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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. [ABSTRACT FROM AUTHOR]

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. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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 PI3Kγ and PI3Kδ 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 PI3Kγ-deficient mice compared with wild-type mice. In addition, AHR and inflammation were attenuated by administration of a selective PI3Kδ inhibitor in a murine model of asthma. These results indicate that PI3Kγ and PI3Kδ may be new therapeutic targets for asthma. However, PI3Kγ and PI3Kδ may differ in terms of the mechanism of regulation. In this review, we focus on the roles of PI3Kγ and PI3Kδ in the pathogenesis of asthma and discuss the mechanistic differences between PI3Kγ and PI3Kδ. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) is known to influence a number of cell types and regulate various biological activities including cytokine production, cell migration, proliferation and survival. Thus, HGF is now recognized to be a key factor in the prevention and attenuation of disease progression. We have reported that HGF reduces allergic airway inflammation, airway hyperresponsiveness, remodeling and development of Th2 cytokines as well as growth factors such as transforming growth factor-β in vivo. In vitro, HGF directly attenuates chemotaxis of eosinophils in the absence of Th2 cytokines and modulates mitogen-activated protein kinases, which play an important role in eosinophil migration. In this review, we discuss the physiological role of HGF in allergic inflammation and its mechanism of anti-inflammatory effects, including the regulation of eosinophil functions. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is recognized as a potent lipid mediator that is derived from PGD2, which is produced abundantly in allergic inflammatory sites. It is now established that 15d-PGJ2 negatively regulates cellular functions through its intracellular targets such as peroxisome proliferator-activated receptor-γ (PPARγ). However, recent studies revealed that 15d-PGJ2 appears to possess not only anti-inflammatory activities but also a proinflammatory potential depending on its concentration and the activation state of the target cell. For instance, at low concentrations, 15d-PGJ2 enhances eotaxin-induced chemotaxis, shape change, and actin reorganization in eosinophils through its ligation with PPARγ. Moreover, 15d-PGJ2 itself is a potent chemoattractant, and it induces calcium mobilization, and up-regulates CD11b expression through its membrane receptor – chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Conversely, at high concentrations, 15d-PGJ2 inhibits eosinophil survival by inducing apoptosis in a PPARγ-independent manner. Here, we discuss the pathophysiological roles of 15d-PGJ2 that could act as a paracrine, autocrine, and intracrine substance to regulate eosinophil functions. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Eosinophilic inflammation is primarily characterized by type 2 immune responses against parasitic organisms. In the contemporary human being especially in developed countries, eosinophilic inflammation is strongly associated with allergic/sterile inflammation, and constitutes an undesired immune reaction. This situation is in stark contrast to neutrophilic inflammation, which is indispensable for the host defense against bacterial infections. Among eosinophilic inflammatory disorders, massive accumulation of eosinophils within mucus is observed in certain cases, and is often linked to the distinctive clinical finding of mucus with high viscosity. Eosinophilic mucus is found in a variety of diseases, including chronic allergic keratoconjunctivitis, chronic rhinosinusitis encompassing allergic fungal sinusitis, eosinophilic otitis media, eosinophilic sialodochitis, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic plastic bronchitis, and eosinophilic asthma. In these pathological conditions, chronic inflammation and tissue remodeling coupled with irreversible organ damage due to persistent adhesion of toxic substances and luminal obstruction may impose a significant burden on the body. Eosinophils aggregate in the hyperconcentrated mucus together with cell-derived crystals, macromolecules, and polymers, thereby affecting the biophysical properties of the mucus. This review focuses on the clinically significant challenges of mucus and discusses the consequences of activated eosinophils on the mucosal surface that impact mucus and persistent inflammation. [ABSTRACT FROM AUTHOR]