the other hand, young doctors can also receive postgraduate clinical training and conduct research not restricted to allergy and infection. We have a policy whereby the Department of Laboratory Medicine always opens its door widely to everyone including students and doctors. Nine staff joined the Department of Laboratory Medicine of Akita University about ten years, and now, can fully provide students with medical education. To solve some problems regarding education in laboratory medicine, we should promote our roles in medical education as well as in hospitals, and increase the number of staff.
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Educación de Postgrado en Medicina/tendencias , Educación de Pregrado en Medicina/tendencias , Ciencia del Laboratorio Clínico/educación , Patología Clínica/educación , Facultades de Medicina , Prácticas Clínicas , Curriculum , Control de Infecciones , JapónRESUMEN
The nuclear receptor PPARgamma exerts a potent anti-inflammatory effects on immune cells and connective tissue cells. Accumulating evidences indicate that pathophysiological contribution of PPARgamma in allergic disease including asthma. Most recently, clinical efficacy and tolerability of PPARgamma agonists for asthma or atopic dermatitis have been reported. PPARgamma agonists seem to be new therapeutic drugs for allergic diseases, although further studies are required. Here we discuss the outlook for clinical significance of PPARgamma agonists for allergic diseases.
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Hipersensibilidad/tratamiento farmacológico , PPAR gamma/agonistas , Animales , Asma/tratamiento farmacológico , Humanos , Rinitis/tratamiento farmacológicoRESUMEN
PPARgamma is expressed in a variety of immunocompetent cells and has immunoregulatory activities. In line with the in vitro observations that PPARgamma agonists down-regulate inflammatory cytokines production and cellular responses, PPARgamma agonists have protective effects in a variety of mouse model of inflammatory disorders. In this review, we summarize the functional roles of PPARgamma in immunocompetent cells from the perspective of the pathophysiology of allergic diseases. The anti-allergic effects of PPARgamma agonist in vitro and in vivo indicate the possibility that PPARgamma agonists could be new therapeutic modality for allergic disease.