Asthma is regarded as an inflammatory disorder of the conducting airways characterized by a mast cell, eosin-ophil and T lymphocyte inflammatory response that is responsive to anti-inflammatory therapy, such as corticosteroids. In more severe and chronic disease, corticosteroids become less effective. As in other chronic inflammatory diseases, the tissue in which the cellular and mediator processes occur plays a major role in maintaining the response and creating a basis for disease persistence. Herein, we describe evidence that the airway epithelium interacting with the underlying mesenchymal cells recapitulates branching morphogenesis, as observed in the developing lung, to create airway wall remodeling. The reciprocal signaling between the susceptible epithelium and responsive mesenchyme (epithelial mesenchymal trophic unit) offers a new paradigm for asthma and creates new opportunities for developing therapeutics based on reversing the 'chronic wound' phenotype of asthmatic airways.

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Multiple cytokines play a critical role in orchestrating and perpetuating inflammation in asthma and several specific cytokine and chemokine inhibitors are now in development as future therapy. Anti-interleukin (IL)-5 antibodies markedly reduce peripheral blood and airway eosinophils, but do not appear to be effective in symptomatic asthma. Inhibition of IL-4, despite promising early results in asthma, has been discontinued and blocking IL-13 may be more effective. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, because systemic delivery produces side-effects. Inhibition of tumor necrosis factor (TNF)-α may be useful in severe asthma. Many chemokines are involved in the inflammatory response of asthma and several small molecule inhibitors of chemokine receptors are in development. The CCR3 antagonists (which block eosinophil chemotaxis) are in clinical development for asthma. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side-effects with these non-specific inhibitors may be reduced by the inhaled route.

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By complete reading of the genome sequence, in the near future we will be able to determine the role of genomic DNA sequence variation among individuals, such a single nucleotide polymorphism (SNP), in the pathogenesis of diseases and responses to drugs. Comprehension of the genome will also accelerate understanding of the transcriptome, the whole transcripts present in a cell. Messages induced by a new therapy, such as an unexpected adverse effects, will not be missed by using such a comprehensive assay. Allergic diseases will be classified into subtypes depending on the impaired or affected molecule. Herein, I introduce our research strategy for genome-wide analysis of SNP related to asthma, granted by the Millennium Genome Project of the Japanese Government, and review the recent results of transcriptome analysis using microarray technology.

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Background: To determine the effects of 1 months treatment with optimized high-dose inhaled corticosteroid on surrogate markers of airways inflammation, as well as lung function, in a clinical setting.
Methods: Nine steroid-treated asthmatics (mean dose 778 µg/day) with uncontrolled disease were all switched to 1 months treatment with 2000 µg/day inhaled beclomethasone dipropionate dry powder. Serial spot clinic measurements were made of pre- and post-treatment effects on sputum eosinophils, serum eosinophil cationic protein (ECP), bronchial hyper-responsiveness (BHR) to methacholine, exhaled nitric oxide (NO), spirometry and domiciliary peak expiratory flow rate (PEF), symptom score and reliever use.
Results: Optimization of inhaled corticosteroid treatment had further significant (P < 0.05) beneficial effects only on sputum eosinophils, BHR, symptom score and morning PEF. Furthermore, treatment decreased the eosinophil count in all cases.
Conclusions: Serial clinic measurements of sputum eosinophils and BHR may provide additional information on asthmatic inflammation to assess the response to inhaled steroids in patients who have uncontrolled asthma.

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Background: Olopatadine hydrochloride is an anti-allergic agent with histamine H₁ receptor antagonistic action. We investigated the effects of olopatadine on passive anaphylaxis reaction- and compound 48/80-induced conjunctivitis in rats.
Methods: Allergic conjunctivitis was induced in rats passively sensitized by injection of rat anti-ovalbumin (anti-OVA) serum into the upper subconjunctiva of the right eye, followed by intravenous administration of the antigen and Evans blue dye. After 30 min, the amount of dye leaking into the conjunctiva was measured. Non-allergic conjunctivitis was induced in rats by injection of compound 48/80. Olopatadine or other reference compounds were orally given 1 h before the challenge.
Results: The amount of dye leaking into the conjunctiva following passive anaphylaxis was significantly inhibited by oral administration of 0.01-1 mg/kg olopatadine and the ID₅₀ value was 0.093 mg/kg. In the control group, pathological examination revealed edema and lymphocyte infiltration in the conjunctiva and the palpebral skin. Olopatadine, at 0.03 and 0.3 mg/kg, reduced the grade of these pathological findings. The other antiallergic drugs (1 mg/kg loratadine, 0.3 mg/kg epinastine, 0.3 mg/kg cetiridine, 1 mg/kg ebastine, 30 mg/kg fexofenadine and 3 mg/kg chlorpheniramine), when administered orally, inhibited the passive anaphylaxis reaction-induced vascular hyperpermeability of the conjunctiva, as was the case with olopatadine hydrochloride. Subconjunctival administration of compound 48/80 induced vascular hyperpermeability, which is presumably mediated by histamine release. Oral administration of 0.1 and 1 mg/kg olopatadine significantly inhibited the amount of dye leakage.
Conclusion: Orally administered olopatadine is expected to improve allergic conjunctivitis.

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Background: Clinical and experimental studies were performed to investigate the kinetics of fibronectin (FN) and its clinical significance in bronchial asthma.
Methods: Measurements of plasma fibronectin (PFN) and sputum fibronectin (SFN) were performed in asthmatic patients. Eosinophil chemotaxis, adherence and activation activity to FN were measured. An animal model of bronchial asthma was created and lung tissues were analyzed by immunohistochemical staining.
Results: Compared with periods without an asthmatic attack, the PFN level was significantly lower during periods with more severe asthmatic attacks in 15 patients with bronchial asthma. In contrast, the SFN level was significantly higher during periods with more severe asthmatic attacks. In a guinea pig model of asthmatic bronchitis, FN was positively stained in the subepithelial or submucosal tissue and abraded epithelial cells in the alveolar space during asthmatic attacks. Marked eosinophilic infiltration was also noted in the same tissues and cells. A negative correlation was noted between the number of peripheral eosinophils and the PFN level. In contrast, a positive correlation was noted between the number of sputum eosinophils, which reflects the severity of asthmatic attacks, and the SFN level. An experimental study was performed to investigate the relationship between eosinophils and FN. A positive relationship was noted between eosiophil chemotaxis, increased adherence of activated eosinophils and FN levels.
Conclusions: It is suggested that FN may enhance allergic reactions at an early or acute phase of bronchial asthma.

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Background: High-molecular size mite antigen fraction (HM1) induced macrophage activation and prolonged airway inflammation from mite-sensitized mice. In the present study, we investigated the inflammatory factors in the HM1-activated macrophage in both non-immunized splenocytes and bronchoalveolar lavage (BAL) from mite-immunized and HM1-exposed mice.
Methods: Dermatophagoides farinae feces (Dff) extract was divided into HM1 and HM1-depleted fraction (DH) by size-exclusion chromatography. Transcriptional gene induction of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-12 and cytokine-inducible nitric oxide synthase (iNOS) in splenic macrophages stimulated with HM1 or DH was analyzed by using semiquantitative reverse transcription-polymerase chain reaction. Nitric oxide (NO) production was measured by using diaminofluoresceins (DAF), fluorescence indicators.
Results: Gene expression of TNF-α, IL-12 p40 and iNOS was observed with HM1 stimulation of splenic macrophages from non-immunized mice. In addition, the release of NO induced by HM1-stimulated splenic macrophages increased in a dose-dependent manner. However, splenic macrophages stimulated with DH induced TNF-α and IL-12 p40, but not iNOS, gene expression. Similarly, significant iNOS mRNA expression was detected in alveolar macrophages recovered from HM1-exposed mice, but not from DH-exposed mice.
Conclusion: In the present study, HM1 induced iNOS mRNA expression and NO production both in vitro and in vivo. The present results suggest that the ability of HM1 to induce NO production may be one of the causes aggravating airway inflammation in HM1-exposed mice.

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Autoimmune hepatitis (AIH) represents a chronic liver disease with a progressive nature. Cortocosteroid therapy is routinely used to control this pathological condition. Herein, we describe a case of AIH with spontaneous remission and exacerbation. A previously healthy young Japanese woman presented with features of acute hepatitis. The patient was not acutely infected with hepatotrophic viruses and the possibility of drug-induced AIH was also excluded. A diagnosis of AIH was made from subjective symptoms and laboratory data, which showed increased levels of liver enzymes, total bilirubin, IgG and positive titers of antinuclear antibody. Finally, liver biopsy revealed an expansion of portal tracts and infiltration of mononuclear cells, including plasma cells. This patient experienced a total of three episodes of acute exacerbation of AIH during the past 5 years, two of which subsided spontaneously. An immunosuppressive drug was used to control the last episode of acute exacerbation of AIH, which was very similar to acute hepatitis. The immunosuppressive drug was withdrawn 7 months after the last epoisode of acute exacerbation of AIH and the patient is now passing an uneventful course. There are cases of spontaneous remission and acute exacerbation of AIH, although the underlying mechanism of this pathological process is yet to be determined. Liver biopsy is needed to diagnose these cases. Periodic follow up of these patients is required for proper management.

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Micronic antigens penetrate to the lower respiratory tract and cause serious lung problems. The existence of micronic antigens in pollinosis-caused pollen has been reported. We examined the appearance and the relationship of micronic particles of birch pollen antigens and birch pollen grains. Airborne particles were collected with a tandem filter system sampler composed of a 5 µm pore filter and a 0.3 µm pore Millipore filter in springtime at the Stockholm University campus in Stockholm. A fairly good correlation was observed between numbers of birch pollen and the amount of birch pollen antigens above 5 µm in diameter. In contrast, a good correlation was not observed between the amount of birch pollen antigens collected in 5 µm pore filters and the amount of the antigens passing through 5 µm pore filters and collected on Millipore filters. The appearance of a maximum value of birch pollen antigens collected on Millipore filters seemed to be delayed a few days after a maximum values had been obtained for birch pollen on a Burkard sampler or birch pollen antigens on 5 µm pore filters. Almost all birch pollen antigens were found during the birch pollen season and recognizable amounts of birch pollen antigens were not detectable after the birch pollen season. Most of the birch pollen antigens collected on 5 µm pore filters originated from birch pollen grains. In contrast, the antigens passing through 5 µm pore filters and collected on Millipore filters did not originate from pollen grains themselves, but were micronic particles, and appeared a few days after maximum values of birch pollen had been obtained.

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