A molecular biological study of mechanism of developing pulmonary fibrosis based upon dysfunction of alveolar type II cells

2008 Fiscal Year Final Research Report

• Project/Area Number: 19590916
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Tokyo Medical University
• Principal Investigator: SETOGUCHI Yasuhiro Tokyo Medical University, 医学部, 教授 (90206649)
• Co-Investigator(Kenkyū-buntansha): TSUBOI Ryoji 東京医科大学, 医学部, 教授 (70221421)
• Project Period (FY): 2007 – 2008
• Keywords: 肺線維化 / 肺胞II型上皮細胞 / 間質性肺炎 / surfactant / SP-C / アポトーシス小胞体 / 遺伝子変異

Research Abstract

1. 本邦に於ける間質性肺炎でこれまで報告のない新たなSP-C(サーファクタント蛋白C)遺伝子変異を6箇所同定した。
SP-C遺伝子変異は、成人発症間質性肺炎に比し新生児、乳児の間質性肺炎で有意に高率であった。本邦の変異の位置は、欧米と異なりexon2からexon3に多いという特徴を示した。
2. 野生型並びに変異SP-C蛋白の細胞内動態と発現細胞への影響の分子生物学的比較解析のために特徴的な遺伝子変異を2箇所(exon2の部分とexon4欠失)を選んでinsertional mutagenesis法によりプラスミド発現ベクターを作成。遺伝子導入による変異SP-C前駆蛋白の細胞内動態の比較解析では、SP-C前駆蛋白の変異部分により細胞内蓄積部位が異なり、遺伝子発現機能解析に於いても細胞の機能上も影響が異なる事を明らかにした。
3. 結論 SP-C遺伝子変異部位が欧米と異なることを考えると民族的な背景によることも考えられ、遺伝子変異部位により影響された細胞機能も異なることから臨床的に薬剤性間質性肺炎等が欧米に比し本邦に多いということにも関連するのではないかという興味ある結論が導きだされた。更に、SP-C発現細胞である肺胞II型上皮細胞の機能異常による間質性肺炎発症という病因論学的に新しいパラダイムの構築につながることが期待された。

Research Products

• [Journal Article] The Frequency of Mutations in the Surfactant Protein C Gene (SFTPC) Is Much Higher in Pediatric Interstitial Lung Disease (PILD) Than Either Adult-Onset Familial or Sporadic (2009)
  • Author(s): Setoguchi Y., Tamaoki F, Nakai,M, Kono,Y
  • Journal Title: Interstitial Pneumonia Am J Crit Care Med A2170
  • Peer Reviewed
• [Journal Article] Lentiviral Vector-Mediated Gene Transfer to Human Hair Follicles (2009)
  • Author(s): Sriwiriyanont P, Hachiya A, Pickens WL, Moriwaki S, Ohuchi A, Kitahara T, Takema Y, Kitzmiller WJ, Visscher MO, Bello A, Tsuboi R, Kobinger GP
  • Journal Title: J Invest Dermatol
  • Peer Reviewed
• [Journal Article] Stem cell factor-KIT signalling plays a pivotal role in regulating pigmentation in mammalian hair (2009)
  • Author(s): Hachiya A, Sriwiriyanont P, Kobayashi T, Nagasawa A, Yoshida H, Ohuchi A, Kitahara T, Visscher MO, Takema Y, Tsuboi R, Boissy RE
  • Journal Title: J athol 218 Pages: 30-9
  • Peer Reviewed
• [Journal Article] Mechanistic effects of long-term ultraviolet B irradiation induce epidermal and dermal changes in human skin xenografts (2009)
  • Author(s): 17. Hachiya A, Sriwiriyanont P, Fujimura T, Ohuchi A, Kitahara T, Takema Y, Kitzmiller WJ, Visscher MO, Tsuboi R, Boissy RE
  • Journal Title: Am J Pathol 174 Pages: 401-13
  • Peer Reviewed
• [Journal Article] Epidermotropic skin metastasis from gastric cancer : immunohistochemical analysis using cytokeratins (2009)
  • Author(s): Hayashi K, Yamamoto T, Oyama K, Nagai T, Tsuboi R
  • Journal Title: Clin Exp Dermatol 34 Pages: 406-8
  • Peer Reviewed
• [Journal Article] Suppressive efficacy of roxithromycin against human peripheral-blood mononuclear cells stimulated with hemolytic streptococci superantigen (2009)
  • Author(s): Kamogawa S, Kagami K, Maeda M, Arai K, Okubo Y, Tsuboi R, Hirano T
  • Journal Title: Eur J Pharmacol 602 Pages: 439-47
  • Peer Reviewed
• [Journal Article] 瀬戸口靖弘 ハイドロキシクロロキンにて治療を行った肺胞サーファクタント遺伝子異常を伴う間質性肺炎の1 例 (2008)
  • Author(s): 高橋寛吉, 木苗優子, 白井眞美, 本郷輝明
  • Journal Title: 日本小児科学会雑誌 113 Pages: 118
  • Peer Reviewed
• [Journal Article] Increased galectin-9 expression in alveolar macrophages in interstitial lung disease (2008)
  • Author(s): Ohkubo M, Setoguchi Y, Kobayashi Y,Kanagasaki S, Ohyashiki K, Tamaya T
  • Journal Title: J Tokyo Medical University 66 Pages: 513-521
  • Peer Reviewed
• [Journal Article] Two Patients With Bepridil-Induced Interstitial Pneumonia (2008)
  • Author(s): Watanabe M, Takata Y, Fukasawa S, Sakota K, Abe T, Goseki Y, Setoguchi Y, Chikamori T, Yamashina A
  • Journal Title: Circ J
  • Peer Reviewed
• [Journal Article] 臨床遺伝子学'08 呼吸器系疾患の遺伝子学 (2008)
  • Author(s): 瀬戸口靖弘
  • Journal Title: 最新医学 63 Pages: 1827-1836
• [Journal Article] 間質性肺炎とSP-C 遺伝子異常 (2008)
  • Author(s): 瀬戸口靖弘
  • Journal Title: 呼吸 27 Pages: 873-879
• [Journal Article] 遺伝子異常と肺疾患 21 世紀ゲノム医学に向けて (2008)
  • Author(s): 貫和敏博, 瀬戸口靖弘, 瀬山邦明, 萩原弘一
  • Journal Title: 呼吸 27 Pages: 859-868
• [Journal Article] bepridil 投与中に認められた間質性肺炎の2 症例 (2008)
  • Author(s): 渡辺雅貴, 深澤伸也, 迫田邦裕, 五関善成, 近森大志郎, 山科章, 阿部哲也, 瀬戸口靖弘
  • Journal Title: Circulation Journal 72 Pages: 941
  • Peer Reviewed
• [Journal Article] 胸腺原発のMALT リンパ腫 (2008)
  • Author(s): 瀬戸口靖弘, 河野雄太, 岸本佳子, 小松広彦, 大久保仁嗣, 臼田実男, 稲垣佳典,松林純, 木村之彦
  • Journal Title: 東京医科大学雑誌 66 Pages: 584-594
  • Peer Reviewed
• [Journal Article] Hair growth stimulatory effect by a combination of 5-aminolevulinic acid and iron ion (2008)
  • Author(s): Morokuma Y, Yamazaki M, Maeda T, Yoshino I, Ishizuka M, Tanaka T, Ito Y, Tsuboi R
  • Journal Title: Int J Dermatol 47 Pages: 1298-303
  • Peer Reviewed
• [Journal Article] In vitro antifungal activities of luliconazole, a new topical imidazole (2008)
  • Author(s): Koga H, Nanjoh Y, Makimura K, Tsuboi R
  • Journal Title: Med Mycol 29 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Anti-p200 pemphigoid associated with annular pustular psoriasis (2008)
  • Author(s): Miyakura T, Yamamoto T, Tashiro A, Okubo Y, Oyama B, Ishii N, Hashimoto T,Tsuboi R
  • Journal Title: Eur J Dermatol 18 Pages: 481-2
  • Peer Reviewed
• [Journal Article] Acne Study Group. Evaluation of the newly established acne severity classification among Japanese and Korean dermatologists (2008)
  • Author(s): Hayashi N, Suh DH, Akamatsu H, Kawashima M
  • Journal Title: J Dermatol 35 Pages: 261-3
  • Peer Reviewed
• [Journal Article] Molecular analysis of Malassezia microflora in seborrheic dermatitis patients : comparison with other diseases and healthy subjects (2008)
  • Author(s): Tajima M, Sugita T, Nishikawa A, Tsuboi R
  • Journal Title: J Invest Dermatol 128 Pages: 345-51
  • Peer Reviewed
• [Journal Article] Spontaneous regression of pulmonary infiltration of adult T-cell leukemia/ lymphoma (2007)
  • Author(s): Jankipersadsing V, Tauchi T, Ohyashiki K, Tanaka Y, Setoguchi Y, Mukai K
  • Journal Title: Int J Hematol 86 Pages: 207
  • Peer Reviewed
• [Journal Article] 間質性肺炎とサーファクタント (2007)
  • Author(s): 瀬戸口靖弘
  • Journal Title: 内科 99 Pages: 292-298
• [Journal Article] Smad ノックアウトマウス分子呼吸器病 (2007)
  • Author(s): 瀬戸口靖弘
  • Journal Title: 10 Pages: 176-182
• [Journal Article] SP-C遺伝子変異を伴った小児間質性肺炎 (2007)
  • Author(s): 瀬戸口靖弘 後藤幹生
  • Journal Title: 分子呼吸器病 11 Pages: 61-66
  • Peer Reviewed
• [Journal Article] 間質性肺疾患におけるガレクチン-9 の発現解析 (2007)
  • Author(s): 大久保仁嗣, 大屋敷一馬, 瀬戸口靖弘
  • Journal Title: 東京医科大学雑誌 65 Pages: 472
  • Peer Reviewed
• [Journal Article] Antisense oligonucleotide targeting fibroblast growth factor receptor (FGFR)-1 stimulates cellular activity of hair follicles in an in vitro organ culture system (2007)
  • Author(s): Tsuboi R, Yamazaki M, Matsuda Y, Uchida K, Ueki R, Ogawa H
  • Journal Title: Int J Dermatol 46 Pages: 259-63
  • Peer Reviewed
• [Journal Article] Gene transfer in human skin with different pseudotyped HIV-based vectors (2007)
  • Author(s): Hachiya A, Sriwiriyanont P, Patel A, Saito N, Ohuchi A, Kitahara T, Takema Y,Tsuboi R, Boissy RE, Visscher MO, Wilson JM, Kobinger GP
  • Journal Title: Gene Ther 14 Pages: 648-56
  • Peer Reviewed
• [Presentation] Surfactant protein C gene mutation associated interstitial pneumonia (2009)
  • Author(s): Setoguchi Y
  • Organizer: Sakura Lung Conference
  • Place of Presentation: Tokyo
  • Year and Date: 20090000
• [Presentation] The Frequency of Mutations in the Surfactant Protein C Gene (SFTPC) Is Much Higher in Pediatric Interstitial Lung Disease (PILD) Than Either Adult-Onset Familial or Sporadic Interstitial Pneumonia American (2009)
  • Author(s): Setoguchi Y., Tamaoki F, Nakai,M, Kono, Y
  • Organizer: Thoracic Society International Conference
  • Place of Presentation: San Diego
  • Year and Date: 2009-05-07
• [Presentation] Clinico-Pathological Consequences of Nnovel Mutations in The Surfactant Protein C Gene(SFTPC)in Japanese Patients with Interstitial Pneumonia (IP) (2008)
  • Author(s): Michiko Nakai, Yuta Kono, Tetsuya Abe, Norihiro Sugiyama, Yasuhiro Setoguchi
  • Organizer: English Mini symposium 48th JRS Meeting
  • Place of Presentation: Kobe
  • Year and Date: 2008-07-05
• [Presentation] Yasuhiro Setoguchi Nonspecific Interstitial Pneumonia and Alveolar Proteinosis Trafficking Resulting From A Novel Mutation in The Surfactant Protein C Gene(SFTPC) (2008)
  • Author(s): Fukami Tamaoki, Yuta Kono
  • Organizer: English Mini symposium 48th JRS Meeting
  • Place of Presentation: Kobe
  • Year and Date: 2008-07-05
• [Presentation] Clinico-Pathological Consequences of Nnovel Mutations in The Surfactant Protein C Gene(SFTPC)in Japanese Patients with Interstitial Pneumonia (IP) (2008)
  • Author(s): Setoguchi Y. Kono Y, Sugiyama S
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: Toronto
  • Year and Date: 2008-05-21
• [Presentation] Identification of novel mutation in the surfactant protein C gene and ABC-A3 gene in patients with familial interstitial pneumonia or sporadic interstitial pneumonia (2007)
  • Author(s): Setoguchi Y. Kohno Y, Abe T, Hattori N
  • Organizer: Am J Respir Crit Care Med(175 : A148)
  • Year and Date: 20070000
• [Presentation] Identification and the clinical consequences of novel mutations of surfactant protein C and ABCA3 gene in patients with interstitial pneumonia RLDC (2007)
  • Author(s): Setoguchi Y
  • Place of Presentation: Rare Lung Disease Consortium
  • Year and Date: 20070000
• [Presentation] Vascalar Eondothelial Growth Factor (UEGF) MAY Play a Role in Developing Airflow (2007)
  • Author(s): Kano Y, Setoguchi Y
  • Organizer: Limitation in Sarcoidosis 12th congress of the APSR
  • Year and Date: 2007-12-30
• [Presentation] Impulse Oscillometry System (IOS) May Be a Promising Tool to Evaluate the Clinical Course of Respiratory (2007)
  • Author(s): Abe T, Setoguchi Y
  • Organizer: Function in Bronchiolitis Obliterans (BO) APSR 2007 CONGRESS
  • Place of Presentation: Gold Coast
  • Year and Date: 2007-10-21
• [Presentation] Identification and the clinical consequences of novel mutations of surfactant protein C and ABCA3 gene in patients with interstitial pneumonia (2007)
  • Author(s): Setoguchi Y
  • Organizer: APSR 2007 CONGRESS
  • Place of Presentation: Gold Coast
  • Year and Date: 2007-10-21
• [Book] 呼吸器症候群(第2 版) その他の呼吸器疾患を含めて】 腫瘍性疾患 間葉系(原発性)腫瘍平滑筋腫、平滑筋肉腫 日本臨床(0047-1852) (2009)
  • Author(s): 中井美智子, 瀬戸口靖弘
  • Total Pages: pp144-146
  • Publisher: 別冊呼吸器症候群III
• [Book] 呼吸器系(成人から老年)からだの年齢辞典 (2008)
  • Author(s): 瀬戸口靖弘
  • Total Pages: pp501
  • Publisher: 朝倉書店
• [Book] 心不全 COPD のすべて (2008)
  • Author(s): 瀬戸口靖弘
  • Total Pages: pp325
  • Publisher: 文光堂
• [Book] 呼吸器症候群(第2版) その他の呼吸器疾患を含めて】 びまん性肺疾患 間質性肺炎Hermansky-Pudlak 症候群日本臨床 (2008)
  • Author(s): 河野雄太, 瀬戸口靖弘
  • Total Pages: pp355-359
  • Publisher: 別冊呼吸器症候群I