Oral allergy induction through skin exposure to previously tolerated food antigens in murine models.

Food allergies (FAs) are caused by a failure of the immune system to regulate oral tolerance (OT). The use of soap containing hydrolyzed wheat overrides acquired OT to wheat through skin exposure. However, in mouse models, the experimental OT is robust, suggesting that acquired OT to allergens prevents the development of FAs. We aimed to analyze the mechanisms and developed a mouse model of FA that overrides acquired OT via skin exposure. Three murine FA models (intraperitoneal [IP], epicutaneous [EC], and intradermal [ID]) were compared to evaluate if allergies to ovalbumin (OVA) that had been previously tolerated orally could be induced. In the ID model, OT was overridden, and allergic reactions of severe anaphylaxis were developed. To analyze this effect in the ID model, we measured the migration of dendritic cells (DCs) into lymph nodes. The induction of OT promoted the migration of CD103+ dermal DCs; moreover, repeated percutaneous doses of OVA for sensitization gradually increased the migration of CD11b+ dermal DCs. The difference in the proportion of regulatory T cells between ID-sensitized groups at the first ID injection disappeared at the tenth injection. Although OT was robust in the IP model, ID sensitization was found to override OT.

Food allergy is linked to season of birth, sun exposure, and vitamin D deficiency.

The season of birth and ultraviolet B exposure have been related to the occurrence of food allergy. The levels of vitamin D produced from skin by ultraviolet B exposure might reflect this relationship. Vitamin D is known to induce antimicrobial peptides, protect intestinal flora, enhance the gut epithelial barrier, suppress mast cell activation and IgE synthesis from B cells, and increase the number of tolerogenic dendritic cells and IL-10-producing regulatory T cells. Vitamin D deficiency has been shown to exacerbate sensitization and allergic symptoms in a murine model of food allergy. However, in clinical situations, contradictory observations have been reported regarding the relationship between food allergy and vitamin D deficiency/supplementation. In this review, we have explored the links between food allergy and vitamin D levels. One explanation for the discrepant findings is confounding factors such as race, age, residency, skin color, and epigenetic changes that contribute to vitamin D levels. In addition, the season of birth influences the development of atopic dermatitis, which could lead to food sensitization. Finally, ultraviolet radiation could lead to regulatory T cell expansion and immunosuppression, irrespective of vitamin D status. Based on our current understanding, we believe that correction of vitamin D deficiency by supplementation, appropriate skin care, and sufficient ultraviolet radiation exposure could alter the prognosis of food allergy. To identify potential treatment strategies for food allergy, it is essential to gain a better understanding of the appropriate levels of vitamin D and ultraviolet radiation exposure.

Immune suppression of food allergy by maternal IgG in murine models.

BACKGROUND: Most of the patients develop food allergy early in life. The factors related to parental immune condition might be one of the conceivable causes. METHODS: We reported murine models of food allergy and oral OVA tolerance. To investigate the influence of parental immune condition on infant food allergy, female and male mice with food allergy or oral tolerance were mated with each other. RESULTS: Food allergy was suppressed by decreased IgE production in the offspring of mice with food allergy. On the contrary, anaphylaxis for OVA was induced in the offspring of mice with oral tolerance. The suppression of food allergy being dependent on a maternal factor was revealed in the offspring after cross-mating mice with food allergy and oral tolerance. Because OVA-specific IgG, presumed to be from the allergic mother, was detected in the serum of naïve infants from mothers allergic to food, we assumed that the suppression was dependent on a specific IgG. The serum IgG purified by a G-protein column was administered before OVA sensitization in the food allergy model, and OVA-specific IgE production was found to be diminished in the administered mice. However, OVA-specific monoclonal IgG1 and IgG2a administration could not suppress food allergy. Because we detected OVA-IgG immune complex in the serum of mothers allergic to food, it might be a cause of maternal immune suppression. CONCLUSIONS: We demonstrated that maternal specific IgG conjugated food antigen is an important factor related to the development of food allergy and acquiring tolerance.

Eppikajutsuto Protects against Food Allergy Induced by Ovalbumin in a Murine Model.

BACKGROUND: Currently, there are no efficient medications available for the prevention and treatment of food allergy (FA). Herbal medicines, including traditional Japanese Kampo medicines (TJKMs), are promising therapeutic drugs. METHODS: We screened 18 TJKMs for treatment of FA symptoms in a mouse FA model induced by ovalbumin (OVA). BALB/c mice were sensitized intraperitoneally by an OVA/aluminum hydroxide gel mixture followed by 4 booster doses of oral OVA and FA symptom induction by 50 mg of OVA. TJKMs were orally administered for 28 days from the day of sensitization to the day before FA symptom induction. Evaluated FA symptoms included a decrease in body temperature and allergic diarrhea. Allergic sensitization was determined by plasma OVA-specific IgE levels. Cytokine mRNA levels in mesenteric lymph nodes, plasma mouse mast cell protease-1, and the number of mast cells in the small and large intestines were analyzed. Additionally, the therapeutic effect of the TJKM eppikajutsuto (EJT) on mast cell degranulation was determined in active anaphylaxis and passive cutaneous anaphylaxis models. RESULTS: EJT effectively prevented FA symptoms. Although OVA-specific IgE levels and the intestinal mast cell numbers were not different between the EJT-treated and untreated FA mice, plasma mMcpt1 and IL-4 levels were lower in EJT-treated FA mice than untreated FA mice. EJT could alleviate symptoms in both active and passive anaphylaxis models. CONCLUSION: EJT prevented OVA-induced FA symptoms in a mouse model, suggesting that EJT might exert its therapeutic activity via IL-4 suppression and the inhibition of mucosal mast cell degranulation.

Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs.

Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice.

Although we previously demonstrated the contribution of the DP1receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP1receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC:Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP1receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP1receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP1receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP1receptor signaling to sneezing was demonstrated using this model, suggesting that DP1receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis.

Collagen gel contraction assay using human bronchial smooth muscle cells and its application for evaluation of inhibitory effect of formoterol.

Collagen gel contraction assay is a method for evaluating contraction of cells embedded in collagen gel matrices through measuring the gel size. In the present study, we established a protocol for collagen gel contraction assay using human bronchial smooth muscle cells obtained commercially, and applied it for evaluation of inhibitory effect of formoterol on histamine-induced contraction. Human bronchial smooth muscle cells were embedded in collagen gel in wells of 24-well plates, and gel contraction against histamine or acetylcholine was observed. Gel size was measured at an interval of 10 min for 60 min from the addition of a stimulant. Both acetylcholine and histamine caused gel contraction in a concentration-dependent manner and the contraction by histamine was apparently potent than that by acetylcholine. Formoterol at concentrations of 10(-10)-10(-7) M inhibited collagen gel contraction caused by histamine concentration-dependently. Pre-treatment with fluticasone at a concentration of 10(-8) M apparently potentiated the inhibitory effect of formoterol at 10(-10) and 10(-8) M on collagen gel contraction by histamine. Prolonged pre-treatment with 10(-8) M formoterol abolished the inhibitory effect of 10(-8) M formoterol. Furthermore, 4 h simultaneous pre-treatment with 10(-8) M formoterol and fluticasone partially but significantly recovered the inhibitory effect of 10(-8) M formoterol. Present results indicate that the collagen gel contraction assay using human bronchial smooth muscle cells is useful for evaluating the effects of bronchodilating drugs, and that fluticasone potentiates the inhibitory effect of formoterol on histamine-induced collagen gel contraction.

Treatment of the chronic itch of atopic dermatitis using standard drugs and kampo medicines.

Atopic dermatitis is a common skin disease accompanied by intense itching. Relapsing eczema is caused by immune imbalances and skin-barrier disruption. The immunopathy and barrier dysfunction are closely related to the onset of itching and subsequent scratching, and intractable dermatitis is amplified by the itch-scratch cycle. The standard therapy for atopic dermatitis is topical corticosteroids and immunosuppressants to lessen the inflammation, along with moisturizing agents to improve the physiologic skin dysfunction. Corticosteroids are the primary treatment for the inflammation in atopic dermatitis. Some clinical trials demonstrated a tendency for the alleviation of pruritus with long-term treatment. Tacrolimus results in instant burning and itching in the short term, but they resolve a few days after the beginning of use and then are relieved. Substance P is a neuropeptide released from sensory nerve fibers and a neurotransmitter of pain and itching. Basic experimental reports indicated that the antipruritic effect of tacrolimus is probably dependent on depleting substance P, followed by transient induction. Oral administration of antihistamines and antiallergics is used as adjunctive pharmacotherapy for pruritus. It is known that second-generation antihistamines are less sedative or nonsedative drugs compared with the first generation, and the drugs have additional efficacy in blocking some chemical mediators. Japanese traditional Kampo medicines are also used for the treatment of atopic dermatitis. This paper discusses the efficacy of representative Kampo medicines in the treatment of inflammation and itching based on murine atopic dermatitis models. Information on the mechanism of action of Kampo medicines will result in more choice of pharmacotherapeutic agents for complex diseases such as atopic dermatitis.

9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant.

9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, induces apoptosis via the generation of reactive oxygen species (ROS) because of 9,10-PQ redox cycling. We have found that intratracheal infusion of 9,10-PQ facilitates the secretion of surfactant into rat alveolus. In the cultured rat lung, treatment with 9,10-PQ results in an increase in a lower-density surfactant by ROS generation through redox cycling of the quinone. The surfactant contains aldo-keto reductase (AKR) 1C15, which reduces 9,10-PQ and the enzyme level in the surfactant increases on treatment with 9,10-PQ suggesting an involvement of AKR1C15 in the redox cycling of the quinone. In six human cell types (A549, MKN45, Caco2, Hela, Molt4 and U937) only type II epithelial A549 cells secrete three human AKR1C subfamily members (AKR1C1, AKR1C2 and AKR1C3) with the surfactant into the medium; this secretion is highly increased by 9,10-PQ treatment. Using in vitro enzyme inhibition analysis, we have identified AKR1C3 as the most abundantly secreted AKR1C member. The AKR1C enzymes in the medium efficiently reduce 9,10-PQ and initiate its redox cycling accompanied by ROS production. The exposure of A549 cells to 9,10-PQ provokes viability loss, which is significantly protected by the addition of the AKR1C3 inhibitor and antioxidant enzyme and by the removal of the surfactants from the culture medium. Thus, the AKR1C enzymes secreted in pulmonary surfactants probably participate in the toxic mechanism triggered by 9,10-PQ.

The potential role of prostaglandin D2 in nasal congestion observed in a guinea pig model of allergic rhinitis.

BACKGROUND: Allergic rhinitis is the most common allergic disease, displaying the typical nasal symptom of congestion. Prostaglandin D(2) (PGD(2)), a chemical mediator released in large amounts by mast cells upon allergic stimulation in humans, is known to be involved in nasal congestion. However, the mechanism by which this congestion occurs remains unclear. METHODS: The effect of PGD(2) on the nasal airflow in guinea pigs was measured using a noninvasive approach that avoided any anesthetic effect. Isometric tension of isolated nasal mucosa and the nasal vascular corrosion resin cast technique were used to clarify the area of nasal mucosal vessels affected by PGD(2), and to examine the mechanism of PGD(2)-induced nasal congestion. Moreover, the involvement of second messengers in PGD(2)-induced mucosal relaxation was investigated. RESULTS: PGD(2) induced an increase in intranasal pressure in a guinea pig model of rhinitis. Additionally, sinusoidal microvessel dilatation appeared around the septum using the vascular corrosion resin cast technique in the nasal mucosa. Moreover, relaxation of the nasal mucosa following stimulation of the prostanoid DP-1 receptor was associated with cAMP levels in the tissue. CONCLUSIONS: PGD(2)-induced nasal congestion is caused by direct dilatation of the sinusoid vessels through the increase of cAMP levels in the nasal mucosa, demonstrating that the mechanism of PGD(2)-induced nasal congestion is different from other chemical mediators. Consequently, antagonists for the prostanoid DP-1 receptor would be an alternative approach for the relief of nasal congestion. Alternatively, the combined administration with antagonists for other mediators involved in nasal congestion may also be a valuable therapy for allergic rhinitis.

Transient receptor potential vanilloid 1 - a polymodal nociceptive receptor - plays a crucial role in formaldehyde-induced skin inflammation in mice.

Formaldehyde (FA) is irritating to the skin and is the main cause of sick building syndrome. However, the cutaneous reaction induced by long-term FA exposure has not been fully investigated. In our previous study, we demonstrated that repeated painting of 2% - 10% FA on mouse ears caused marked ear swelling and increased mRNA expression of transient receptor potential vanilloid 1 (TRPV1) and neurotrophins in the ear. TRPV1 is reported to be involved in neurogenic inflammation; therefore, in the present study, we investigated the role of TRPV1 in FA-induced skin inflammation using TRPV1 gene-knockout mice. Mice were painted with 5% FA once a week for 5 weeks, and ear swelling and mRNA expression were investigated. Ear swelling and increased expression of neurotrophins mRNA by FA provocation in wild-type mice were attenuated by disruption of the TRPV1 gene. Furthermore, painting with a threshold dose of capsaicin, which does not induce ear swelling in intact mice, caused marked ear swelling after painting the ear 5 times with FA, indicating that inflamed tissues after FA application are hypersensitive to various ligands of TRPV1 in mice. These results demonstrated that neurogenic inflammation via TRPV1 and neurotrophins could be involved in FA-induced dermatitis.

Lactobacillus acidophilus strain L-92 induces CD4(+)CD25(+)Foxp3(+) regulatory T cells and suppresses allergic contact dermatitis.

The anti-allergic mechanism of heat-killed Lactobacillus acidophilus strain L-92 has not been fully investigated. Recent studies have reported that CD4(+)CD25(+)Foxp3(+) (forkhead box P3) T regulatory (Treg) cells play important roles in controlling allergic diseases. Hence, we examined the effect of orally administered L-92 on CD4(+)CD25(+)Foxp3(+) cell populations. BALB/c mice were supplemented daily with L-92 by gavage for 5 weeks. 2,4-Dinitrofluorobenzene (DNFB) was used to induce allergic contact dermatitis (ACD) in mice. Fluorescent-activated cell sorter (FACS) analysis was used to determine CD4(+)CD25(+)Foxp3(+) T cell populations in spleen and cervical lymph nodes (CLN). Interleukin-10 (IL-10), transforming growth factor-ß (TGF-ß), and Foxp3 mRNA expressions in mouse ear skin were investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR). The percentage of CD4(+)CD25(+)Foxp3(+) T cell populations were significantly increased in both spleen and CLN of L-92-fed group than vehicle and control. In addition, L-92 produced higher levels of Foxp3, IL-10 and TGF-ß compared to control mice. These results suggest that L-92 can up-regulate the number of Treg cells to suppress the progression of DNFB-induced contact dermatitis in mice.

Periostin contributes to the pathogenesis of atopic dermatitis by inducing TSLP production from keratinocytes.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease where Th2-type immune responses are dominant. Keratinocytes persistently secrete proinflammatory cytokines and chemokines, amplifying Th2-type responses in AD. We have recently reported that periostin, an extracellular matrix protein induced by Th2 cytokines, plays a critical role in AD. In the present study, we have further investigated the characteristics of our allergen-induced AD model mice and the role of periostin in the pathogenesis of AD. METHODS: The ears of C57BL/6 mice, BALB/c mice, and Rag-2-/- γ(c)-/- mice (BALB/c background) were epicutaneously sensitized repeatedly with HDM. Mice were analyzed after the final sensitization. To examine the direct role of periostin, we reconstituted skin in vitro by coculture of keratinocytes with wild-type or periostin-deficient fibroblasts. RESULTS: Epicutaneous sensitization with HDM induced AD-like phenotypes and accumulation of periostin in dermis in C57BL/6 mice but not in Rag-2-/- γ(c)-/- mice. In vitro organotypic coculture systems revealed that periostin promoted survival and proliferation of keratinocytes and directly induced production of thymic stromal lymphopoietin (TSLP). CONCLUSIONS: Our results suggest that periostin exacerbates the pathogenesis of AD through TSLP production from keratinocytes.

Extracellular-superoxide dismutase expression during monocytic differentiation of U937 cells.

Leukemic cell lines, such as U937, THP-1, and HL60 cells, can differentiate into macrophages following exposure to various agents including 12-O-tetradecanoylphorbol-13-acetate (TPA) in vitro. It is well known that TPA enhances reactive oxygen species (ROS) generation through the activation of NADPH oxidase (NOX), and ROS act as mediators in TPA signaling. Extracellular-superoxide dismutase (EC-SOD) is a major anti-oxidative enzyme that protects the cells from damaging effects of superoxide. Recently, the reduction of Cu/Zn-SOD and the induction of Mn-SOD by TPA in leukemic cells have been reported; however, the regulation of EC-SOD by TPA remains poorly understood. Here, we explored the regulation of EC-SOD during the monocytic differentiation of U937 cells by TPA. We observed the reduction of EC-SOD and Cu/Zn-SOD, whereas the induction of Mn-SOD during the differentiation of U937 cells. The reduction of EC-SOD and Cu/Zn-SOD was attenuated by pretreatments with GF109203X (an inhibitor of protein kinase C, PKC), diphenyleneiodonium (an inhibitor of NOX), and U0126 (an inhibitor of mitogen-activated protein kinase kinase, MEK/extracellular-signal regulated kinase, ERK). Interestingly, pretreatment with BAY11-7082 (an inhibitor of nuclear factor-κB, NF-κB) suppressed the reduction of Cu/Zn-SOD, but not of EC-SOD. Furthermore, we also determined the involvement of newly synthesized protein and the instability of mRNA in the reduction of EC-SOD. Overall, our results suggest that the expression of EC-SOD is decreased by TPA through intracellular signaling consisting of PKC, NOX-derived ROS and MEK/ERK, but not of NF-κB signaling.

Characterization of skin inflammation induced by repeated exposure of toluene, xylene, and formaldehyde in mice.

Volatile organic compounds (VOCs) are considered the main cause of sick building syndrome and they are likely to irritate the skin, eyes, and mucous membrane; however, the toxic threshold and the mechanisms of cutaneous reaction induced by long-time VOC exposure have not been clarified. In the present study, we investigated the effect of repeated painting of VOCs onto mouse skin. Various concentrations of toluene, xylene, and formaldehyde (FA) were applied once a week for 5 weeks. While FA solution (2-10%) induced remarkable ear swelling and caused evident infiltration of inflammatory cells, high concentrations of toluene and xylene (50 or 100%) evoked mild ear swelling and marginal inflammatory cell invasion. In addition, FA exposure markedly increased the expression of interleukin-4 (IL-4), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and transient receptor potential vanilloid-1 (TRPV-1) mRNAs in the ears and IL-4 and NT-3 mRNAs in the cervical lymph nodes. Furthermore, capsazepine, a TRPV-1 antagonist, significantly suppressed ear swelling caused by repeated painting of 5% FA. These findings demonstrate that FA has more potent irritancy against skin than toluene or xylene and suggest that the Th2 response, neurotrophins and TRPV-1 play important roles in FA-induced skin inflammation.

Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network.

Montelukast is a selective leukotriene receptor antagonist that is widely used to treat bronchial asthma and nasal allergy. To clarify the association between montelukast and neuropsychiatric adverse events (AEs), we evaluated case reports recorded between January 2004 and December 2018 in the Food and Drug Administration Adverse Event Reporting System (FAERS). Furthermore, we elucidated the potential toxicological mechanisms of montelukast-associated neuropsychiatric AEs through functional enrichment analysis of human genes interacting with montelukast. The reporting odds ratios of suicidal ideation and depression in the system organ class of psychiatric disorders were 21.5 (95% confidence interval (CI): 20.3-22.9) and 8.2 (95% CI: 7.8-8.7), respectively. We explored 1,144 human genes that directly or indirectly interact with montelukast. The molecular complex detection (MCODE) plug-in of Cytoscape detected 14 clusters. Functional analysis indicated that several genes were significantly enriched in the biological processes of "neuroactive ligand-receptor interaction." "Mood disorders" and "major depressive disorder" were significant disease terms related to montelukast. Our retrospective analysis based on the FAERS demonstrated a significant association between montelukast and neuropsychiatric AEs. Functional enrichment analysis of montelukast-associated genes related to neuropsychiatric symptoms warrant further research on the underlying pharmacological mechanisms.

Evidence that integrin alpha IIb beta 3-dependent interaction of mast cells with fibrinogen exacerbates chronic inflammation.

Integrin alpha IIb beta 3 is expressed in mast cells as well as in megakaryocytes/platelets. A recent study has shown that surface expression levels of integrin alpha V beta 3 are elevated in integrin alpha IIb-deficient bone marrow-derived mast cells (BMMCs) as compared with wild-type (WT) counterparts, but the underlying mechanism remains obscure. Here we demonstrate by transducing integrin alpha IIb into integrin alpha IIb-deficient BMMCs that surface expression levels of integrin alpha V beta 3 are inversely related to those of integrin alpha IIb beta 3. Thus, competitive association of integrin beta 3 with integrin alpha IIb or integrin alpha V determines surface expression levels of integrin alpha IIb beta 3 or alpha V beta 3 in mast cells. We compared WT and integrin alpha IIb-deficient BMMCs as well as integrin alpha IIb-deficient BMMCs transduced with integrin alpha IIb(WT) or non-functional alpha IIb(D163A) mutant and found that enhancement of proliferation, degranulation, cytokine production, and migration of BMMCs through interaction with fibrinogen (FB) depended on integrin alpha IIb beta 3. In addition, elevated surface expression of integrin alpha V beta 3 failed to compensate for loss of FB-associated functions in integrin alpha IIb-deficient BMMCs while enhancing adhesion to vitronectin or von Willebrand factor. Importantly, integrin alpha IIb deficiency strongly suppressed chronic inflammation with the remarkable increase of mast cells induced by continuous intraperitoneal administration of FB, although it did not affect acute allergic responses or mast cell numbers in tissues in steady states. Interestingly, soluble FB promoted cytokine production of BMMCs in response to Staphylococcus aureus with FB-binding capacity, through integrin alpha IIb beta 3-dependent recognition of this pathogen. Collectively, integrin alpha IIb beta 3 in mast cells plays an important part in FB-associated, chronic inflammation and innate immune responses.

Effect of diesel exhaust particles on house dust mite-induced airway eosinophilic inflammation and remodeling in mice.

Recent research has focused on the effects of ambient particulate pollution and much evidence has indicated that particulate pollution is associated with the onset of asthma and allergy; however, the effect of diesel exhaust particles (DEP) on the development of allergen-induced airway remodeling has not been fully investigated in vivo. In the present study, we examined the effects of DEP on Dermatophagoides farinae allergens (Der f)-induced asthma-like phenotypes in mice. Mice were administered i.t. 8 times with Der f. DEP were injected i.t. with Der f 4 times throughout the experiment or twice at the sensitization period. In both cases, DEP aggravated Der f-induced increases in airway responsiveness to acetylcholine, the number of eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF), serum Der f-specific IgG1 levels, Th2 cytokines and transforming growth factor-beta1 levels in BALF, and amount of hydroxyproline in the right lungs. Furthermore, goblet cell hyperplasia and subepithelial fibrosis were also markedly aggravated. These findings indicate that DEP can potentiate airway remodeling induced by repeated allergen challenge as well as Th2-drived airway hyperresponsiveness, eosinophilic inflammation, and IgG1 production and that DEP can exhibit adjuvant activity for airway remodeling, probably due to the enhancement of allergen sensitization and/or of Th2 polarizing pathways.