Background: In atopic dermatitis (AD) there is evidence of tissue fibrosis involving a number of structural changes, including papillary dermal fibrosis and epidermal hyperplasia. These changes are ...suggested to be the result of chronic inflammation of the skin. Several remodeling-associated cytokines, including transforming growth factor (TGF) β1, IL-11, and IL-17, have been shown to be increased in allergic diseases, including asthma. Objective: We investigated TGF-β1, IL-11, and IL-17 expression in skin biopsy specimens recovered from acute and chronic skin lesions from patients with AD, as well as from uninvolved skin of patients with AD and skin from healthy volunteers. We also examined the correlation between the expression of these cytokines and the extent of total, type I, and type III collagen deposition. Methods: We evaluated the expression of TGF-β1, IL-11, and IL-17 by means of immunohistochemistry. Collagen deposition was assessed by means of immunohistochemistry and van Gieson staining. Results: TGF-β1 expression was markedly enhanced in both acute and particularly chronic lesions (
P < .001). Although IL-11 expression was significantly increased only in chronic lesions (
P < .0001), IL-17 was preferentially associated with acute lesions (
P < .005). Although collagen type III deposition was not significantly different among the groups, type I collagen deposition was significantly increased in chronic AD lesions (
P < .0005). There was a significant correlation between IL-11 and type I collagen deposition, as well as the number of eosinophils in skin specimens from patients with AD (
r
2 = 0.527, and
r
2 = 0.622, respectively;
P < .0001). Conclusion: These results suggest that TGF-β1, IL-11, and IL-17 are involved in the remodeling of skin lesions in patients with AD. However, IL-11 and IL-17 are preferentially expressed at different stages of the disease. Type I collagen appeared to be the major subtype involved in this repair process.
Background: Allergic rhinitis is a complex upper airways disorder characterized by the infiltration of eosinophils and T
H2-type T lymphocytes. GATA-3 is a novel transcription factor recently shown ...to regulate IL-5 and, possibly, IL-4 gene expression. We previously reported that GATA-3 is increased within the bronchial mucosa of allergic asthmatic subjects compared with control subjects.
Objective: In the present study we set out to determine whether there is also an increased number of cells expressing GATA-3 messenger (m)RNA within the nasal mucosa of patients with allergic rhinitis.
Methods: Inferior turbinate biopsy specimens were obtained from patients with allergic rhinitis and nonatopic control subjects before and after local allergen provocation in vivo. To assess the contribution of resident cells expressing GATA-3 mRNA, we also performed isolated explant studies in which nasal mucosal tissue from subjects with allergic rhinitis and nonatopic control subjects was cultured in allergen-treated medium. The presence of mRNA coding for GATA-3, IL-5, IL-4, IL-13, and GM-CSF was assessed by using in situ hybridization.
Results: The number of GATA-3 mRNA
+ cells was increased after local allergen provocation in vivo (increase in GATA-3 mRNA
+ cells mean ± SEM: subjects with allergic rhinitis, 11.3 ± 8.7; control subjects, 1.2 ± 4.1;
P < .05) and in explanted nasal mucosa in vitro (subjects with allergic rhinitis, 10.2 ± 3.8; control subjects, 2.7 ± 4.4;
P < .05). The gene expression of GATA-3 was significantly correlated to the numbers of IL-5 (
r = 0.87) and GM-CSF (
r = 0.79) mRNA
+ cells but not with IL-4 or IL-13 mRNA
+ cells.
Conclusion: In summary, the expression of the transcription factor GATA-3 was increased after allergen challenge, and this was evident in the absence of de novo inflammatory cell recruitment. GATA-3 may be a potential target in the treatment of allergic diseases, such as rhinitis. (J Allergy Clin Immunol 2000;105:1146-52.)
To identify risk factors for childhood wheezing and allergies, a questionnaire regarding family histories and environmental factors was added to the International Study of Asthma and Allergies in ...Childhood (ISAAC) Phase One questionnaire and the associations between current prevalence and risk factors were analyzed.
Questionnaires were completed by 4466 schoolchildren, who were 13–14 years of age, in Tochigi Prefecture. Children were divided into groups on the basis of risk factors and the severity of each allergic disease according to answers to the ISAAC questionnaire.
In analyses of family histories, the odds ratios (OR) of children who have a family history with no symptoms were significantly lower by risk factor-based analyses compared with those children with a family history of symptoms of wheezing (OR = 2.34-4.39), rhinitis (1.76-2.68) and eczema (2.54-7.81), and significant correlations were observed between severity and family history in all diseases by the Mantel test (P < 0.001). Although the OR of household smoking was not significant, heavier smoking in a household had an effect on severity and showed a significant correlation with severity in rhinitis (P < 0.05) and eczema (P < 0.01). Regarding road traffic, the percentage of children living in an area with heavy traffic showed a significant correlation with the severity of wheezing (P < 0.05) and no children with severe wheezing lived in areas with light traffic. In addition, the mean percentage of children with current wheezing between school locations was significantly higher in the city area (10.2 ± 0.7%) compared with that in the suburbs (6.6 ± 0.9%; P = 0.01) and industrial areas (6.6 ± 0.7%; P = 0.01).
These results suggest that the family histories may have potential effects on the severity of allergic diseases and that household smoking for rhinitis and eczema and heavy road traffic for asthma may be more important modifiable risk factors for severity in Japan.
Interleukin (IL)-9 has recently been shown to play an important role in allergic disease because its expression is strongly associated with the degree of airway responsiveness and the asthmatic-like ...phenotype. IL-9 is a pleiotropic cytokine that is active on many cell types involved in the allergic immune response. Mucus hypersecretion is a clinical feature of chronic airway diseases; however, the mechanisms underlying the induction of mucin are poorly understood. In this report, we show that IL-9 regulates the expression of a subset of mucin genes in lung cells both in vivo and in vitro. In vivo, the constitutive expression of IL-9 in transgenic mice results in elevated MUC2 and MUC5AC gene expression in airway epithelial cells and periodic acid-Schiff-positive staining (reflecting mucous glycogenates). Similar results were observed in C57BL/6J mice after IL-9 intratracheal instillation. In contrast, instillation of the T helper 1-associated cytokine interferon gamma failed to induce mucin production. In vitro, our studies showed that IL-9 also induces expression of MUC2 and MUC5AC in human primary lung cultures and in the human muccoepidermoid NCI-H292 cell line, indicating a direct effect of IL-9 on inducing mucin expression in these cells. Altogether, these results suggest that upregulation of mucin by IL-9 might contribute to the pathogenesis of human inflammatory airway disorders, such as asthma. These data extend the role of the biologic processes that IL-9 has on regulating the many clinical features of asthma and further supports the IL-9 pathway as a key mediator of the asthmatic response.
: Interleukin (IL)-9 is a pleiotropic T helper 2-type cytokine that has been shown to be up-regulated in allergic airway disease, including asthma. IL-9 has been demonstrated to be a potent stimulus ...for the production and secretion of mucus from airway epithelial cells via induction of a calcium-activated chloride channel, hCLCA1. The objective of this study was to investigate the expression of IL-9 and hCLCA1 following allergen challenge in the nasal mucosa of allergic rhinitis patients. Nasal biopsies were obtained from allergic rhinitis patients out of allergen season both before (baseline) and after local antigen challenge with either ragweed or diluent (control). Immunohistochemistry and in situ hybridization were used to assess IL-9 protein and hCLCA1 messenger ribonucleic acid. Eosinophils and T cells were detected using immunohistochemistry. IL-9 and hCLCA1 were very low at baseline, and expression was significantly up-regulated following ragweed challenge. Whereas the number of eosinophils increased after allergen challenge, T-cell counts did not change significantly. The results of this study demonstrate the relationship between specific allergen challenge and expression of both IL-9 and hCLCA1, suggesting a possible mechanism for the increased production of mucus from airway epithelial cells in allergic rhinitis.
Background: One of the cardinal features of airway remodeling in asthma is mucus gland hyperplasia and mucus overproduction and hypersecretion. Recently, a calcium-activated chloride channel, HCLCA1 ..., was described that is upregulated by IL-9 and thought to regulate the expression of soluble gel-forming mucins, such as MUC5A/C, a critical component of mucus in the airways. Objective: We sought to examine the expression of HCLCA1 in bronchial biopsy specimens of asthmatic subjects compared with those of control subjects and to demonstrate its relationship with IL-9, IL-9 receptor (IL-9R), and markers of mucus production. Methods: Bronchial biopsy specimens from asthmatic (n = 9) and control (n = 10) subjects were stained with periodic acid-Schiff to identify mucus glycoconjugates. IL-9- and IL-9R-positive cells were identified with immunocytochemistry, and HCLCA1 expression was detected by means of in situ hybridization with cRNA probes. Results: We demonstrate significant increases in IL-9 (P < .001) and IL-9R (P < .05) immunoreactivity, as well as increased expression of HCLCA1 mRNA (P < .001), in the epithelium of asthmatic patients compared with that found in control subjects. There was also an increase in the number of mucusproducing cells in biopsy specimens from asthmatic subjects (P < .001). HCLCA1 mRNA was strongly and selectively colocalized with periodic acid-Schiff and IL-9R-positive epithelial cells. In particular, a strong positive correlation was observed between HCLCA1 mRNA expression and IL-9-positive (r = 0.69, P < 0.01) or IL9R-positive (r = 0.79, P < .01) cells. Conclusion: An upregulation of HCLCA1 in the IL-9- responsive mucus-producing epithelium of asthmatic subjects compared with that seen in control subjects supports the hypothesis that this channel may be responsible, in part, for the overproduction of mucus in asthmatic subjects. These preliminary findings suggest the inhibition of HCLCA1 may be an important new therapeutic approach to control mucus overproduction in chronic airway disorders. (J Allergy Clin Immunol 2002;109:246-50.)
To analyze the prevalence and severity of asthma, rhinitis and eczema in children living in different countries, the International Study of Asthma and Allergies in Childhood (ISAAC) was developed. ...The ISAAC Phase One study evaluated approximately 720 000 children in 56 countries, including Japan. In late 1995 and early 1996, we administered the ISAAC questionnaire to 4466 schoolchildren aged 13–14 years of age in 24 schools in Utsunomiya City and Tochigi City (both in Tochigi Prefecture, Japan). With regard to asthma, the reported prevalence of wheezing in the preceding 12 months was 8.4%, of frequent wheezing attacks 0.6% and of wheezing with sleep disturbance 0.5%. The prevalence in the preceding 12 months of rhinitis was 42.1% and of rhinoconjunctivitis was 21.5%. Nasal symptoms were most frequent in April (19.9%) and least frequent in July (5.6%). The prevalence of atopic eczema in the prior 12 months was 9.6% and atopic eczema with sleep disturbance was 0.6%. All prevalence values were slightly increased in Utsunomiya City, the largest city in Tochigi Prefecture, in comparison with Tochigi City. In conclusion, in Japanese cities, 33.3% of children had some allergic symptoms and 2.4% of children reported severe allergic symptoms.
Background: We have recently demonstrated an increased number of glucocorticoid receptor-β (GRβ)–positive cells in steroid-insensitive subjects with severe asthma. Insensitivity to steroids may be a ...major contributing factor in fatal asthma; however, no such direct evidence has been report previously. Objective: Our aims were to investigate the expression of GRβ immunoreactivity, an endogenous inhibitor of steroid action previously associated with steroid insensitivity, within the airways of patients who died of slow-onset fatal asthma and to compare its expression in patients with emphysema and in nonasthmatic subjects who died of unrelated causes. Sections from airways, both large and small, were obtained from 7 patients who died of asthma, 6 who died from emphysema, and 8 who died from nonpulmonary diseases. Sections from lungs of 6 patients with mild asthma whose lungs were resected for carcinoma were also included as controls. Methods: Tissue samples were processed for immunocytochemistry with a polyclonal antibody to GRβ with use of the avidin-biotin technique and with monoclonal CD3, major basic protein, CD68, and elastase antibodies with the alkaline phosphatase–anti-alkaline phosphatase technique. Sequential immunocytochemistry was performed to phenotype the GRβ immunoreactive cells. Tissue sections from both large (>2 mm) and small (<2 mm) airways were examined. Results: There was a significantly greater number of GRβ immunoreactive cells in fatal asthma compared with emphysema and controls (P < .001 and P < .05, respectively). There was no difference in the expression of GRβ in emphysema compared with controls. GRβ immunoreactivity was also significantly higher in fatal asthma compared with mild asthma. The expression of GRβ in the small airways of patients with severe asthma did not differ significantly from that in the large airways. The majority of GRβ-positive cells were T cells and to a lesser extent eosinophils, macrophages, and neutrophils. Conclusion: The results of this study support the association of GRβ expression with fatal asthma and suggest that alternative anti-inflammatory agents need to be considered in the acute setting for patients who are not responding to steroid therapy. (J Allergy Clin Immunol 2000;106:479-84.)
When a manufacturer and its retailers and consumers are spatially separated, the retailers’ market size may be limited by the manufacturer who provides consumers with an option to purchase goods ...directly from them. The manufacturer uses this tactic to increase profit when a few retailers dominate the market. The mill price of a manufacturer, that is, the price of the good at delivery from a manufacturer’s factory, is critical under these circumstances.
If the manufacturer charges a franchise fee, thus absorbing the retailer’s profit, this fee is a function of the mill price. Mill price policy can be used to maximize profit on the sale of goods and collection of the franchise fee. The resulting retail market structure becomes preferable for the manufacturer and consumers since the manufacturer’s profit is larger, as is the quantity purchased, compared with a competitive equilibrium in which every firm entering the market area is assumed to move its location instantly without cost.
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