Therapy with inhaled corticosteroids (ICS) has been regarded as first-line treatment for persistent asthma because of its highly potent anti-inflammatory effects. However, the limitations of such therapy are also well known. Although the anti-inflammatory effects of ICS are initially dose dependent, a plateau of response is reached at medium doses and a further increase of the dose is not associated with any significant additional therapeutic benefit. In contrast, it has been reported that a proportion of patients with severe asthma may benefit from prolonged treatment with higher doses of ICS in terms of a reduction in the frequency of severe acute exacerbations. Inhaled corticosteroids also exhibit a dose-response relationship for systemic adverse effects, which are most pronounced in patients receiving high doses of ICS. Thus, the long-term systemic burden of steroids should be minimized by always attempting to reduce the dose of ICS to the minimum required to maintain acceptable control of asthma symptoms and instituting, where required, add-on therapy with other controller agents, such as inhaled long-acting β2-adrenergic receptor agonists and leukotriene receptor antagonists.
Respiratory syncytial virus (RSV) infection in early childhood is a risk factor for the development of wheezing, significant decreases in pulmonary function and increases in airway reactivity. Respiratory syncytial virus infection also exacerbates recurrent wheezing attacks in patients with established asthma. Here we review the present understanding of RSV-induced bronchial asthma, especially concerning the role of eosinophils. Recent evidence suggests that eosinophils are important in RSV infection and RSV-induced asthma. For example, the eosinophil count and concentrations of eosinophil cationic protein, an eosinophil toxic granule protein, were elevated in samples of blood and nasopharyngeal secretions from patients with RSV infection or RSV-induced asthma; this suggests that eosinophils degranulate in the respiratory tract during RSV infection. Respiratory syncytial virus can infect human eosinophils, which produce chemokines such as RANTES, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α. We have demonstrated that RSV enhances superoxide production by human eosinophils stimulated with a lipid mediator, such as platelet-activating factor. This response is dependent on β2 integrin, αMβ2, which is critical for eosinophil effector functions. Previous studies have demonstrated that RSV-infected epithelial cells produce multiple cytokines and chemokines. We have found that RSV enhances eosinophil adhesion and degranulation following infection of BEAS-2B bronchial epithelial cells and that another eosinophil toxic granule protein, major basic protein or eosinophil peroxidase, synergistically augments RSV-induced epithelial cell damage and apoptosis in A549 cells. These results suggest that eosinophils and their products enhance RSV-induced airway inflammation in asthma. Closely delineating the mechanism by which RSV enhances eosinophilic inflammation in asthma should be useful in devising more effective therapy.
Early introduction of inhaled steroids as a treatment for childhood asthma is recommended in the guidelines to achieve not only early control of symptoms with an improvement in patients' quality of life, but also for the inhibition of airway remodeling. The evidence suggesting clinical usefulness of early intervention with inhaled steroids exists in school-age or older children with asthma. However, further investigations are required to determine the value of early intervention with inhaled steroids in asthmatic infants and very young children, because the disease concept and diagnosis of asthma, as well as clinical usefulness and adverse reactions to inhaled steroids, have not been sufficiently investigated.
In a recent epidemiological study, 15-20% of the population in Japan was estimated to have allergic conjunctivitis. Allergic conjunctival diseases (ACD) have a wide spectrum of clinical severity and the treatment strategy depends on the severity and duration of the disease. Most cases of the non-proliferative type of ACD, such as seasonal or perennial allergic conjunctivitis, can be treated with topical anti-allergic drugs. Of the ACD, vernal keratoconjunctivitis (VKC) is characterized by typical proliferative lesions, such as giant papillae and severe corneal lesions. Corticosteroid eye drops should be used in combination with anti-allergic eye drops when an anti-allergic drug is insufficient in cases of VKC and atopic keratoconjunctivitis with proliferative lesions. In spite of the high effectiveness of corticosteroid eye drops, they have important side-effects, such as elevation of intraocular pressure leading to glaucoma. Immunosuppressive agents and non-steroidal anti-inflammatory drugs (NSAIDs) are alternative topical agents to corticosteroids. Topically administered immunosuppressive agents, such as ciclosporin and tacrolimus, have antifibroblastic actions by inhibiting remodeling-inducing cells and act as a controller in the treatment of ACD. Non-steroidal anti-inflammatory drug eye drops can be used to inhibit remodeling in ACD because of their excellent anti-inflammatory and antifibroblastic effects, next to corticosteroids and immunosuppressive agents. Substitution of the topical treatment with corticosteroids by these agents in ACD not only spares the use of corticosteroids and decreases the risk of side-effects, but also brings about a more favorable effect in the long-term control of proliferative-type ACD.
It is believed that G-protein-coupled receptors are the most promising target proteins for drug research. The β2-adrenergic receptor has been analyzed extensively in terms of its structure, regulation and signaling as a prototype G-protein-coupled receptor. Recent development of a recombinant β2-adrenergic receptor reveals that the receptor exists in different conformations in addition to the resting and active forms. Furthermore, different conformations that are important for coupling with G-proteins are induced in a ligand-specific manner. After the receptor binds an agonist, the receptor is phosphorylated by G-protein-coupled receptor kinase or second messenger-dependent kinase. β-Arrestin is a cytosolic protein that binds to receptors phosphorylated by G-protein-coupled receptor kinase, but not those phosphorylated by second messenger-dependent kinase, and plays important roles in agonist-induced desensitization. However, β-arrestin has recently been recognized as a scaffold protein that helps to achieve efficient transmission of internalization and signaling. Receptor agonists can be divided into two groups: full and partial agonists. Partial agonists have an advantage over full agonists because desensitization is less likely to be induced following stimulation with a partial agonist. However, the effects of partial agonists on β-arrestin-mediated signaling and internalization have not been fully examined so far. Information regarding the binding sites of partial agonists is still not sufficient to explain why they cannot fully activate the receptor. In the present study, recent progress regarding the structure, regulation and signaling of β2 adrenergic receptors and about differences between full and partial agonists will be summarized.
Background: Atopic dermatitis (AD) is characterized by repetitious eczematous skin and is Th2 dominant in nature. Atopic dermatitis lesions have been observed to improve in patients during viral or bacterial infection, such as herpes simplex virus (HSV). A Th1 pathway established to counter viral infection may possibly be the mechanism for the relief of skin lesions in AD. Methods: In animal AD models using NC/Nga mice, the effects of local intra- and/or subcutaneous injection of ultraviolet inactivated-HSV were examined for Th1/Th2 regulation through a negative regulation pathway with suppressor of cytokine signaling (SOCS)-3 and 5 using immunohistochemistry, in situ hybridization and reverse transcription-polymerase chain reaction. Results: Lesional skin of HSV-treated mice displayed extensive interleukin (IL)-12p40-positive cellular infiltration compared with non-treated mice and IL-12p40/signal transducers and activators of transcription (STAT) 4/SOCS5 mRNA expression was noted basically the same in the three groups. Interleukin-4 receptor-positive cellular infiltrates in HSV-treated mice decreased significantly more than in non-treated mice and IL-4 mRNA expression in the three groups was essentially the same, but the expression of STAT6 and SOCS3 mRNA specific for the Th2 regulation pathway was reduced more in HSV-treated compared with non-treated mice. Expression of SOCS3 mRNA in situ in HSV-treated epidermis underwent a far greater reduction compared with expression in non-treated mice. Conclusions: Ultraviolet-inactivated HSV treatment would appear to induce a Th1 cellular response and downregulate that of the Th2 pathway in AD-like lesions of NC/Nga mice by bringing about a reduction of SOCS3 expression in the skin. From the present results, certain HSV DNA components may be effective candidates for a new therapeutic approach in refractory AD.
Background: The efficacy of montelukast, a specific cysteinyl leukotriene receptor antagonist, in preventing recurrent asthma attacks was evaluated for post-emergency management of acute asthma exacerbation. Methods: Twenty-two patients with a history of chronic asthma whose symptoms were responsive to an inhaled β-adrenergic receptor agonist in an emergency room setting, were randomized into two groups, those with and those without montelukast (n = 11 for each group). Patients in the montelukast group received an oral dose of 10 mg montelukast before leaving the emergency room following rescue treatment with an inhaled β-adrenergic receptor agonist. Patients in both groups were instructed to use an inhaled β-adrenergic receptor agonist for shortness of breath or dyspnea in post-emergency management. Additional β-adrenergic receptor agonist use, subjective asthma symptoms, sleep impairment, additional emergency visits and/or hospitalization were monitored for 24 hours following the emergency room visit. Results: In the montelukast group, the need for a rescue β-adrenergic receptor agonist was significantly decreased; 54.5% of patients in the montelukast group required use of β-adrenergic receptor agonist compared with 100% in the non-montelukast group (P < 0.05). The average number of uses of a β-adrenergic receptor agonist was 2.67 ± 3.58 times/24 h in the montelukast group compared with 11.95 ± 3.60 times/24 h in the non-montelukast group (P < 0.01). The average subjective asthma symptom scores were significantly decreased in the montelukast group, whereas no score change occurred in the non-montelukast group. The sleep impairment score was significantly lower in the montelukast group compared with that in the non-montelukast group (P < 0.05). No patients in either group had an emergency visit or hospitalization during this period. Conclusions: The results demonstrate that montelukast can prevent recurrent asthma exacerbations in the home environment.
Background: Itching, a typical symptom in dermatitis, including atopic dermatitis (AD), leads to scratching. In the present study, we investigated whether histamine-induced itching is involved in scratching behavior seen in NC/Nga (NC) mice, in which AD-like dermatitis is induced spontaneously. Methods: The severity score of dermatitis, the number of scratches, histamine content, activity of the histamine-forming enzyme histidine decarboxylase (HDC), the number of mast cells and the effect of histamine receptor antagonists were examined. Results: We found two types of scratching behavior in NC mice, one of a short duration (0.3-1.0 s) and the other of a longer duration (over 1.0 s). The number of short scratchings and HDC activity increased with age (4-13 weeks) in parallel with the severity of dermatitis in NC mice raised in conventional surroundings. The number of longer-duration scratchings had increased before any apparent development of dermatitis and this type of scratching behavior increased at 13 weeks, as did histamine content and mast cell number in the skin. There were no changes in these parameters in NC mice raised in specific pathogen-free surroundings during the experimental period. Chlorpheniramine (a histamine H1 receptor antagonist), but not histamine H2 and H3/4 receptor antagonists, decreased the number of short scratchings. None of the histamine receptor antagonists decreased the number of long scratchings, whereas tacrolimus reduced both short and long scratching behavior. Conclusions: The findings of the present suggest that histamine produced by enhanced HDC activity is involved in the induction of short scratchings in NC mice.
Background: It has been reported that measurements of eosinophil-derived neurotoxin (EDN) may be useful to determine eosinophil activities in allergic diseases. Methods: Serum, plasma and urine concentrations of EDN in patients with allergic diseases were measured by enzyme-linked immunosorbent assay. Samples of blood and urine were obtained from the same patients when their symptoms were active and when patients were well. The number of eosinophils in peripheral blood was also counted. Results: The median concentrations of EDN in blood and urine and the number of eosinophils in peripheral blood from patients with active symptoms were all significantly higher compared with values obtained when patients were well. Compared with healthy control subjects, EDN concentrations in the serum, plasma and urine from asymptomatic asthmatic patients, as well as EDN concentrations in the serum and plasma from patients with mild atopic dermatitis and asymptomatic patients with seasonal allergic rhinitis, were significantly higher. Blood and urine concentrations of EDN in patients with active symptoms, but not urine concentrations of EDN from symptomatic patients with seasonal allergic rhinitis, were significantly increased compared with values obtained for healthy control subjects. The concentrations of EDN in the serum and plasma from bronchial asthmatic patients, serum from patients with atopic dermatitis and plasma from patients with mild atopic dermatitis correlated with the number of eosinophils in peripheral blood; however, the concentration of EDN in the serum correlated with the number of eosinophils from asymptomatic patients with seasonal allergic rhinitis. Conclusions: Determination of blood and urinary concentrations of EDN is useful to monitor eosinophil activity in allergic diseases.
Background: Because fungi in the indoor environment strongly affect not only damage to and the deterioration of building materials, but also affect human health, it is important to know the distribution of fungi within an indoor environment. Therefore, in the present study, we examined fungi in houses over a period of 1 year and attempted to produce an indoor fungal contamination map for Japanese houses. Methods: Fungi were collected at approximately 100 fixed points in 81 ordinary houses around the Kanto District using either the stamp or dressing tape methods between 1999 and 2000. A commercially available potato dextrose agar culture medium was used to incubate the fungi collected. After incubation, fungi were quantified and identified by routine methods and the fungal conditions in the indoor environment was evaluated. Results: The relationships between the fungal conditions in the indoor environment found around the Kanto District and parameters such as the season, area in the house and indoor environment were analyzed. According to the fungal flora found in the present study, the indoor environment in Japanese homes was classified into three areas: (i) relatively wet areas, such as the bathroom, lavatory and kitchen, where hygrophilic fungi and yeasts are often detected; (ii) relatively dry areas, such as the living room and Japanese-style rooms, where xerophilic fungi are often detected; and (iii) areas where wet and dry parts coexist, such as bedrooms and closets containing futons and clothes with moisture, where both hydrophilic and xerophilic fungi, as well as yeasts, are detected. In the presnt survey, seasonal changes in the fungi detected in the indoor environment were small. Conclusions: We confirmed the actual fungal conditions in the indoor environment and produced a fungal map.
This is the first report that suggests that azelastine hydrochloride (AZE) and biscoclaurine alkaloids (CEPH; Cepharanthin®; Kaken Shoyaku, Tokyo, Japan) are useful in the treatment of idiopathic hypereosinophilic syndrome (HES). A 9-year-old boy was referred to our hospital because of fever and a cutaneous eruption. Full blood examination showed a normal hemoglobin level and leukocytosis of 66 400 /µL with 95% mature eosinophils. There was no history of allergy, no clinical or serological evidence of a parasitic infection and no evidence of a connective tissue disease, neoplastic disease, leukemia or immunodeficiency. The patient was treated with prednisolone, which induced a rapid but not sustained remission. Cepharanthin was then given to reduce the dose of the intermittent courses of prednisolone required. Azelastine HCl, prescribed by an otolaryngologist for perennial rhinitis when the patient was also receiving CEPH, unexpectedly reduced and maintained the eosinophil count at normal levels. Ultimately, AZE alone was tried and was ceased after 3.5 months; however, 5 weeks after discontinuation of AZE therapy, the eosinophil count had risen again to > 25 000 /µL. After reinstitution of AZE with CEPH followed by AZE alone, the patient did well for 30 months, so the AZE was ceased. Eleven months later the eosinophil count again increased. Reinstitution of AZE with CEPH in doses proportional to the weight increase that had occurred in the interim resulted in a complete resolution of symtoms. Azelastine HCl with or without CEPH may be effective in HES patients, enabling the adverse effects of long-lasting steroid therapy to be minimized.
Urticaria is one of the most common dermatoallergic conditions occurring mainly in children and adolescents and in atopic individuals. The term of chronic idiopathic urticaria (CIU) is used when the pathophysiological mechanisms remain unclear. Chronic infections and parasitic infestations have been suggested to play an important role in the etiology of CIU. In the present paper, we describe a case of chronic, apparently idiopathic urticaria in an adult woman where Dirofilaria has been recognized to play a pathogenic role in the determination of the cutaneous disease.