Phosphoinositide 3-kinases (PI3Ks) contribute to the pathogenesis of asthma by regulating the activation of inflammatory mediators, inflammatory cell recruitment and immune cell function. Recent findings have indicated that PI3Ks also regulate the expression of interleukin (IL)-17, which has been recognised as an important cytokine involved in airway inflammation.In the present study, we investigated a role of PI3Kd in the regulation of IL-17 expression in allergic airway disease using a murine model of asthma.After ovalbumin inhalation, administration of a selective p110d inhibitor, IC87114, significantly attenuated airway infiltration of total cells, lymphocytes, neutrophils and eosinophils, as well as airway hyperresponsiveness, and attenuated the increase in IL-17 protein and mRNA expression. Moreover, IC87114 reduced levels of IL-4, -5 and -13, expression of keratinocyte chemoattractant protein and mRNA, and nuclear factor (NF)-kB activity. In addition, a NF-kB inhibitor, BAY 11-7085 substantially reduced the increase in IL-17 protein levels. Our results also showed that inhibition of IL-17 activity with an anti-IL-17 antibody remarkably reduced airway inflammation and hyperresponsiveness.These findings suggest that inhibition of the p110d signalling pathway suppresses IL-17 expression through regulation of NF-kB activity and, thus, has therapeutic potential in asthma.

Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-κB and hypoxia-inducible factor-1α (HIF-1α ) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-κB and HIF-1α as well as reducing ROS generation in allergic airway disease.

Lactoferrin (LF), a pleiotropic iron-binding glycoprotein, is known to modulate the humoral immune response. However, its exact role in Ig synthesis has yet to be elucidated. In this study, we investigated the effect of LF on Ig production by mouse B cells and its underlying mechanisms. LF, like transforming growth factor (TGF)-β1, stimulated B cells to produce IgA and IgG2b, while downregulating other isotypes. Using limiting dilution analysis, LF was shown to increase the frequency of IgA-secreting B-cell clones. This was paralleled by an increase in Ig germ-line α (GLα) transcripts, indicating that LF plays a role as an IgA switch factor. Interestingly, LF directly interacted with betaglycan (TGF-β receptor III, TβRIII) and in turn induced phosphorylation of TβRI and Smad3 through formation of the TβRIII/TβRII/TβRI complex, leading to IgA isotype switching. Peroral administration of LF increased intestinal/serum IgA production as well as number of IgA plasma cells in lamina propria. Finally, we found that LF has an adjuvant activity when nontoxigenic Salmonella typhimurium was inoculated perorally, conferring protection against intragastrical infection of toxigenic S. typhimurium. These results suggest that LF has an important effect on the mucosal/systemic IgA response and can contribute to protection against intestinal pathogens.

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Pulmonary cryptococcosis tends to occur commonly in immunocompromized patients. However, as more individuals are undergoing regular medical examinations, the number of cases of pulmonary cryptococcosis detected incidentally in immunocompetent individuals is increasing. The aim of the present study was to evaluate the radiologic manifestations of pulmonary cryptococcosis in immunocompetent patients with no significant symptoms. The clinical records and radiographic findings of 7 immunocompetent subjects with isolated pulmonary cryptococcosis who were diagnosed by pathological examinations, were reviewed. The mean age of patients was 68.4 y (range 58-80 y), and 6 of them were female. The radiographic manifestations in all patients were 1 or more nodules. Computed tomography (CT) demonstrated 22 pulmonary nodules with diameter from 3 mm to 22 mm, and multiple nodules were more frequent than solitary nodules (5 cases versus 2 cases). Axial analysis of patients showed that an involvement of the upper lobe was observed in all patients. Most nodules were well defined and smoothly marginated (21 nodules) and cavitations were infrequent findings (2 nodules). Lymphadenopathies were found in 2 patients. The most common imaging finding of pulmonary cryptococcosis in asymptomatic immunocompetent hosts was the presence of multiple nodules marginated smoothly with upper lobe predominance.