Airway remodeling in asthma is characterized by goblet cell hyperplasia, subepithelial fibrosis, and hyperplasia and hypertrophy of airway smooth muscle cells. The airway wall thickness increases because of subepithelial fibrosis, and hyperplasia and hypertrophy of the airway smooth muscle cells and submucosal glands. Airway remodeling, therefore, can often cause irreversible airflow limitation and an increase of airway hyperresponsiveness. Recent studies have described the molecular and cellular mechanisms of collagen deposition in the airway wall such as subepithelial fibrosis. Fibroblasts or myofibroblasts play a critical role in the exaggerated deposition of collagen in asthmatic airways. Bone marrow derived fibroblasts may play a role in fibrotic remodeling in asthmatic airways. Airway remodeling is induced by cytokines and mediators produced in chronic allergic airway inflammation. Since, once formed, remodeling is resistant to asthma therapy, early intervention with inhaled corticosteroid should be considered to prevent the progress of airway remodeling.

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Asthma is a chronic inflammatory disease characterized by reversible airflow limitation and airway hyperresponsiveness. Persistent inflammation in airway tissues may lead to structural changes known as airway remodeling and consequently airway obstruction that is not fully reversible and progressive loss of lung function over time.
It is generally accepted that airway remodeling is closely related to progression of airway hyperresponsiveness, and the severity of asthma. The structural changes observed in chronic persistent asthma, which includes airway smooth muscle hypertrophy and hyperplasia, collagen deposition to sub-epithelial basement membrane, hyperplasia of goblet cells, thickening of airway mucosa and an increase in vascularity, are derived from airway inflammation. For instance, the thickened airway mucosa might be produced by cytokines and growth factors released from inflammatory cells and airway epithelial cells, and associated with bronchial hyperreactivity and asthma severity.
To date, many studies have identified candidate mechanisms and mediators for these observed structural changes, which are thus potential targets in the treatment of asthma. In this review, we describe the recent knowledge of the mechanisms and clinical implications of airway remodeling in asthma.

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Airway remodeling can be defined as changes in the composition, content, and organization of the cellular and molecular constituents of the airway wall. Airway remodeling is a characteristic feature of asthma, and has important functional implications. These structural changes include epithelial detachment, subepithelial fibrosis, increased airway smooth muscle (ASM) mass, decreased distance between epithelium and ASM cells, goblet cell hyperplasia, mucus gland hyperplasia, proliferation of blood vessels and airway edema and changes in the cartilage. Each can contribute to airway hyperreactivity (AHR), and may eventually lead to irreversible airflow obstruction with disease progression.
Structural changes can be observed from early onset of the disease and thus remodeling is thought to be characteristic of asthma. Some aspects of airway remodeling can be explained as a consequence of TH2 inflammation, although it has also been suggested that the exaggerated inflammation and remodeling seen in asthmatic airways is the consequence of abnormal injury and repair responses stemming from the susceptibility of bronchial epithelia to components of the inhaled environment. According to this view, remodeling occurs by way of a noninflammatory mechanism, where inflammation of airways and altered structure and function of the airways are parallel and interacting factors.
Airway remodeling in established asthma is poorly responsive to current therapies, such as inhalation of corticosteroids and administration of β₂-agonists, antileukotrienes, and theophylline.

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In Japan, the prevalence of food allergy has been increasing and a variety of problems have emerged regarding what should be considered a food allergy. A treatment regimen consists of avoiding the offending food (elimination diet therapy) and receiving nourishment from alternative foods (substitutional diet therapy). There is a growing concern that confusion has resulted from the lack of a consensus on the procedures for diagnosing and treating food allergies. The Food Allergy Committee of the Japanese Society of Pediatric Allergy and Clinical Immunology established the "Guidelines for Diagnosis and Management of Pediatric Food Allergy." Definition, classification, pathophysiology, clinical disorders and management of food allergy are discussed and determined.

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Despite numerous studies on possible associations between environmental exposure and allergic disorders, any conclusions made remain a matter of controversy. We conducted a review of evidence in relation to environmental and nutritional determinants and wheeze, asthma, atopic dermatitis, and allergic rhinitis. Identified were 263 articles for analysis after consideration of 1093 papers that were published since 2000 and selected by electronic search of the PubMed database using keywords relevant to epidemiological studies. Most were cross-sectional and case-control studies. Several prospective cohort studies revealed inconsistent associations between various environmental factors and the risk of any allergic disorder. Therefore, the evidence was inadequate to infer the presence or absence of a causal relationship between various environmental exposures and allergic diseases. However, evidence is suggestive of positive associations of allergies with heredity. Because almost all the studies were performed in Western countries, the application of these findings to people in other countries, including Japan, may not be appropriate. Further epidemiological information gained from population-based prospective cohort studies, in particular among Japanese together with other Asians, is needed to assess causal relationships between various environmental factors and allergic diseases.

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Known susceptibility genes to atopy and asthma have been identified by linkage or associations with clinical phenotypes, including total serum IgE levels. IgE-mediated sensitivity reactions require a high-affinity IgE receptor (FcεRI), which immobilizes the immunoglobulin on the surface of the effector cells, mostly mast cells and basophils. In this mini-review, recent findings are presented on genetic variation of this receptor, as related to atopy. Transcription of FCER1A gene encoding the receptor α subunit can be initiated from two separate promoters, the proximal one and the distal one, which results in a transcript containing two novel untranslated exons (1A, 2A). Our knowledge on the role of this mechanism in allergic diseases is still at an infancy stage. Within regulatory elements of FCER1A some common single nucleotide polymorphisms have functional associations, which were recently reported and replicated in different ethnical groups. Interestingly, these associations do not confer susceptibility to allergic diseases, but rather modulate serum concentrations of IgE. Similarly to the previously investigated β subunit of the receptor, FCER1A is a good candidate for a quantitative trait locus (QTL) in allergic diseases, and appears to participate in the systemic regulation of IgE levels.

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Background: Atopic dermatitis is a chronic or chronically relapsing, pruritic inflammatory skin disease. The incidence of atopic dermatitis has dramatically increased during the past three decades in industrialized countries. We attempted to develop an improved method to induce an animal model of atopic dermatitis and to use it to evaluate the efficacy of a Tec family kinase inhibitor.
Methods: We treated dermatitis-prone inbred mice, NC/Nga, by repetitive epicutaneous applications of a house dust mite allergen and staphylococcal enterotoxin B to induce atopic dermatitis-like skin lesions.
Results: We established a highly efficient protocol to induce skin lesions in NC/Nga mice, which were histologically and immunologically similar to human atopic dermatitis. Similar to human patients, serum IgE levels were increased in dermatitis-induced mice. Consistent with the proposed roles of infiltrated immune cells in the pathogenesis of human atopic dermatitis, skin lesions were treatable with terreic acid, an inhibitor of Tec family kinases, as well as dexamethasone.
Conclusions: We established a highly efficient, highly reproducible protocol to induce skin lesions in NC/Nga mice and successfully applied it to show the efficacy of terreic acid in treating skin lesions. This mouse model of atopic dermatitis will be useful to study the pathogenetic processes of atopic dermatitis and to evaluate the efficacy of drug candidates.

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Background: Epigenetic control of gene expression profiles is a ubiquitous mechanism during cell differentiation, organogenesis and chronic inflammatory reactions. Recent studies have shown that allergen exposure during very early pregnancy increases bronchial hypersensitivity in offspring in a murine model of bronchial asthma. However, no such phenomena were reported in humans. In the present study, the role of epigenetic control in the onset of allergic diseases was investigated.
Methods: A total of 400 pairs of mothers with physician-diagnosed allergic rhinitis (AR) and their offspring (age 7-18 months) who participated in a large-scale medical check-up were enrolled in this retrospective cohort study. Family history of allergic diseases and the presence or absence of AR symptoms during pregnancy were inquired about using a self-answered questionnaire. A logistic regression model adjusted for age, gender, birth month and father's history of allergic diseases was statistically analyzed.
Results: Offspring whose mothers had any AR symptoms during early pregnancy showed a significantly higher adjusted odds ratio for the onset of AR in offspring than those whose mothers had no symptoms during pregnancy (adjusted Odds Ratio: 6.26, p = 0.036). However, the symptoms of AR during late pregnancy showed no effects on the odds ratio. In contrast, the presence or absence of AR symptoms during early or late pregnancy showed no association with the prevalence of food allergy, atopic dermatitis or asthma in offspring.
Conclusions: Our results suggest the presence of possible epigenetic mechanisms regulating the onset of AR in humans presumably through increased organ-specific hypersensitivity.

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Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with high mortality.
Methods: To present the current clinical characteristics and treatment of SJS and TEN in Japan, we retrospectively analyzed reports of SJS and TEN published in medical journals from 2000 to 2006.
Results: Fifty-two cases of SJS (19 males and 33 females; mean age, 45.2 years) and 65 cases of TEN (31 males and 34 females; mean age, 45.7 years) were reported. Thirty-six cases of SJS (69.2%) and all cases of TEN were caused by drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and anticonvulsant drugs. Hepatitis was the most common organ involvement in both SJS and TEN. Renal dysfunction and respiratory disorders were also involved in some cases. The major complication was sepsis, but in only 1.9% of SJS and 10.8% of TEN. Most cases were treated systemically with corticosteroids, and 42 cases (80.8%) of SJS and 39 cases (60.0%) of TEN were treated with corticosteroids alone. Plasmapheresis and/or immunoglobulin therapy was combined with corticosteroid therapy in some cases. The mortality rates for patients with SJS and TEN were 1.9% and 6.2%, respectively. The mortality in TEN decreased remarkably from 21.6% (58/269) during the previous 17 years (1981 to 1997).
Conclusions: Improvement of treatment may be one of the reasons for the decrease in mortalities of both SJS and TEN.

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Background: Bodies of evidences have suggested that upper and lower airways are intricately interconnected with each other in patients with allergic airways diseases, however, few data are available concerning the impact of allergic rhinitis on self-assessed asthma condition and treatment satisfaction. The present study was conducted to clarify the association between nasal condition and self-assessment of asthma control and treatment satisfaction.
Methods: Adult patients with asthma were consecutively recruited for a systematic self-administered questionnaire to obtain information on nasal condition, self-perceived condition of asthma, and asthma treatment satisfaction.
Results: 3,140 adult patients with asthma completed the questionnaire, and of these 634 patients (mean age:53.1, 389 female) had physician-diagnosed allergic rhinitis. There were significant correlations between nasal symptoms (sneeze, rhinorrhea, nasal obstruction) and self-perceived asthma condition (limited daily activity, wheeze, dyspnea/chest tightness, cough, sputum, sleep disturbance, overall asthma condition). Patients who considered their overall nasal condition as unfavorable or bad were more likely than those who considered their condition as good or favorable to be dissatisfied with asthma treatment (p<0.01).
Conclusions: Nasal condition is closely associated with self-assessed asthma condition and asthma treatment satisfaction. Controlling allergic rhinitis is critical to attain optimal management of asthma in patients complicated by allergic rhinitis.

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Background: It has been reported that measurements of eosinophil-derived neurotoxin (EDN) may be useful for identifying eosinophil activities in allergic diseases including atopic dermatitis.
Methods: EDN concentrations in the urine were measured by enzyme-linked immunosorbent assay, and the number of eosinophils in the peripheral blood was counted in 30 patients with atopic dermatitis. The severity of atopic dermatitis was graded on the criteria proposed by Rajka and Langeland. The disease activity was assessed by each patient on a visual analogue scale (VAS).
Results: Urinary concentrations of EDN in patients with atopic dermatitis showed a significant positive correlation with disease severity. Urine EDN concentrations also correlated with VAS scores for itching, skin condition, overall skin symptoms and total VAS score, but not with the VAS score for skin dryness. Urinary EDN concentrations did not correlate with the number of eosinophils in the peripheral blood.
Conclusions: The urinary EDN concentration in patients with atopic dermatitis is a useful clinical marker for monitoring disease activity.

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Background: High-dose pooled human immunoglobulin (PHIG) treatment is sometimes effective in superantigen related inflammatory diseases, such as toxic shock syndrome and Kawasaki disease. Neutralizing antibody to superantigen might provide protection, but antigen independent immune regulation of PHIG is also a proposed mechanism.
Methods: Staphylococcal enterotoxin B (SEB)-specific IgG antibody in PHIG products (Venoglobulin IH^®) was detected by ELISA. The suppressive effect of PHIG or its fragments on proliferation and cytokine (IL-4 and IFN-γ) production from SEB-stimulated peripheral blood mononuclear cells was examined.
Results: SEB-specific IgG was detected in PHIG products. PHIG (6.25-25mg/ml) suppressed SEB-induced proliferation and cytokine production in a dose-dependent manner. Fab and F (ab') 2 fractions of PHIG also suppressed the responses, but depletion of SEB-specific antibody from PHIG did not affect the inhibitory effects. The Fc fragment of PHIG also showed partial, but significant suppression.
Conclusions: These data suggested the possibility that PHIG suppressed SEB-induced proliferation and cytokine production by some mechanisms independent of the presence of neutralizing antibody.

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Background: Pathogenesis of COPD is, at least in part, attributable to the chronic accumulation of neutrophils in the airways, and morphological changes such as hyperplasia of goblet cells in the airways are often observed in this disease. These structural changes were induced in guinea pigs by repetitive inhalations of LPS, and the effects of theophylline and dexamethasone were examined.
Methods: Male Hartley Guinea pigs weighing about 300 g were exposed to a nebulized solution of LPS (30μg/mL) for 1 hour. Exposure to LPS was performed 15 times at 48-hour intervals. Histological analysis was performed, and infiltration of leukocytes in BALF, airway hyperreactivity and hydroxyproline content of the lung were measured 24 or 48 hours after the final exposure of LPS. Drugs were administered every day until 30 minutes before the final exposure.
Results: Repetitive exposure to LPS induced an influx of inflammatory cells into the BALF. Histological changes such as accumulation of inflammatory cells in the lung parenchyma, enlargement of alveoli, swelling of the alveolar walls and goblet cell hyperplasia in the airways were observed. Airway hyperreactivity and increased lung hydroxyproline content were also found in this model of chronic inflammatory lung injury. Some of these changes induced by repetitive LPS exposure were improved by treatment with theophylline or dexamethasone.
Conclusions: Theophylline improved airway injury as well as airway hyperreactivity induced by repetitive exposure of the guinea pigs to LPS. These results suggest that theophylline treatment has ameliorative effects on airway disease with chronic inflammation.

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Background: Osteoclasts are bone-resorbing multinuclear polykaryons essential for bone remodeling, formed through cell fusion of mononuclear macrophage/monocyte lineage precursor cells upon stimulation by the RANK/RANKL system. Recent studies have revealed that a family of tetraspanin proteins, such as CD9, is critically involved in the cell fusion/polykaryon formation of these cell types. Until now, however, there is limited knowledge about the types of tetraspanins expressed in osteoclasts and their precursors.
Methods: The expression of different tetraspanin proteins in a monocyte/macrophage-lineage osteoclast precursor cell line, RAW264.7, was cyclopedically investigated using RT-PCR with specific primers and quantitative real-time RT-PCR. The function of two kinds of tetraspanins, Tspan-5 and NET-6, whose expression pattern was altered by RANKL stimulation, was examined by transfecting gene-specific short-interfering RNAs into these cell types.
Results: Of the 17 tetraspanins in mammalian hematopoietic cells, RAW264.7 cells express mRNA for 12 different kinds of tetraspanins, namely, CD9, CD37, CD53, CD63, CD81, CD82, CD151, NAG-2, NET-6, SAS, Tspan-3, and Tspan-5. Interestingly, during their maturation into osteoclasts upon RANKL stimulation, the transcript for Tspan-5 is up-regulated, whereas that for NET-6 is down-regulated. Targeted inhibition of Tspan-5 by using gene-specific RNA interference suppressed RANKL-induced cell fusion during osteoclastogenesis, whereas inhibition of NET-6 augmented the osteoclastogenesis itself. These results suggest that Tspan-5 and NET-6 have a reciprocal function during osteoclastogenesis, i.e., positive and negative regulation by Tspan-5 and NET-6, respectively. RANKL regulates osteoclastogenesis by altering the balances of these tetraspanin proteins.
Conclusions: These data indicate that a diversity of tetraspanins is expressed in osteoclast precursors, and that cell fusion during osteoclastogenesis is regulated by cooperation of distinct tetraspanin family proteins such as Tspan-5 and NET-6. This study indicates that functional alterations of tetraspanin family proteins may have therapeutic potential in diseases where osteoclasts play a major role, such as rheumatoid arthritis and osteoporosis.

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Background: We are developing an immunotherapeutic peptide, Cry-consensus peptide, for Japanese cedar pollinosis. Cry-consensus peptide is a recombinant polypeptide containing six major human T-cell epitopes derived from both Cry j 1 and Cry j 2, two major allergens of Japanese cedar pollen. We examined the effect of Cry-consensus peptide on an allergic rhinitis model in B10.S mice, which have one common T-cell epitope in the Cry-consensus peptide.
Methods: B10.S mice were sensitized with Cry j 1/alum, then the Cry-consensus peptide was administered subcutaneously once a week for 5 weeks from the last sensitization. Histamine was dropped in both nostrils (10μL per nostril) of each mouse on the day before continuous intranasal instillation of Cry j 1. Soon after the final challenge with Cry j 1, the mice were observed for 5 minutes for the resulting number of sneezes. In addition, serum levels of Cry j 1-specific IgE and IgG2a antibody, eosinophil infiltration in nasal tissue, and Cry j 1-specific cytokine production from splenocytes were evaluated.
Results: Cry-consensus peptide markedly inhibited Cry j 1-induced sneezes, eosinophil infiltration, and eosinophil peroxidase (EPO) activity in nasal tissue. Cry-consensus peptide inhibited the production of anti-Cry j 1 IgE (Th2-mediated) and significantly enhanced anti-Cry j 1 IgG2a (Th1-mediated). In cytokine production from splenocytes, Cry-consensus peptide significantly decreased in IL-4/IFN-γ and IL-5/IFN-γ ratios.
Conclusions: It was concluded that Cry-consensus peptide effectively controlled allergic responses, which results from shifting from a Th2-dominated to a Th1-dominated immune response.

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Background: Food protein-induced enterocolitis syndrome (FPIES) is a severe, cell-mediated food allergy in which digestive symptoms such as severe vomiting and diarrhea are induced by cow's milk and/or soy protein in infants. Generally, a food-specific IgE is not detected, and FPIES may be caused by inadvertent exposure to allergenic foods.
Case Summary: The patient in our case was a male infant in whom vomiting had been induced by ingestion of a cow's milk-based formula and bloody diarrhea had been caused by ingestion of breast milk during the neonatal period. Accidental ingestion of a new and extensively hydrolyzed casein/whey formula, MA-mi, caused watery diarrhea at 8 months of age, and FPIES was diagnosed based on these symptoms. In antigen-specific lymphocyte stimulation tests, New MA-1 was negative, but MA-mi and cow's milk antigens were positive. The only causative antigens were derived from cow's milk, and the symptoms were not induced by another extensively hydrolyzed casein formula, New MA-1. The patient grew and developed normally thereafter, and no symptoms were induced by solid food during the course of the condition.
Discussion: MA-mi is likely to be used increasingly for allergic infants, but it is not necessarily a substitute for other hydrolyzed milk formulae in all cases, and care should be taken regarding its use and possible misuse.

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