Folia Pharmacologica Japonica
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
Volume 120, Issue 1
Displaying 1-8 of 8 articles from this issue
Reviews: Physiological Function of the Mucosa and Potential Prologues of Its Dysfunction and Pathological Implications
  • Yuichi KURONO
    Article type: Reviews
    2002 Volume 120 Issue 1 Pages 7-12
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    Nasal mucosa is equipped with several physiological functions such as mucociliary transportation of invading pathogens as well as allergens and nonspecific host-defending function with lysozyme and glycoconjugates. Furthermore, the mucosal immune system protects nasal mucosa mainly with secretory IgA. Secretory IgA cannot activate complements and kill bacteria, but can inhibit bacteria by adhering to epithelial cells by agglutination and coupling the receptors. Nasal secretions contain a high concentration of secretory IgA, which is much higher than the concentrations of serum type IgA, IgG, and IgM. In chronic sinusitis, the production of those immunoglobulins is increased, and the concentrations are higher than those in healthy subjects. However, the pathogen-specific antibody activities of those immunoglobulins are decreased in chronic sinusitis, suggesting that the local immune system is damaged by chronic inflammation. Those findings indicate that activation of the mucosal immune system might be effective for preventing nasal as well as sinus infections. Animal experiments using mice demonstrated that intranasal immunization is more effective than oral or systemic immunization to induce antigen-specific immune responses in the nose. The results suggest that nasal vaccination might be a useful and promising strategy for preventing upper respiratory infections including nasal infectious diseases.
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  • Hiroyuki TANAKA, Hiroichi NAGAI
    Article type: Reviews
    2002 Volume 120 Issue 1 Pages 13-19
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    The lungs and airways are mucosal surfaces, which are a common site encountering foreign protein, viruses, and microorganisms. Most of the mammalians have the common mucosal immune system, including airway epithelium, submucosal glands, and bronchus-associated lymphoid tissue, to protect against infection and airway inflammation. Bronchial asthma is one of diseases in the airways, which is characterized by airway obstruction, eosinophilic inflammation, and airway hyperresponsiveness (AHR). Recent studies demonstrated the involvement of T helper type 2 (Th2) cytokines, chemokines, and costimulatory molecules in IgE synthesis and airway eosinophilia; however, the mechanism of AHR is still obscure. Among the candidates, Th2 cytokines, eicosanoids, and transcriptional factors are thought to play an important role in the development of allergen-induced AHR. In addition, recent observations have shown structural changes, “airway remodeling”, which is characterized by epithelial thickening, goblet cells hyperplasia/hypertrophy, subepithelial fibrosis, and smooth muscle hyperplasia/hypertrophy. These structural changes may be involved in the inefficacy of the response to β2 agonists and AHR. It is a better strategy for control of the disease to inhibit or suppress multi-functional molecules rather than to inhibit a sole factor, because so many factors (genetical and environmental) are involved in the pathophysiology of the disease.
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  • Koji TAKEUCHI, Shinichi KATO, Shigeru KAGAWA
    Article type: Reviews
    2002 Volume 120 Issue 1 Pages 21-28
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    The gastric mucosa responds to damaging agents by decreasing acid secretion (luminal alkalinization), together with increase in mucosal prostaglandin (PG) content and luminal release of nitric oxide (NO), histamine and Ca2+. The acid inhibitory mechanism in the damaged stomach involves endogenous NO as well as PG, and the acid secretion turns into “stimulation” only in the presence of NG-nitro-L-arginine methyl ester (L-NAME) but not aminoguanidine. The acid stimulation caused by L-NAME in the damaged stomach is mediated by endogenous histamine released from mucosal mast cells, the process being inhibited by a mast cell stabilizer and chelation of luminal Ca2+ as well as sensory deafferentation and also facilitated by PG. The acid and PG biosynthetic responses in the damage stomach are inhibited by SC-560 the selective cyclooxygenase (COX)-1 inhibitor but not rofecoxib the selective COX-2 inhibitor. Thus, damage in the gastric mucosa enhances the acid stimulatory pathway in addition to the COX-1/PG and cNOS/NO-mediated inhibitory pathways, although the latter effect normally overcomes the former, resulting in a decrease of acid secretion. Since luminal alkalinization caused by a decrease of acid secretion contributes to maintenance of the miroclimate for cellular restitution, this response is physiologically important for tissue recovery from injury.
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  • Toshikatsu OKUMURA, Yutaka KOHGO
    Article type: Reviews
    2002 Volume 120 Issue 1 Pages 29-31
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    Gycemic control is essential for patients with diabetes mellitus. To better understand the pathophysiology of diabetes, we need to know how blood glucose level is regulated. Alpha-glucosidase inhibitors are well known as antidiabetic drugs. These drugs inhibit alpha-glucosidase to delay the absorption of glucose in the small intestinal mucosa. Thus, regulation of enzyme activity in the small intestinal mucosa is involved in the glycemic control in diabetes mellitus. Apolipoprotein A-IV produced in the small intestinal mucosal cells acts in the brain to inhibit feeding and delay gastric emptying. Suppression of feeding and gastric emptying might suggest that apolipoprotein A-IV may be relevant for diabetic patients because inhibition of energy intake and delayed absorption of glucose may be favorable for diabetic patients. We therefore raise a possibility that apolipoprotein may be a novel molecule that improves glycemic control.
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  • Yoshikazu YUKI, Noriyuki OHTA, Takachika HIROI, Hiroshi KIYONO
    Article type: Reviews
    2002 Volume 120 Issue 1 Pages 32-38
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    In this review, a new relationship between IL-15 and mucosal immunity/inflammation was discussed based on the results obtained by a novel IL-15-induced inflammatory bowel disease murine model. First, we provide new evidence that IL-15 is a critically important mucosal cytokine for the regulation of IgA responses. It has been shown that intestinal B-1 cells preferentially express IL-15R. Furthermore, it has been demonstrated that IL-15 acts on two different stages (sIgM sIgA+ and sIgM+ sIgA) of CMIS-independent B-1 cells development, while IL-5 only acts on the stage of sIgM sIgA+ B-1 cells. In contrast, CMIS-dependent B-2 cells originating from IgA inductive sites (e.g., PP) express IL-5R and IL-6R, but not IL-15R, and can respond to stimulation signals provided by both IL-5 and IL-6 to become IgA-producing cells. Secondly, we have established a new model of small intestinal inflammation by selective overexpression of IL-15 in the murine gastrointestinal tract (T3b-IL-15 Tg mice). IL-15-induced CD8-alpha beta+ T cells expressing NK1.1 appear to be critical in the pathogenesis of the small intestinal lesions in the transgenic mice. Further more, this unique subset of CD8-alpha beta+ T cells preferentially produced Th-1-type cytokines, and the preferential expansion of these T cells could be attributed to the anti-apoptotic activity of IL-15. These results suggest that dysregulation of IL-15 results in deleterious effects for the host, in spite of it being a critically important mucosal cytokine for the regulation of IgA responses.
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  • Takanori KANAI, Mamoru WATANABE, Toshifumi HIBI
    Article type: Reviews
    2002 Volume 120 Issue 1 Pages 39-45
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    Crohn's disease(CD) affects more than 400,000 individuals in the United States and more than 18,000 in Japan. Its incidence is CD, one of the chronic inflammatory bowel diseases(IBD), is debilitating disorder of unknown ethiology, characterized by a marked accumulation of activated T cells and monocytes/macrophages in the inflamed mucosa. Various proinflammatory cytokines, such as TNF-α, INF-γ, IL-6, IL-12, and IL-18, might be involved in its pathogenesis. In this review, we describe the role of various cytokines in the development of CD and the new therapeutic trials modulating cytokine networks for the treatment of CD.
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Technical Note
  • Ichiro SORA, Kazutaka IKEDA, Yuji MISHINA
    Article type: Technical Note
    2002 Volume 120 Issue 1 Pages 47-54
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    Knockout transgenic mice of opioid receptors make it possible to analyze molecular mechanisms of opioid receptors that could not be done by traditional pharmacological techniques. Generation of knockout mice requires a variety of technologies such as molecular genetics, cell biology, and embryology. Making knockout mice also requires a long period of labor-intensive work. Knockout mice can be obtained after several experimental steps: constructing a targeting vector, introduction of the vector into embryonic stem cell, and generation of the chimeric animal. Special attention may be required for behavioral and biochemical analyses of knockout mice. This review will be focused on the outline and pitfalls for audiences who are interested in analysis of existing knockout mice as well as making new ones.
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Review on New Drug
  • Masatoshi FUJIWARA, Shyh-Yuh LIOU
    Article type: Review on New Drug
    2002 Volume 120 Issue 1 Pages 55-62
    Published: 2002
    Released on J-STAGE: January 28, 2003
    JOURNAL FREE ACCESS
    Lamivudine ((-)-1-[(2R, 5S)-2-hydroxymethyl-1,3-oxathiolan-5-yl]cytosine, Zefix®), one of the deoxycytidine derivatives, inhibits the HBV replication directly, and the mode of action of lamivudine has been proven to be its prevention of HBV-DNA synthesis in the transcription phase after conversion of lamivudine triphosphate in the cells. At 0.01-0.116 µM, lamivudine inhibits 50% of the virus production in in vitro studies. In the HBV infectious model (Trimera mice), the HBV-DNA level in serum was decreased in the lamivudine-treated group in comparison with the untreated group. In Phase III clinical trials, lamivudine therapy had a profound inhibitory effect on serum HBV-DNA-provoked HBe antigen resulting in rapid suppression viraemia and resolution of the progression of necro-inflammatory changes and fibrosis in the liver. Furthermore, lamivudine also has an excellent safety profile. Although lamivudine-resistant viruses emerged in the treatment of patients, the viruses had greatly impaired replication as compared with that of the wild-type virus. Thus, lamivudine is a useful agent for patients with persistent hepatitis B with virus proliferation and expected to be a novel chemotherapeutic drug.
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