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Volume 117 (2001)
- Issue 6 Pages 377-
- Issue 5 Pages 319-
- Issue 4 Pages 243-
- Issue 3 Pages 159-
- Issue 2 Pages 105-
- Issue 1 Pages 5-
Volume 117, Issue 4
Displaying 1-9 of 9 articles from this issue
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Reviews: The Prostanoid Receptors: Molecular Approaches to Drug Development
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[in Japanese]Subject area: Others
2001 Volume 117 Issue 4 Pages 243-247
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSDownload PDF (338K) -
Yasushi KURAISHI, Fumitaka USHIKUBISubject area: Others
2001 Volume 117 Issue 4 Pages 248-254
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSAlthough it has been known that prostanoids are involved in pain regulation and fever, the precise roles of their receptors and receptor subtypes are unclear. All prostanoid receptors have been cloned and mice deficient in each receptor have been developed. Recent studies using prostanoid-receptor-knockout mice are shedding some light on these issues. Nociceptive responses to an intraperitoneal injection of acetic acid and hyperalgesia induced by carrageenan were abolished by IP-receptor deficiency. In addition, the use of mice lacking prostanoid receptor is revealing an interesting role of prostanoid in neuropathic as well as inflammatory pain. With regard to pyrexia, PGE2 injected intracerebroventricularly induced the febrile response in wild-type mice, but it was without effect in mice lacking the EP3 receptor. Furthermore, febrile responses induced by IL-1β, an endogenous pyrogen, and LPS, an exogenous pyrogen, were specifically suppressed in mice lacking the EP3 receptor. These results indicate that PGE2 works as a common final mediator of the febrile response and that this action of PGE2 is medited by the EP3 receptor. The determination of precise roles of prostanoids in pain and fever may provide novel targets for antipyretic analgesics with fewer side effects.View full abstractDownload PDF (743K) -
Akinori UENO, Sachiko OH-ISHISubject area: Others
2001 Volume 117 Issue 4 Pages 255-261
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSIt is known that prostaglandins (PGs) modify the inflammatory reaction in concert with other biologically active mediators. However, characteristics of these interactions or modulating actions have not yet been clarified well. Recently, the production of mice with specific receptor deficiencies by using the gene targetting procedure for PG receptors has accelerated elucidation of the roles of PGs through correlation of their phenotypes and experimental features. Here I discuss roles of PGs in experimental paw edema, the writhing reaction of a pain model, and regulation of cytokine production, as determined using some PG-receptor-deficient mice. From the experiment of carrageenin-induced paw edema in IP receptor-deficient mice, with an indomethacin or bradykinin antagonist, we conclude that bradykinin initially induces paw swelling and then stimulates the release PGI2, which in turn enhances the swelling with bradykinin. By comparing the writhing responses in IP-deficent and wild-type mice, we found that PGI2 is a main mediator for this pain reaction. However, in the LPS-pretreated mice, not only PGI2 but also other PGs produced by COX-2 may be involved in pain induction. Production of TNFα and IL-10 was modified with PGI2 or PGE2; the production of TNFα was down-regulated by the stimulation via IP-, EP2- or EP4 receptor, but that of IL-10 was up-regulated by these receptors, resulting in an anti-inflammatory effect.View full abstractDownload PDF (1091K) -
Hiroyuki TANAKA, Hiroichi NAGAISubject area: Others
2001 Volume 117 Issue 4 Pages 262-266
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSAllergic inflammation is orchestrated by mainly antigen-specific CD4+ T cells, eosinophils and mast cells, which is a characteristic feature of bronchial asthma, rhinitis and atopic dermatitis. Prostanoids are one of the arachidonic metabolites, which are produced by a variety of inflammatory cells upon stimulation and are thought to be involved in the pathogenesis of diseases as well as the regulation of homeostasis. We investigated the role of a prostanoid, prostaglandin D2 (PGD2), in the pathogenesis of allergic bronchial asthma using its receptor, DP, gene-deficient mice. We found that the disruption of the DP gene attenuated the allergen-induced airway eosinophilic inflammation, Th2 type cytokine production and bronchial hyperresponsiveness to cholinergic stimuli, suggesting that PGD2 is an important mediator of allergic asthma. In contrast, the treatment of non-steroidal anti-inflammatory agents, which are known to be inhibitors of cyclooxygenases, did not inhibit or instead exaggerated these responses in asthmatics or experimental animal models, indicating that there are regulatory prostanoids in allergic inflammation. Recently, strategies of gene manupulation such as the “knockout” or “transgenic” techniques are important means to understand the role of a certain functional molecule. These approaches and the development of their antagonists/inhibitors could help us to understand the function of prostanoids in the pathophysiology of allergic disorders.View full abstractDownload PDF (409K) -
Kazuhito TSUBOI, Atsushi ICHIKAWASubject area: Others
2001 Volume 117 Issue 4 Pages 267-273
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSProstanoids, which consist of prostaglandins (PGs) and thromboxane, are produced from arachidonic acid by cyclooxygenases (COXs) as a rate-limiting step, and they exert various biological actions. Classically, prostanoids are suspected to be closely related to female reproductive processes such as ovulation, luteolysis and uterine contraction, as well as pathological processes such as fever generation and pain modulation. Recently the cDNA cloning of a series of prostaglandin-synthesizing enzymes and receptors enabled us to clarify which isoform or subtype is involved in each reproductive process by generating individual gene-deficient mice. In late pregnancy, PGF2α synthesized by COX-1 is essential for induction of parturition via luteolysis. Furthermore, impaired induction of COX-2 in the myometrium of PGF2α receptor-deficient mice is accompanied with loss of parturition, suggesting that COX-2 is presumably responsible for producing uterotonic PGs. In early pregnancy, PGE2 synthesized by COX-2 induces the expansion of cumulus cells through EP2 receptor and contributes to ovulation and fertilization. These results may be useful in not only developing novel drugs in the reproductive area but also understanding and overcoming harmful reproductive side effects of classical and novel drugs in non-reproductive areas.View full abstractDownload PDF (1170K) -
Koji TAKEUCHI, Shinichi KATO, Akiko TANAKASubject area: Others
2001 Volume 117 Issue 4 Pages 274-282
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSEndogenous prostaglandins (PGs) play important roles in modulating the mucosal integrity and various functions of the gastrointestinal tract. Among them, E-type PGs are most effective in these actions. This article reviews recent studies dealing with the relationship of the cytoprotective action of PGE2- and EP-receptor subtypes in the gastrointestinal mucosa. PGE2 exerts gastric cytoprotection aganist HCl/ethanol and indomethacin. These effects were mimicked by only EP1 agonists and attenuated by EP1 antagonists. Likewise, the adaptive cytoprotection induced by a mild irritant was attenuated by EP1 antagonists as well as indomethacin. On the other hand, the protective effect of dmPGE2 against indomethacin-induced small intestinal lesions was mimicked by only EP3 and EP4 agonists. Similar results were obtained in EP-receptor knockout mice; ie., PGE2 failed to exhibit both direct and adaptive cytoprotection in EP1-receptor knockout mice, while the protective action in both the duodenum and small intestine was hampered in EP3-receptor knockout mice. The underlying mechanism related to these actions of PGE2 in the stomach, duodenum or small intestine may be related to inhibition of stomach contraction, stimulation of duodenal alkaline secretion, or suppression of bacterial translocation due to inhibition of intestinal contraction as well as stimulation of mucus secretion, respectively.View full abstractDownload PDF (959K) -
Masataka MAJIMA, Hideki AMANO, Izumi HAYASHISubject area: Others
2001 Volume 117 Issue 4 Pages 283-292
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSAngiogenesis is a process involved in several physiological events including embryonic development, female reproductive cycle placentation and wound repair. It also plays a part in various pathological conditions such as tumor growth, diabetic retinopathy and rheumatoid arthritis. Angiogenesis is a very complex multistep process involving a variety of biologically active substances, among which are the prostaglandins (PGs), which can induce several growth factors and proliferation of endothelial cells in vitro and in vivo. Angiogenesis is reportedly enhanced by prostaglandins (PGs). We investigated whether or not COX-2 mediated angiogenesis in chronic and proliferate granuloma. In rat sponge implants, angiogenesis was gradually developed over a 14-day experimental period as granuloma formed. In sponge granuloma, mRNA of COX-1 was constitutively expressed, whereas that of COX-2 was increased with neovascularization in parallel with the increased expression of vascular endothelial growth factor (VEGF). bFGF-stimulated angiogenesis was inhibited by indomethacin or a selective COX-2 inhibitor, NS-398. These results suggested that endogenous PGs generated through COX-2 may enhance the neovascularization in sponge granuloma by increased expression of VEGF and that a COX-2 inhibitor would facilitate the management of conditions involving angiogenesis.View full abstractDownload PDF (1332K) -
Chisato MIYAURASubject area: Others
2001 Volume 117 Issue 4 Pages 293-297
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSProstaglandin E2 (PGE2) acts as a potent stimulator of bone resorption. We examined PGE2-induced bone resorption using mice lacking each subtype (EP1, EP2, EP3 and EP4) of PGE receptor and identified the PGE receptor subtype(s) mediating PGE2 action. In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE2 stimulated bone resorption to a similar extent to that found in calvaria from the wild-type mice. On the other hand, a marked reduction in bone resorption in response to PGE2 was found in the calvarial culture from EP4-knockout mice. DbcAMP greatly stimulated bone resorption similarly in both wildtype and EP4-knockout mice. In mouse calvarial cultures, EP4-agonist markedly stimulated bone resorption, but its maximal stimulation was less than that induced by PGE2. EP2-agonist also stimulated bone resorption, but only slightly. EP1- and EP3-agonists did not stimulate it at all. These findings suggest that PGE2 stimulates bone resorption by a mechanism involving cAMP, which is mediated mainly by EP4 and partially by EP2.View full abstractDownload PDF (937K)
Review
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Yasufumi KANEDASubject area: Others
2001 Volume 117 Issue 4 Pages 299-306
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSAs of summer 2000, more than 400 protocols developed for human gene therapy have been reported, and there have been recent successful applications in some diseases such as arteriosclerosis obliterance, immunodeficiency X-1 (SCID-X1) and hemophilia B. However, complications have also occurred. Successful gene therapy is dependent on the development of an effective gene delivery system. One approach is development of chimeric vector systems that combinine at least two different vector systems. However, a perfect vector system has not yet been constructed. Difficulties of in vivo gene transfer appear to result from resistance of living cells to invasion by foreign materials and from interference of cellular functions. We should reevaluate what barriers in tissues affect in vivo gene transfection and how to solve these problems for gene therapy. Moreover, in Japan, there should be more extensive preparation of social systems to promote clinical trials based on basic research.View full abstractDownload PDF (849K)
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