COPDにおける新規生理活性ペプチドグレリンの病態生理学的意義と臨床応用の試み

• Project/Area Number: 18659240
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Miyazaki
• Principal Investigator: 中里 雅光 宮崎大学, 医学部, 教授 (10180267)
• Co-Investigator(Kenkyū-buntansha): 芦谷 淳一 宮崎大学, 医学部, 助教授 (50347069) ; 松元 信弘 宮崎大学, 医学部, 助手 (70418838) ; 小玉 剛士 宮崎大学, 医学部, 医員 (80404424) ; 京樂 由佳 宮崎大学, 医学部, 医員 (90404425) ; 柳 重久 宮崎大学, 医学部, 助手 (60404422)
• Project Period (FY): 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2006: ¥3,200,000 (Direct Cost: ¥3,200,000)
• Keywords: COPD / グレリン / 下肢リハビリテーション / 抗炎症効果 / グレリン受容体欠損マウス / PTENノックアウトモデルマウス / 展開医療 / カヘキシア

Research Abstract

本研究では、COPDにおけるグレリンの病態生理学的意義について、基礎と臨床の両面から研究を進め、以下の成果を得た。臨床的研究では、COPDに対するグレリンの効果を評価するために二重盲検比較試験を開始した。体重減少をきたしたCOPD患者を対象に、エルゴメーターを用いた下肢リハビリテーションに加えて、2μg/kgのグレリンを一日2回3週間経静脈的に投与し、運動耐容能の改善を評価した。本試験はRCTで、現在7例を集積し、進行中である。さらに、症例を追加することでエビデンスの確立が期待できる。この臨床研究では、DEXAを用いて体組成の変化を検討し、血液検査で栄養状態の改善を評価する予定である。また、血中カテコラミンや呼気ガスや尿中の8-イソプロスタンを測定して、グレリンが酸化ストレスや交感神経に与える影響を解析している。基礎的研究では気道上皮細胞や単球由来細胞、好中球のグレリン受容体の発現とグレリンの抗炎症効果を検討した。培養単球由来細胞ではサイトカインの産生を抑制する効果がみられ、グレリンの抗炎症作用が確認された。動物実験モデルとして、グレリンと受容体欠損マウスやPTENノックアウトモデルマウスを対象に、慢性喫煙曝露とエラスターゼ併用によるCOPDモデルを現在作成中で、解析準備を進めている。以上のように研究計画は確実に進捗しており、生理活性ペプチドという観点からみたCOPDの病態解明と臨床展開はこれまでには全く無かった手法で、今後の研究で、難治性の病態であるCOPDに対する新規治療としてのグレリンの可能性が解明される。さらに、本年度の成果は、COPDだけでなく他の呼吸器疾患におけるグレリン研究の基盤になることが予想される。詳細な解析を進めて、呼吸器疾患におけるグレリンの病態生理学的意義の解明や臨床応用に向けた研究を推進したい。

Research Products

• [Journal Article] Ghrelin stimulates growth hormone secretion and food intake in aged rats. (2007)
  • Author(s): Toshinai K, Mondal MS, Shimbara T, Yamaguchi H, Date Y, Kangawa K, Nakazato M
  • Journal Title: Mech Ageing Dev 128 Pages: 182-186
• [Journal Article] Long-term treatment with theophylline reduces neutrophils, interleukin-8 and tumor necrosis factor-ain the sputum of patients with chronic obstructive pulmonary disease. (2007)
  • Author(s): Iiboshi H, Ashitani J, Katoh S, Sano A, Matsumoto N, Mukae H, Nakazato M
  • Journal Title: Pulm Pharmacol Ther 20 Pages: 46-51
• [Journal Article] Elevated levels of antimicrobial peptides in bronchoalveolar lavage fluid in patients with chronic eosinophilic pneumonia. (2007)
  • Author(s): Ashitani J, Matsumoto N, Nakazato M
  • Journal Title: Respiration 74 Pages: 69-75
• [Journal Article] Significance of human beta-defensins in the epithelial lining fluid of patients with chronic lower respiratory tract infections. (2007)
  • Author(s): Yanagi S, Ashitani J, Imai K, Kyoraku Y, Sano A, Matsumoto N, Nakazato M
  • Journal Title: Clin Microbiol Infect 13 Pages: 63-69
• [Journal Article] Elevated BALF concentrations of alpha- and beta-defensins in patients with pulmonary alveolar proteinosis. (2007)
  • Author(s): Mukae H, Ishimoto H, Yanagi S, Ishii H, Nakayama S, Ashitani JI, Nakazato M, Kohno S
  • Journal Title: Respir Med 101 Pages: 715-721
• [Journal Article] Cardiovascular actions of central neuropeptide W in conscious rats. (2007)
  • Author(s): Yu N, Chu C, Kunitake T, Kato K, Nakazato M, Kannan H
  • Journal Title: Regul Pept 138 Pages: 82-86
• [Journal Article] Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus. (2006)
  • Author(s): Date Y, Shimbara T, Koda S, Toshinai K, Ida T, Murakami N, Miyazato M, Kokame K, Ishizuka Y, Ishida Y, Kageyama H, Shioda S, Kangawa K, Nakazato M
  • Journal Title: Cell Metab 4 Pages: 323-331
• [Journal Article] Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. (2006)
  • Author(s): Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Murakami N, Miyazato M, Kangawa K, Nakazato M
  • Journal Title: Endocrinology 147 Pages: 2306-2314
• [Journal Article] Central effects of CRSP-1 on energy homeostasis in rats. (2006)
  • Author(s): Sawada H, Yamaguchi H, Shimbara T, Toshinai K, Mondal MS, Date Y, Murakami N, Katafuchi T, Minamino N, Nunoi H, Nakazato M
  • Journal Title: Endocrinology 147 Pages: 2043-2050
• [Journal Article] Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. (2006)
  • Author(s): Uno K, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Imai J, Hasegawa Y, Gao J, Kaneko K, Iwasaki H, Ishihara H, Sasano H, Inukai K, Mizuguchi H, Asano T, Shiota M, Nakazato M, Oka Y
  • Journal Title: Science 312 Pages: 1656-1659
• [Journal Article] Neuropeptide W is present in antral G cells of rat, mouse, and human stomach. (2006)
  • Author(s): Mondal MS, Kawagoe T, Yamaguchi H, Date Y, Kawagoe T, Tsuruta T, Kageyama H, Kawamura Y, Shioda S, Shimomura Y, Mori M, Nakazato M
  • Journal Title: J Endocrinol 188 Pages: 49-57
• [Journal Article] Isolation of human β-defensin-4 in lung tissue and its increase in lower respiratory tract infection. (2006)
  • Author(s): Yanagi S, Ashitani J, Ishimoto H, Date Y, Mukae H, Chino N, Nakazato M
  • Journal Title: Respir Res 6 Pages: 130-130
• [Journal Article] Plasma leptin and ghrelin concentrations in patients with Crohn's disease. (2006)
  • Author(s): Nishi Y, Isomoto H, Ueno H, Ohnita K, Wen CY, Takeshima F, Mishima R, Nakazato M, Kohno S
  • Journal Title: World J Gastroenterol 11 Pages: 7314-7317
• [Journal Article] Galanin-like peptide promotes feeding behavior via activation of orexinergic neurons in the rat lateral hypothalamus. (2006)
  • Author(s): Kageyama H, Kita T, Toshinai K, Guan JL, Date Y, Takenoya F, Kato S, Ohtaki T, Matsumoto H, Nakazato M, Shioda S
  • Journal Title: J Neuroendocrinol 18 Pages: 33-41
• [Journal Article] Maternal ghrelin plays an important role in rat fetal development during pregnancy. (2006)
  • Author(s): Nakahara K, Nakagawa M, Baba Y, Sato M, Toshinai K, Date Y, Nakazato M, Kojima M, Miyazato M, Kaiya H, Hosoda H, Kangawa K, Murakami N
  • Journal Title: Endocrinology 147 Pages: 1333-1342
• [Journal Article] Postnatal development of orexin-A and orexin-B like immunoreactivities in the eastern grey kangaroo (macropus giganteus) hypothalamus. (2006)
  • Author(s): Yamamoto Y, Mckinley MJ, Nakazato M, Yamashita H, Shirahata A, Ueta Y
  • Journal Title: Neurosci Lett 392 Pages: 124-128
• [Journal Article] Prognostic value of cardiac I-123 metaiodobenzylguanidine imaging in patients with non-insulin-dependent diabetes mellitus. (2006)
  • Author(s): Nagamachi S, Fujita S, Nishii R, Futami S, Tamura S, Mizuta M, Nakazato M, Kurose T, Wakamatsu H
  • Journal Title: J Nucl Cardiol 13 Pages: 34-42
• [Journal Article] Identification of hBD-3 in respiratory tract and serum and its increase in pneumonia. (2006)
  • Author(s): Ishimoto H, Mukae H, Date Y, Shimbara T, Mondal MS, Ashitani J, Hiratsuka T, Kubo S, Kohno S, Nakazato M
  • Journal Title: Eur Respir J 27 Pages: 253-260
• [Journal Article] Fasting-induced reduction in locomotor activity and reduced response of orexin neurons in carnitine-deficient mice. (2006)
  • Author(s): Yoshida G, Li MX, Horiuchi M, Nakagawa S, Sakata M, Kuchiiwa S, Kuchiiwa T, Jalil MA, Begum L, Lu YB, Iijima M, Hanada T, Nakazato M, Huang ZL, Eguchi N, Kobayashi K, Saheki T.
  • Journal Title: Neurosci Res 55 Pages: 78-86
  • NAID: 10020616692
• [Journal Article] Chemical Synthesis of human β-defensin-1,-2,-3 and -4:optimization of the oxidative folding reaction. (2006)
  • Author(s): Chino N, Kubo S, Nishio H, Nishiuchi Y, Nakazato M, Kimura T
  • Journal Title: Int J Pept Res Therapeutics 12 Pages: 203-209
• [Journal Article] Ghrelin concentrations and cardiac vagal tone are decreased after pharmacologic and cognitive-behavioral treatment in patients with bulimia nervosa. (2006)
  • Author(s): Tanaka M, Nakahara T, Muranaga T, Kojima S, Yasuhara D, Ueno H, Nakazato M, Inui A
  • Journal Title: Horm Behav 50 Pages: 261-265
• [Journal Article] Centrally administered neuropeptide W-30 activates magnocellular neurosecretory cells in the supraoptic and paraventricular nuclei with neurosecretion in rats. (2006)
  • Author(s): Kawasaki M, Onaka T, Nakazato M, Saito J, Mera T, Hashimoto H, Fujihara H, Okimoto N, Ohnishi H, Nakamura T, Ueta Y
  • Journal Title: J Endocrinol 190 Pages: 213-223
• [Journal Article] Fasting-induced reduction in locomotor activity and reduced response of orexin neurons in carnitine-deficient mice. (2006)
  • Author(s): Yoshida G, Li MX, Horiuchi M, Nakagawa S, Sakata M, Kuchiiwa S, Kuchiiwa T, Jalil MA, Begum L, Lu YB, Iijima M, Hanada T, Nakazato M, Huang ZL, Eguchi N, Kobayashi K, Saheki T
  • Journal Title: Neurosci Res 55 Pages: 78-86
  • NAID: 10020616692
• [Journal Article] Changes in plasma ghrelin levels, gastric ghrelin production, and body weight after Helicobacter pylori cure. (2006)
  • Author(s): Osawa H, Kita H, Ohnishi H, Nakazato M, Date Y, Bowlus CL, Ishino Y, Watanabe E, Shiiya T, Ueno H, Hoshino H, Satoh K, Sugano K
  • Journal Title: J Gastroenterol 41 Pages: 954-961
• [Journal Article] Effects of ghrelin and des-acyl ghrelin on neurogenesis of the rat fetal spinal cord. (2006)
  • Author(s): Sato M, Nakahara K, Goto S, Kaiya H, Miyazato M, Date Y, Nakazato M, Kangawa K, Murakami N
  • Journal Title: Biochem Biophys Res Commun 350 Pages: 598-603
• [Journal Article] Incomplete restoration of the secretion of ghrelin and PYY compared to insulin after food ingestion following weight gain in anorexia nervosa.
  • Author(s): Nakahara T, Kojima S, Tanaka M, Yasuhara D, Harada T, Sagiyama KI, Muranaga T, Nagai N, Nakazato M, Nozoe SI, Naruo T, Inui A
  • Journal Title: J Psychiatr Res. (in press)
• [Journal Article] Ontogeny of a New Enteric Peptide, Neuropeptide W (NPW), in the Developing Rat Stomach.
  • Author(s): Mondal MS, Yamaguchi H, Date Y, Tsuruta T, Shimbara T, Toshinai K, Shimomura Y, Mori M, Nakazato M
  • Journal Title: Regul Pept. (in press)
• [Journal Article] The role of PYY3-36 in the feeding regulation.
  • Author(s): Ueno H, Yamaguchi H, Mizuta M, Nakazato M
  • Journal Title: Regul Pept. (in press)