Jiu Yao Wang

Predicted risk of childhood allergy, asthma, and reported symptoms using measured phthalate exposure in dust and urine

UNLABELLED   The associated risk of phthalate exposure, both parent compounds in the home and their metabolites in urine, to childhood allergic and respiratory morbidity, after adjusting for exposures of indoor pollutants, especially bioaerosols, was comprehensively assessed. Levels of five phthalates in settled dust from the homes of 101 children (3-9 years old) were measured, along with their corresponding urinary metabolites. Other environmental risk factors, including indoor CO2, PM2.5, formaldehyde, 1,3-β-D-glucan, endotoxin, allergen and fungal levels, were concomitantly examined. Subjects health status was verified by pediatricians, and parents recorded observed daily symptoms of their children for the week that the home investigation visit took place. Significantly increased level of benzylbutyl phthalate, in settled dust, was associated with test case subjects (allergic or asthmatic children). Higher levels of dibutyl phthalate and its metabolites, mono-n-butyl phthalate, and mono-2-ethylhexyl phthalate were found to be the potential risk factors for the health outcomes of interest. Similarly, indoor fungal exposure remained a significant risk factor, especially for reported respiratory symptoms. The relative contribution from exposure to phthalates and indoor biocontaminants in childhood allergic and respiratory morbidity is, for the first time, quantitatively assessed and characterized. PRACTICAL IMPLICATIONS For asthmatic and allergic children living in subtropical and highly developed environments like homes in Taiwan, controlling environmental exposure of phthalates may be viewed as equally important as avoiding indoor microbial burdens, for the management of allergy-related diseases. It is also recognized that multidisciplinary efforts will be critical in realizing the true underlying mechanisms associated with these observations.

Acetaminophen and/or antibiotic use in early life and the development of childhood allergic diseases

BACKGROUND Our understanding of whether the use of acetaminophen and/or antibiotics in early life can cause allergic diseases in later childhood remains inconclusive. The objective of this study was to investigate the temporal relationship between exposure to acetaminophen and/or antibiotics in early life and the development of allergic diseases in later childhood, using two independent birth cohorts derived from the National Health Insurance Research Database (NHIRD) in Taiwan. METHODS The authors conducted a prospective birth cohort study of 263 620 children born in 1998 and 9910 children born in 2003, separately, from the NHIRD. Exposure status of acetaminophen and/or antibiotics and potential confounding factors were included in the analyses. Cox proportional hazards models were applied to determine the temporal relationship between acetaminophen and/or antibiotic exposure and the development of allergic diseases. RESULTS We observed a positive relationship between acetaminophen and/or antibiotic exposure during the 1st year of life and the subsequent development of the three examined allergic diseases (atopic dermatitis, asthma and allergic rhinitis) in the 1998 birth cohort, but the observed relationship of drug exposure in the 2003 cohort, especially for atopic dermatitis and asthma, was lower than for those in the 1998 cohort and was not statistically significant. CONCLUSIONS Our findings provide suggestive evidence that the temporal effect of exposure to acetaminophen and/or antibiotics influences the development of common allergic diseases in later childhood. Further functional studies and/or animal studies are needed to better understand the underlying regulatory mechanisms driving this important clinical and public health issue.

The Innate Immune Response in House Dust Mite-Induced Allergic Inflammation

Hypersensitivity to house dust mite (HDM; Dermatophagoides sp.) allergens is one of the most common allergic responses, affecting up to 85% of asthmatics. Sensitization to indoor allergens is the strongest independent risk factor associated with asthma. Additionally, >50% of children and adolescents with asthma are sensitized to HDM. Although allergen-specific CD4+ Th2 cells orchestrate the HDM allergic response through induction of IgE directed toward mite allergens, activation of innate immunity also plays a critical role in HDM-induced allergic inflammation. This review highlights the HDM components that lead to activation of the innate immune response. Activation may due to HDM proteases. Proteases may be recognized by protease-activation receptors (PARs), Toll-like receptors (TLRs), or C-type lectin receptors (CTRs), or act as a molecular mimic for PAMP activation signaling pathways. Understanding the role of mite allergen-induced innate immunity will facilitate the development of therapeutic strategies that exploit innate immunity receptors and associated signaling pathways for the treatment of allergic asthma.

Lactobacillus gasseri suppresses Th17 pro-inflammatory response and attenuates allergen-induced airway inflammation in a mouse model of allergic asthma

Probiotics are normal inhabitants of the gastrointestinal tract of man and are widely considered to exert a number of beneficial effects in many diseases. But the mechanism by which they modulate the immune system is poorly understood. The present study was planned to explore the anti-allergic effect of Lactobacillus gasseri on a mouse model of allergic asthma. Dermatophoides pteronyssinus (Der p) sensitised and challenged BALB/c mice were orally administered via oral administration with three different doses of L. gasseri (low, 1 × 10(6) colony-forming units (CFU); medium, 2 × 10(6) CFU; high, 4 × 10(6) CFU), in 700 μl of PBS daily, starting from 2 weeks before Der p sensitisation for 4 weeks. After the allergen challenge, airway responsiveness to methacholine, influx of inflammatory cells to the lung, and cytokine levels in bronchoalveolar lavage (BAL) fluids and splenocytes culture were assessed. Our results showed that oral administration of a high dose of L. gasseri (4 × 10(6) CFU) decreased airway responsiveness to methacholine, attenuated the influx of inflammatory cells to the airways and reduced the levels of TNF-α, thymus and activation-regulated chemokine (TARC) and IL-17A in BAL fluids of Der p-sensitised and -challenged mice. Moreover, L. gasseri decreased IL-17A production in transforming growth factor-α and IL-6 stimulated splenocytes and cell numbers of IL-17 producing alveolar macrophages in L. gasseri-treated mice as compared to non-treated, Der p-sensitised and -challenged mice. In conclusion, oral administration with L. gasseri can attenuate major characteristics of allergen-induced airway inflammation and IL-17 pro-inflammatory immune response in a mouse model of allergic asthma, which may have clinical implication in the preventive or therapeutic potential in allergic asthma.

Children with atopic dermatitis show clinical improvement after Lactobacillus exposure.

The role of probiotics in the treatment of atopic dermatitis (AD) is not clearly established. Further clinical trials with new probiotic formulations are warranted.

Mite allergen decreases DC-SIGN expression and modulates human dendritic cell differentiation and function in allergic asthma

House dust mites (HDMs) induce allergic asthma in sensitized individuals, although how HDMs activate immature mucosal dendritic cells (DCs) to render the T helper cell type 2 (Th2)-mediated immune response is unclear. In this study, our results showed a significant calcium-dependent lectin binding of Dermatophagoides pteronyssinus (Der p) extracts to DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), the C-type lectin receptors (CLRs) of DCs. Moreover, monocyte-derived DCs (MDDCs) of Der p-sensitized asthmatics (AS) exhibited decreased expression of DC-SIGN, increased endocytosis, and impaired differentiation of DC precursors. The Der p-induced downregulation of DC-SIGN expression in the differentiation of immature MDDCs may be because of the internalization of Der p-DC-SIGN complex. MDDCs of AS produced more interleukin (IL)-6 and less IL-12p70 cytokines when stimulated with lipopolysaccharide (LPS) or Der p than those of nonallergic controls (NC). In the co-culture experiments, MDDCs pretreated with Der p induced GATA-3 expression and IL-4 cytokine productions in naive CD4+ T cells. These effects of Der p on the differentiation and function of MDDCs could be partially blocked by anti-DC-SIGN antibodies. In conclusion, our results suggest a critical step of allergen sensitization that involves CLRs in the innate immune response of DCs, which may provide a therapeutic or preventive potential for allergic asthma.

A retrospective study of catastrophic invasive fungal infections in patients with systemic lupus erythematosus from southern Taiwan

As very few large scale publications of invasive fungal infection (IFI) have been reported in lupus patients from individual medical centers, a retrospective study was performed from 1988 to 2009 in southern Taiwan. Demographic characteristics, clinical and laboratory data, and mycological examinations were analyzed. Twenty cases with IFI were identified in 2397 patients (0.83% incidence). There were 19 females and one male with an average age of 31.8 ± 12.6. Involved sites included eight disseminated cases, six central nervous system, four lungs, one abdomen and one soft tissue. IFI contributed to a high mortality with 10 deaths (50%), and there were no survivors for the disseminated cases and Candida-infected patients. High activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) > 8) was noted in 50% of IFI episodes. The survival from IFI diagnosis to death was only 7.7 ± 4.2 days, all in a rapid course. No statistical difference was found between survivors and non-survivors when comparing their SLEDAI. Eighty-five percent of IFI episodes under high dosages of corticosteroids therapy and 95% of patients had lupus nephritis. There was an increased risk of IFI in the lupus patients receiving high daily dosage of prednisolone therapy. Critical information from analyses of the present large series could be applied into clinical practices to reduce the morbidity and mortality in such patients.

Innate Immune Response of Alveolar Macrophage to House Dust Mite Allergen Is Mediated through TLR2/-4 Co-Activation

House dust mite, Dermatophagoides pteronyssinus (Der p), is one of the major allergens responsible for allergic asthma. However, the putative receptors involved in the signalization of Der p to the innate immune cells are still poorly defined as well as the impact of their activation on the outcome of the allergen-induced cell response. We previously reported that the HDM activation of mouse alveolar macrophages (AM) involves the TLR4/CD14 cell surface receptor complex. Here using a TLR ligand screening essay, we demonstrate that HDM protein extract engages the TLR2, in addition to the TLR4, in engineered TLR-transfected HEK cells but also in the MH-S mouse alveolar macrophage cell line model. Moreover we found that the concomitant recruitment of the MH-S cell’s TLR2 and TLR4 receptors by the HDM extract activates the MyD88-dependent signaling pathway and leads to the secretion of the NF-κB regulated pro-inflammatory factors NO and TNF-α. However unlike with the canonical TLR4 ligand (i.e. the bacterial LPS) mobilization of TLR4 by the HDM extract induces a reduced production of the IL-12 pro-inflammatory cytokine and fails to trigger the expression of the T-bet transcription factor. Finally we demonstrated that HDM extract down-regulates LPS induced IL-12 and T-bet expression through a TLR2 dependent mechanism. Therefore, we propose that the simultaneous engagement of the TLR2 and TLR4 receptors by the HDM extract results in a cross regulated original activation pattern of the AM which may contribute to the Th2 polarization of the allergen-induced immune response. The deciphering of these cross-regulation networks is of prime importance to open the way for original therapeutic strategies taking advantage of these receptors and their associated signaling pathways to treat allergic asthma.

Dermatophagoides pteronyssinus 2 regulates nerve growth factor release to induce airway inflammation via a reactive oxygen species-dependent pathway

Group 2 allergen of Dermatophagoides pteronyssinus 2 (Der p2) induces airway inflammation without protease activity, and elevated nerve growth factor (NGF) levels are also found in this inflammation. How the allergen Der p2 regulates NGF release via reactive oxygen species (ROS) to induce inflammation remains unclear. In the present study, intratracheal administration of Der p2 to mice led to inflammatory cell infiltration, mucus gland hyperplasia, and NGF upregulation in the bronchial epithelium, as well as elevated ROS and NGF production in bronchoalveolar lavage fluids. In addition, Der p2 caused fibrocyte accumulation and mild fibrosis. p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) inhibitors inhibited Der p2-induced NGF release in LA4 lung epithelial cells and MLg lung fibroblasts. Pretreatment with an antioxidant, tiron, reduced the Der p2-induced ROS production, NGF expression and release, p38 MAPK or JNK phosphorylation, and airway inflammation. These results suggest that Der p2 allergen-induced airway inflammation and elevated NGF release were through increasing ROS production and a MAPK-dependent pathway. The use of an antioxidant, tiron, may provide a new therapeutic modality for the treatment of allergic asthma.

Propolis inhibits TGF-β1-induced epithelial–mesenchymal transition in human alveolar epithelial cells via PPARγ activation

Emerging evidence suggests that the transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) may contribute to airway remodeling in severe asthma and fibrotic lung diseases. Studies have shown that extracts from propolis protect chemical-induced cardiac and liver fibrosis in animals. This study assesses the inhibitory effect of propolis on TGF-β1-induced EMT in serum-deprived A549 cells (human AECs). Experimental results show progressive cell morphological changes, decreased E-cadherin, increased N-cadherin production, intracellular F-actin rearrangement, increased reactive oxygen species (ROS) production, and increased cell motility with increasing TGF-β1 concentration. A549 cells pretreated with propolis and then treated with TGF-β1 for 24 h regained epithelial cell morphology, decreased the production of N-cadherin and ROS, and had reduced motility. Propolis prevents the effects of TGF-β1-induced Smad2 and AKT activation pathways and Snail expression. Moreover, propolis pretreatment may prevent the TGF-β1-induced down-regulation of nuclear hormone receptors and peroxisome proliferator-activated receptor gamma (PPARγ) protein in A549 cells, whose effect was blocked by adding PPARγ antagonist, GW9662. Two active components of propolis, caffeic acid phenethyl ester (CAPE) and pinocembrin (PIN), only had partial effects on TGF-β1-induced EMT in A549 cells. The results of this study suggest that natural propolis extracts may prevent TGF-β1-induced EMT in immortalized type II AECs via multiple inhibitory pathways, which may be clinically applied in the prevention and/or treatment of EMT-related fibrotic diseases as well as airway remodeling in chronic asthma.