Sex Plays a Multifaceted Role in Asthma Pathogenesis.

Sex is considered an important risk factor for asthma onset and exacerbation. The prevalence of asthma is higher in boys than in girls during childhood, which shows a reverse trend after puberty-it becomes higher in adult females than in adult males. In addition, asthma severity, characterized by the rate of hospitalization and relapse after discharge from the emergency department, is higher in female patients. Basic research indicates that female sex hormones enhance type 2 adaptive immune responses, and male sex hormones negatively regulate type 2 innate immune responses. However, whether hormone replacement therapy in postmenopausal women increases the risk of current asthma and asthma onset remains controversial in clinical settings. Recently, sex has also been shown to influence the pathophysiology of asthma in its relationship with genetic or other environmental factors, which modulate asthmatic immune responses in the airway mucosa. In this narrative review, we highlight the role of sex in the continuity of the asthmatic immune response from sensing allergens to Th2 cell activation based on our own data. In addition, we elucidate the interactive role of sex with genetic or environmental factors in asthma exacerbation in women.

Novel Toll-Like Receptor 9 Agonist Derived from Cryptococcus neoformans Attenuates Allergic Inflammation Leading to Asthma Onset in Mice.

INTRODUCTION: The enhanced type 2 helper (Th2) immune response is responsible for the pathogenesis of allergic asthma. To suppress the enhanced Th2 immune response, activation of the Th1 immune response has been an alternative strategy for anti-asthma therapy. In this context, effective Th1-inducing adjuvants that inhibit the development of allergic asthma but do not flare the side effects of the primary agent are required in clinical treatment and preventive medicine. OBJECTIVE: In this study, we aimed to determine the regulation of the Th2 type immune response in asthma by a novel immunostimulatory oligodeoxynucleotide (ODN) derived from Cryptococcus neoformans, termed ODN112, which contains a cytosine-guanine (CG) sequence but not canonical CpG motifs. METHODS: Using an ovalbumin-induced asthma mouse model, we assessed the effect of ODN112 on prototypical asthma-related features in the lung and on the Th1/Th2 profile in the lymph nodes and lung of mice treated with ODN112 during sensitization. RESULTS AND CONCLUSION: ODN112 treatment attenuated asthma features in mice. In the bronchial lymph nodes of the lungs and in the spleen, ODN112 increased interferon-γ production and attenuated Th2 recall responses. In dendritic cells (DCs) after allergen sensitization, ODN112 enhanced cluster of differentiation (CD) 40 and CD80 expression but did not alter CD86 expression. Interleukin-12p40 production from DCs was also increased in a Th2-polarizing condition. Our results suggest that ODN112 is a potential Th1-inducing adjuvant during Th2 cell differentiation in the sensitization phase.

[A case of late-onset paraphrenia in a very elderly patient receiving home medical care].

A 94 year old woman with a late-onset paraphrenia was referred to our clinic from a community care center. The patient showed symptoms of paranoia and auditory hallucination. The patient was in conflict with her neighbors regarding noise-related problems and was experiencing loss of appetite. Because the patient had a strong aversion to outpatient treatment due to difficulty in commuting, home visits were commenced. Improvements were observed after administration of 2.5 mg per day of olanzapine.In home medical care, precise definitive diagnosis and determination of treatment approach is necessary under limited time and resources. The fact that elderly people often exhibit psychological symptoms such as hallucinations is well known among clinical professions. However, this is not well known among home care patients, families and other professionals, and, therefore, is often overlooked. As the population ages further, it can be predicted that cases of elderly patients requiring treatment for psychological symptoms will increase in home medical care situations. In Japan, with a super-aging society, understanding and continuously supporting late-onset paraphrenia among elderly people is a pressing issue for all communities in advancing home medical care and nursing.

The interplay between neuroendocrine activity and psychological stress-induced exacerbation of allergic asthma.

Psychological stress is recognized as a key factor in the exacerbation of allergic asthma, whereby brain responses to stress act as immunomodulators for asthma. In particular, stress-induced enhanced type 2 T-helper (Th2)-type lung inflammation is strongly associated with asthma pathogenesis. Psychological stress leads to eosinophilic airway inflammation through activation of the hypothalamic-pituitary-adrenal pathway and autonomic nervous system. This is followed by the secretion of stress hormones into the blood, including glucocorticoids, epinephrine, and norepinephrine, which enhance Th2 and type 17 T-helper (Th17)-type asthma profiles in humans and rodents. Recent evidence has shown that a defect of the µ-opioid receptor in the brain along with a defect of the peripheral glucocorticoid receptor signaling completely disrupted stress-induced airway inflammation in mice. This suggests that the stress response facilitates events in the central nervous and endocrine systems, thus exacerbating asthma. In this review, we outline the recent findings on the interplay between stress and neuroendocrine activities followed by stress-induced enhanced Th2 and Th17 immune responses and attenuated regulatory T (Treg) cell responses that are closely linked with asthma exacerbation. We will place a special focus on our own data that has emphasized the continuity from central sensing of psychological stress to enhanced eosinophilic airway inflammation. The mechanism that modulates psychological stress-induced exacerbation of allergic asthma through neuroendocrine activities is thought to involve a series of consecutive pathological events from the brain to the lung, which implies there to be a "neuropsychiatry phenotype" in asthma.

The involvement of glucocorticoids in psychological stress-induced exacerbations of experimental allergic asthma.

BACKGROUND: Psychological stress is associated with the aggravation of asthma symptoms. Glucocorticoids (GC), which are stress hormones released upon exposure to stress, have the potential to shift immune responses towards a predominant Th2 response by priming antigen-presenting cells to produce lower levels of IL-12 as well as reducing the development of regulatory T cells. However, the involvement of GC in psychological stress-induced exacerbations of allergic asthma has not yet been clarified. METHODS: Sensitized mice were exposed to restraint stress followed by forced swimming stress, during which a GC receptor antagonist or a GC synthesis inhibitor was administered, and then antigen was inhaled. Corticosterone levels in the blood were measured in stressed and nonstressed mice. After antigen inhalation, the airway responses to aerosolized methacholine, epithelial mucus secretion and airway inflammation were evaluated, and the IL-13 contents in bronchoalveolar lavage fluid were measured. RESULTS: The exposure to stress significantly increased corticosterone levels. Allergic airway responses and the increase of IL-13 contents evoked by antigen inhalation were significantly higher in stressed mice than in nonstressed mice. The administration of a GC receptor antagonist and a GC synthesis inhibitor during stress exposure significantly reduced the exacerbation of the airway responses and the increase of IL-13 contents in stressed mice challenged with antigen. CONCLUSIONS: These results indicate that the increased release of GC upon exposure to stress has a priming effect on the aggravation of allergic airway responses following the exposure, suggesting a pathophysiological role for the neuroendocrine axis in linking psychological stress to asthma exacerbations.

Contribution of CD4+ T cells and dendritic cells to female-dominant antigen-induced T helper type 2 cytokine production by bronchial lymph node cells.

BACKGROUND: After puberty, asthma severity is higher in women than in men. The underlying mechanisms of this gender difference are not fully understood. In murine models of allergic asthma, more severe airway inflammation in female mice is associated with higher levels of T helper type 2 (Th2) cytokines. The aim of this study was to investigate the contributions of CD4(+) T cells and dendritic cells (DCs) to the differences in Th2 cytokine production between sexes. METHODS: Bronchial lymph node (BLN) cells from ovalbumin (OVA)-sensitized male and female C57BL/6 mice were stimulated with OVA and anti-CD3/CD28 antibodies. The CD4(+) T cells and DCs purified from BLN cells were cocultured with OVA in a sex-matched or mismatched fashion. The CD4(+) T cells were also stimulated with anti-CD3/CD28 antibodies. The concentrations of interleukin (IL)-5, IL-4, IL-13 and interferon (IFN)-γ in the culture supernatants were measured. RESULTS: The concentrations of IL-5, IL-4 and IL-13, but not IFN-γ, were significantly higher in female BLN cells stimulated with OVA than in male BLN cells. Sex differences were also observed in the CD4(+) T cells stimulated with anti-CD3/CD28 antibodies, whereas only IL-4 was significantly different in the BLN cells stimulated with antibodies. IL-5 production by OVA-stimulated male and female CD4(+) T cells, but not IL-4 or IL-13 production, was significantly increased in the coculture with female DCs when compared to the male DCs. CONCLUSIONS: The differences in Th2 cytokine production between sexes by the BLN cells may be attributable, at least in part, to the differing functions of CD4(+) T cells and DCs between sexes.

Higher sensitivity of male CD4+ T cells to suppressive effects of CD8+ T cells on IL-5 production compared to female CD4+ T cells.

BACKGROUND: Asthma prevalence and severity are higher in females than in males after puberty. The underlying mechanisms of this gender difference are not fully understood. More severe airway inflammation in female mice has been reported to be associated with higher levels of T helper type 2 (Th2) cytokines in asthma models. The aim of this study was to investigate sex differences in CD4+ and CD8+ T cell functions in Th2 cytokine production. METHODS: Splenocytes from naive mice were stimulated with anti-CD3/CD28 antibodies and the proportions of CD4+ and CD8+ T cells were analyzed. CD4+ T cells were stimulated in the presence of CD8+ T cells. The concentrations of interleukin (IL)-5, IL-10 and interferon (IFN)-γ in the cultures were measured. RESULTS: The concentration of IL-5, but not IFN-γ, was significantly higher in female splenocytes than in male splenocytes. There were no sex differences in the proportions of CD4+ and CD8+ T cells in the splenocytes. Although the IL-5 production levels in male and female CD4+ T cells were similar, IL-5 production in male CD4+ T cells, but not female CD4+ T cells, was suppressed by both male and female CD8+ T cells. While IL-5 and IL-10 were not detected in the cultures from both male and female CD8+ T cells, IFN-γ concentration in female CD8+ T cells was significantly higher than in male CD8+ T cells. CONCLUSIONS: The sex difference in the sensitivity of CD4+ T cells to CD8+ T cell suppression might contribute to the sex difference in IL-5 production by splenocytes.

CD4 and CD8 T cells require different membrane gangliosides for activation.

Initial events of T-cell activation involve movement of the T-cell receptor into lipid rafts. Gangliosides are major components of lipid rafts. While investigating T-cell activation in ganglioside-deficient mice, we observed that CD4(+) and CD8(+) T cells required different ganglioside subsets for activation. Activation of CD4(+) T cells from GM3 synthase-null mice, deficient in GM3-derived gangliosides, is severely compromised, whereas CD8(+) T-cell activation is normal. Conversely, in cells from GM2/GD2 synthase-null mice, expressing only GM3 and GD3, CD4(+) T-cell activation is normal, whereas CD8(+) T-cell activation is deficient. Supplementing the cells with the corresponding missing gangliosides restores normal activation. GM3 synthase-null mice do not develop experimental asthma. Distinct expression patterns of ganglioside species in CD4(+) T and CD8(+) T cells, perhaps in uniquely functional lipid rafts, define immune functions in each T-cell subset. Control of ganglioside expression would offer a strategy targeting for specific T-cell subpopulations to treat immune diseases.

µ-opioid receptor-mediated alterations of allergen-induced immune responses of bronchial lymph node cells in a murine model of stress asthma.

BACKGROUND: Psychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of µ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear. METHODS: MOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured. RESULTS: Stress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-γ/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes. CONCLUSIONS: Restraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs.

T cell subsets related with a sex difference in IL-5 production.

BACKGROUND: Before puberty, the prevalence and severity of asthma are higher in boys than in girls, but this pattern is reversed after puberty. The underlying mechanisms of these gender differences in asthma are not fully understood. Using murine models of allergic asthma, a sex difference in Th2 cytokine production has been suggested to contribute to the gender differences in asthma. Therefore, we determined which subsets of T cells are involved in the sex difference in Th2 cytokine production. METHODS: Splenocytes from wild-type mice and CD4+ T cell-, CD8+ T cell-, and iNKT cell-deficient mice were stimulated with anti-CD3/CD28 antibodies for 3 days, and the concentrations of IL-4, IL-5, IL-13, and IFN-γ in the cultures were measured by ELISA. RESULTS: IL-5, but not IL-4 and IL-13, concentrations in culture derived from female wild-type mice were significantly higher than those in male wild-type mice. The sex difference in IL-5 concentrations was not observed in the cultures of splenocytes from CD4+ and CD8+ T cell-deficient mice. The disappearance of the sex differences in CD4+ and CD8+ T cell-deficient mice was attributable to a decrease in IL-5 concentration in female mice and an increase in IL-5 concentration in male mice. In iNKT cell-deficient mice, the sex difference was still observed. There was no significant difference between the sexes in any type of mice with respect to IFN-γ production. CONCLUSIONS: There was a sex difference in IL-5 production by splenocytes stimulated by TCR activation. The difference might be attributable to sex differences in CD4+ and CD8+ T cell functions.

Gender differences in transcriptional regulation of IL-5 expression by bronchial lymph node cells in a mouse model of asthma.

BACKGROUND AND OBJECTIVE: The severity of asthma after puberty is higher in women than in men. Increased numbers of eosinophils in the airways of female mice after antigen challenge was associated with increased levels of T helper (Th)2 cytokines at the site of inflammation, and in human and mouse studies, the profile of cytokines produced by immune cells from women showed greater Th2 predominance. The aim of this study was to investigate gender differences in the development of Th2 immune responses. METHODS: Male and female C57BL/6 mice were sensitized with ovalbumin. Cells prepared from bronchial lymph nodes were cultured in the absence or presence of ovalbumin. Cytokine concentrations in the culture supernatants were measured, and IL-5 and GATA-binding protein 3 (GATA-3) gene expression were evaluated. T-cell subsets were analysed using specific surface markers. RESULTS: The concentrations of IL-4, IL-5, IL-13 and IL-10, but not interferon-gamma or transforming growth factor-beta(1), were higher in cell supernatants from female mice than in those from male mice. IL-5 and GATA-3 gene expressions were higher in cells from women than in cells from men. The numbers of CD3(+)CD4(+)T1/ST2(+) cells, but not CD3(+)CD4(+) or CD4(+)CD25(+) cells, were significantly higher in cells from women than in cells from men. CONCLUSIONS: Greater antigen-induced Th2 cytokine production by bronchial lymph node cells from female mice was associated with enhanced Th2 cell differentiation and increased expression of the Th2-specific transcription factor, GATA-3.

The involvement of micro-opioid receptors in the central nervous system in the worsening of allergic airway inflammation by psychological stress in mice.

BACKGROUND: Psychological stress has a recognized association with asthma symptoms. However, the mechanisms linking stress to the exacerbation of asthma are not well defined. mu-Opioid receptors (MOR) have been shown to be involved in the shift of the immune system toward a Th2-predominant response caused by psychological stress. OBJECTIVE: To test the hypothesis that MOR play a role in the worsening of allergic airway inflammation evoked by psychological stress. METHODS: Sensitized mice were exposed to restraint stress followed by antigen challenge. The levels of corticosterone and ovalbumin (OVA)-specific IgE in the blood and the levels of inflammatory cells and cytokine contents in bronchoalveolar lavage fluid were compared between stressed and nonstressed mice. The effects of MOR gene deletion and MOR antagonists/agonists were also investigated. RESULTS: Stress exposure was confirmed by an increase in corticosterone levels. Although OVA-specific IgE levels were not significantly different, the numbers of inflammatory cells and Th2 cytokine levels after antigen challenge in stressed mice were significantly higher than in nonstressed mice. MOR gene deletion ameliorated the stress-induced worsening of antigen-induced airway inflammation, and the administration of morphine, a MOR agonist, reproduced the stress-induced antigen-induced airway inflammation. Selective blocking of MOR in the central nervous system (CNS) significantly reduced stress-induced inflammatory exacerbation, but the blocking of peripheral MOR did not. CONCLUSIONS: MOR in the CNS are involved in psychological stress-induced aggravation of allergic airway inflammation.

Trends in antimicrobial susceptibility of Streptococcus pneumoniae in the Tohoku district of Japan: a longitudinal analysis from 1998 to 2007.

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.

Thiamine tetrahydrofurfuryl disulfide improves energy metabolism and physical performance during physical-fatigue loading in rats.

Impaired energy metabolism is considered a possible cause of fatigue. The thiamine derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is prescribed and is also an over-the-counter drug for the attenuation of fatigue. It is readily absorbed from the intestinal tract and converted into thiamine pyrophosphate (TPP), which plays an important role as a cofactor for enzymes of metabolic pathways involved in the production of adenosine triphosphate (ATP). We postulated that TTFD has an anti-fatigue effect by improving energy metabolism during physical-fatigue loading. Here, we initially used the forced swimming test to determine whether daily TTFD or thiamine for 5 days has anti-fatigue effects on weight-loaded rats. The swimming duration of TTFD-, but not of thiamine-treated rats, was significantly longer than that of control rats (P < .05). Based on these findings, we examined changes in the levels of thiamine and its phosphate esters in various organs and the effect of TTFD on ATP levels in skeletal muscle after forced swimming, to determine the cellular mechanisms of the anti-fatigue effect of TTFD. Daily TTFD resulted in a characteristic distribution of thiamine and its phosphate esters in rat skeletal muscle, liver, kidney, heart, brain, and plasma. Furthermore, daily TTFD attenuated the decrease in ATP content in the skeletal muscle caused by forced swimming with a weight load for a defined period (150 s). These results indicate that TTFD exerts anti-fatigue effects by improving energy metabolism during physical fatigue.

Allergic airway hyperresponsiveness, inflammation, and remodeling do not develop in phosphoinositide 3-kinase gamma-deficient mice.

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.

Mental and physical fatigue-related biochemical alterations.

OBJECTIVE: To confirm fatigue-related biochemical alterations, we measured various parameters just before and after relaxation and fatigue-inducing mental or physical sessions. METHODS: Fifty-four healthy volunteers were randomized to perform relaxation and fatigue-inducing mental and physical sessions for 4 h in a double-blind, three-crossover design. Before and after each session, subjects were asked to rate their subjective sensations of fatigue, and blood, saliva, and urine samples were taken. RESULTS: After the fatigue-inducing mental and physical sessions, subjective scores of fatigue were increased. After the fatigue-inducing mental session, the vanillylmandelic acid level in urine was higher and plasma valine level was lower than after the relaxation session. In contrast, after the fatigue-inducing physical session, serum citric acid, triacylglycerol, free fatty acid, ketone bodies, total carnitine, acylcarnitine, uric acid, creatine kinase, aspartate aminotransferase, lactate dehydrogenase, cortisol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, plasma branched-chain amino acids, transforming growth factor-beta1 and -beta2, white blood cell and neutrophil counts, saliva cortisol and amylase, and urine vanillylmandelic acid levels were higher and serum free carnitine and plasma total amino acids and alanine levels were lower than those after the relaxation session. CONCLUSION: Some mental or physical fatigue-related biochemical changes were determined. Various biochemical alterations reflecting homeostatic perturbation and its responses might be shown. We believe that our results contribute to clarifying the mechanism of fatigue, developing evaluation methods, and establishing a basis for treatment.

Prolongation of neutrophil survival by the culture supernatant of Pseudomonas aeruginosa.

BACKGROUND AND OBJECTIVES: The pathogenesis of airway inflammation in diffuse panbronchiolitis (DPB) is unknown. Neutrophil survival-enhancing activity, partially mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF), has been shown in the sputum from DPB patients. This study investigated the mechanisms of GM-CSF expression in the airways of DPB patients. This involved examining the effects of mucoid Pseudomonas aeruginosa strains derived from chronically colonized patients with DPB on neutrophil survival and GM-CSF expression. METHODS: Neutrophils from healthy subjects were cultured with the culture supernatants of P. aeruginosa isolated from sputum of DPB patients in the presence or absence of anti-GM-CSF and anti-GM-CSF receptor (alpha chain) antibodies, and viable neutrophils were counted daily. GM-CSF gene expression in neutrophils was evaluated by RT-PCR. RESULTS: Neutrophils cultured with the culture supernatants showed significantly prolonged survival, compared with neutrophils cultured with the control broth. The neutrophil survival-enhancing activity in the culture supernatants was lost by heating. The enhanced survival of neutrophils was abolished in the presence of anti-GM-CSF and anti-GM-CSF receptor (alpha chain) antibodies. GM-CSF mRNA was detected in neutrophils cultured with the bacterial supernatants, but not in those with the control broth. CONCLUSION: P. aeruginosa-derived factors (rich in proteins) stimulated neutrophils to synthesize GM-CSF, which enhanced neutrophil survival in an autocrine/paracrine fashion.

The distinctive effects of acute and chronic psychological stress on airway inflammation in a murine model of allergic asthma.

BACKGROUND: Psychological stress has long been recognized to be associated with asthma symptoms. There appear to be individual differences in the susceptibility to even the same kind of stress, and furthermore, stress responses are different between the types of the stress, acute and chronic, even in the same person. However, the mechanisms linking stress to asthma are not well defined. Psychological stress upregulates the expression of endogenous opioids. The opioids stimulate the hypothalamus-pituitary-adrenal axis and sympathetic and adrenomedullary system, through the activation of mu-opioid receptor (MOR) to release stress hormones, such as cortisol and catecholamines, respectively. These hormones can modulate immune responses via the induction of Th1 immunity. METHODS: Female BALB/c and C57BL/6, wild and MOR-deficient, mice sensitized with ovalbumin (OVA) were exposed to OVA with or without either acute or chronic restraint stress. Airway inflammation was evaluated by the measurement of the number of inflammatory cells and cytokine contents in bronchoalveolar lavage fluids. RESULTS: In BALB/c mice, but not in C57BL/6 mice, the number of total cells, eosinophils and lymphocytes in the acute stress group were significantly decreased compared with those in the non-acute stress group. In contrast, chronic stress significantly increased the cell numbers and the contents of IL-4 and IL-5 in both mouse strains. Furthermore, these exacerbations were abolished in MOR-deficient mice. CONCLUSIONS: These results suggest that acute stress modifies the allergic airway responses distinctively depending on the genetic background, and MOR is involved in the chronic psychological stress-induced exacerbation of allergic airway inflammation.

Ciglitazone inhibits the antigen-induced leukotrienes production independently of PPARgamma in RBL-2H3 mast cells.

Peroxisome prolifelator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor, through which PPARgamma agonists have been demonstrated to down-regulate inflammatory cell functions. Recently, the agonists are reported to exert, in some conditions, their inhibitory actions independently of PPARgamma. Previously, we showed that a PPARgamma agonist, troglitazone, inhibited cysteinyl (Cys)-leukotrienes production in RBL-2H3 cells after IgE receptor triggering. Here we examined whether the inhibition of cycteinyl-leukotrienes production in the cells was dependent on the activation of PPARgamma. A PPARgamma agonist, ciglitazone, significantly inhibited Cys-leukotrienes, but not prostaglandin D2, production. The inhibition was not attenuated by the pretreatment with a PPARgamma antagonist. Ciglitazone did not alter the mRNA expression of acyl-coenzyme A binding protein, the gene expression of which is up-regulated by PPARgamma, nor induce the nucleus translocation of PPARgamma. These results suggest that the inhibition by PPARgamma agonists of Cys-leukotrienes production in RBL-2H3 cells after IgE receptor triggering is not through the activation of PPARgamma.

Inhibition of eosinophil survival by a selective inhibitor of phosphodiesterase 4 via the induction of apoptosis.

Selective inhibitors of phosphodiesterases (PDEs) have been suggested to have anti-inflammatory effects on bronchial asthma through the inhibition of chemotaxis, adhesion, degranulation, the respiratory burst, and survival prolongation of eosinophils. However, the mechanisms by which these agents inhibit eosinophil survival remain unclear. We therefore investigated the possible mechanisms of inhibitory effects of selective inhibitors of PDE 3 (cilostazol) and PDE 4 (rolipram) on granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated eosinophil survival. Purified blood eosinophils were cultured with medium alone or GM-CSF (0.01 ng/ml) in the presence or absence of the agents for up to 6 d. DNA was extracted from freshly isolated eosinophils and eosinophils cultured for 2 d with medium alone, GM-CSF, or GM-CSF in the presence of the agents, and analyzed using agarose gel electrophoresis. The presence of rolipram (10(-4), 10(-5), 10(-6) M), but not cilostazol, significantly inhibited eosinophil survival at days 2, 4, and 6. A laddering pattern was observed in the DNA of eosinophils cultured with medium alone and with GM-CSF in the presence of rolipram. The results reveal that selective PDE 4 inhibitors inhibit GM-CSF-mediated eosinophil survival through the induction of apoptosis.