Recent extensive biotechnological studies produced many kinds of gene engineering mice. In the present article, the alternations of the genes of T helper 2 cytokines and of the receptors for allergic inflammatory mediators were described. So far, we have demonstrated an important role of IL-4, IL-5, 5-lipoxygenase, prostaglandin D₂ and prostaglandin I₂ in the development of allergic airway inflammation by using their corresponding gene deficient mice. Simultaneously, we have indicated the role of IL-4, IL-5, 5-lipoxygenase, prostaglandin D₂ and thromboxane A₂ in the onset of airway hypersensitivity by examining above gene deficient mice. In addition, we have also indicated the role of IL-4, IL-5, IL-10, prostaglandin I₂ and thromboxane A₂ in the onset and development of allergic contact dermatitis. Therefore, gene engineered mice are useful for investigating the role of certain kind of mediator in the pathological condition. But many discrepancies are pointed out in the results obtained from the experiments using gene-engineered mice. We have discussed about the problems in the studies using gene-engineered mice.

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Hyaluronan (HA) is an unbranched glycosaminoglycan (GAG) which is the only nonsulfated disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. HA is synthesized by most cells in various animal tissues and has by far the largest molecular size, with an average molecular weight of several million. HA plays important roles in tissue development, tissue hydration, cell surface-matrix interactions, cell migration, inflammation, and wound healing. The biosynthesis of HA is unique among the GAG. Rather than being made in the Golgi apparatus, HA is synthesized via HA synthase (HAS) which is located at the plasma membrane. Recently, it has been reported that 3 subtypes of HAS, named HAS 1, HAS 2 and HAS 3, have been cloned and that each of those plays a different role in HA production in vivo. Several lines of evidence demonstrated that expression of HAS and synthesis of HA are regulated by a variety of mechanisms other than cytokines and that the inducible HA production generates HA with relatively high molecular weight. Furthermore, recent observation demonstrated that HA with low molecular weight showed various biological activities such as induction of chemokines and iNOS. These data may suggest that HA plays crucial roles both in continuation of inflammatory responses and in restoration and maintenance of tissue homeostasis.

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Calprotectin, also called MRP 8/MRP 14, is a complex of calcium binding proteins which belong to S-100 protein family. Calprotectin is selectively present in myeloid cells, namely, neutrophils or macrophages. It is especially abundant in cytosol of the former cell type. It has been observed that protein complex highly increases in extracellular fluids of patients with many inflammatory diseases. We recently elucidated that calprotectin induced apoptosis of tumor cell lines as well as normal fibroblasts, suggesting that the factor modulates inflammatory reaction through the effect on survival or growth states of fibroblasts or other cell types. It is also possible that high amount of calprotectin in inflammatory sites may cause tissue destruction. Several authors also reported the extracellular functions of the factor, including anti fungal activity, chemotactic activity and activity modifying leucocyte functions. The reports accumulated recently, together with ours, raise the possibility that calprotectin may be not only an useful marker but also an important mediator in inflammatory reactions.

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In this review, we will discuss cyclic AMP response element binding protein (CREB), a cAMP-and Ca²⁺-dependent transcription factor originally isolated from rat brain, and its roles in diverse cellular activities. In the introduction, we briefly describe the molecular mechanism for transcriptional enhancement by CREB and CREB/ATF family proteins. We also review the biological importance of CREB in long-term memory and T lymphocyte activation established by knockout and transgenic mice, respectively. The involvement of CREB in inflammatory responses through an induction of immunoregulatory and preinflammatoy cytokine genes is also discussed. Then we focus on the possible involvement of CREB in the regulation of cell cycle progression and apoptosis induction, presenting our published data along with our preliminary observations. We show that the expression level of CREB protein highly correlates with the growth activity of the cells and an over-expression of CREB enhances cyclin A expression. Surprisingly, an enforced expression of CREB induces apoptosis. Deletion analysis indicates that neither the transactivation domain nor kinase inducible domain is required but the C-terminal b-Zip structure, consisting of DNA-binding and dimerization domain, and the juxta four amino acids to its N-terminus are important for apoptosis induction, suggesting that the two functions of CREB, transcriptional enhancement and apoptosis induction, are accomplished by distinct mechanisms. The physiological relevance of CREB induced apoptosis and the possible therapeutic applications for diseases with malignant cell proliferation will be discussed.

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Twenty pediatric cases of aseptic chronic cystitis due to allergy are presented. In 6 of these, eosinophilic inflammation was histologically confirmed, however the remaining cases also seemed to have similar causative factors. The average age of these patients was 7.1 years (male: 14 cases, female: 6 cases), and gross hematuria and bladder irritation were prominent and more severe than in common bacterial cystitis. Practically almost all of the patients had allergic disorders, and 17 cases had eosinophilia, while elevation of serum IgE was detected in 10 cases. Endoscopically, the lesions were classified into 2 groupes: one was diffuse congestion with edema of the mucosa, and the other was granulomatous lesions similar to botryoid sarcoma. Biopsy specimens obtained from 6 cases of each lesion type showed infiltration of eosinophilic cells into the submucosa and muscular layers with congestion and edema of the mucosa. All of the patients improved without steroid administration or surgical intervention, within only 4 weeks of hospitalization free from certain allergens. In follow-up studies, recurrences have not been experienced with the exception of two cases.
This result show that eosinophilic cystitis in children should be considered as a temporary reaction to some category of allergens, from which the patients should simply be kept free without any special urological management.

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Increase in pulmonary vascular permeability by oxygen free radicals derived from neutrophils participates deeply in the pathophysiology of acute lung injury such as ARDS. Cyclic AMP restrains hyperpermeability of pulmonary vasculature in previous studies using? isolated perfused lungs, and endothelial cell monolayers. Cyclic GMP is also supposed to have the similar action. Atrial natriuretic peptide (ANP) increases intracellular cGMP content through a receptor on the cell surface. ANP is applied for the treatment of a heart failure, because its Na-diuretic effect and dilating effect on blood vessel reduce prelord and afterload of the heart. We paid attention for ANP to increase intracellular cGMP content and examined the action of ANP to inhibit H₂O₂-induced hyperpermeability of pulmonary vasculature. We used isolated perfused lungs of rabbit, and H₂O₂ was administered at dose of 100 μM, 200 μM, 500 μM. Left atrial pressure (Pla), pulmonary artery pressure (Ppa) and lung weight gain (ΔW) were measured. Pulmonary capillary pressure was also measured with a double occlusion method and capillary filtration coefficient (Kfc) was calculated using a Paul's method. ΔW and Kfc were significantly increased dose-dependently after H₂O₂ administration (p <0.05) . Increase of ΔW, Kfc and Ppa were significantly attenuated (p <0.05) by ANP. These results suggest that ANP attenuates the H₂O₂-induced hyper-permeability of pulmonary vascular and ANP is a useful therapeutic agent for the patient with hyperpermeability lung edema.

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A 28-year-old pregnant woman who was serologically positive for anti-SS-A/-B antibody developed reactive hemophagocytosis, and gammaglobulin therapy was very effective in treating it. This case showed the underlying not only pregnancy but also disease such as some infections and serological abnormality. We suspect that the possible involvement of an immunological disorder of pregnancy in the pathogenesis of the hemophagocytosis.

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