Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

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  Japan Society for Medical Education

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  日本呼吸器学会

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  日本内科学会

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  日本肺癌学会

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  THE JAPAN SOCIETY FOR RESPIRATORY ENDOSCOPY

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   Department of Respiratory Medicine and Allergology   Associate Professor  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• Idiopathic Pulmonary Fibrosis

• 内科学 呼吸器病学

• サーファクタント蛋白質

• Clinical Clerkship

• Medical Education

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• 間質性肺炎・急性肺傷害における肺胞II型上皮細胞の役割(びまん性肺疾患に対する分子生物学的アプローチ : 間質性肺炎から肺気腫まで)(第24回日本気管支学会総会)

  白鳥 正典, 相坂 治彦, 大塚 満雄, 今井 良成, 今 勇人, 藤嶋 卓哉, 黒沼 幸治, 原田 一暁, 明田 晶子, 工藤 和実, 高橋 弘毅, 阿部 庄作

  気管支学 : 日本気管支研究会雑誌 ( 日本呼吸器内視鏡学会 )  23 ( 8 ) 721 - 725  2001.12

  　View Summary

  間質性肺炎・急性肺傷害では, 肺胞中隔への炎症細胞浸潤と線維芽細胞の増加による末梢肺組織の線維化が認められる。肺胞I型上皮細胞(type I cell)が傷害されると肺胞II型上皮細胞(type II cell)が肥大・増生し、type I cellへと分化, 肺胞壁を被覆し修復する方向へ働く。type II cellから合成・分泌される肺サーファクタント蛋白質(Surfactant Protein;SP)のうち, 疎水性であるSP-B, SP-Cは, 末梢肺組織の線維化の契機の1つと考えられている肺胞の虚脱を防ぐ機能を担う。我々は間質性肺炎における血清マーカーとしてのSP-A, SP-Dの有用性を報告してきたが, 放射線起因急性肺傷害動物モデルを用いて生体内での各SPの推移を検討した結果, 放射線照射後にサーファクタント産生の増加を認めたが, SPのmRNA発現においては, SP-A mRNAに対するSP-B, SP-C mRNA発現の相対的低下を認めた。このことから, 急性肺傷害における肺サーファクタント組成の変化は肺胞表面張力上昇を惹起させ, 肺胞虚脱による呼吸状態の悪化や末梢肺組織の線維化の一因となることが推測された。最近ではARDSに対するサーファクタント補充療法等が報告され, 今後, type II cellからみた間質性肺炎・急性肺傷害の病態に関する新たな検討が期待される。

  DOI CiNii

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• Therapeutic application of lung collectin in acute lung injury

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2011

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  2013

   

  TAKAHASHI HIROKI, KUROKI Yoshio, SHIRATORI Masanori, CHIBA Hirofumi, KUDO Kazumi, KURONUMA Koji

  　View Summary

  The purpose of this project were to clarify the mechanism of regulation by which Toll-like receptors (TLRs) act against drug-induced acute lung injury (ALI), to evaluate the protective effect by lung a collectin, SP-A and to establish the molecular basis for the clinical application of it. Bleomycin (BLM)-administered SP-A(-/-) mice had significantly higher mortality rate and more increase of inflammatory cytokines in the lungs than wild types. SP-A inhibited BLM-induced inflammatory cytokines from rat alveolar macrophages. sTLR2 gene-transfected HEK293 cells showed up-regulation of NF-kB. BML bound directly with sTLR2 and its binding was blocked by SP-A. These results indicate that BLM-induced signal depends on TLR2 and lung collectin, SP-A has protective function against ALI via TLR2 dependent signal pathway.

• Pulmonary collectin regulates drug-induced lung injury.

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2008

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  2010

   

  TAKAHASHI Hiroki, KUROKI Yoshio, SHIRATORI Masanori, CHIBA Hirofumi, KUDO Kazumi, KURONUMA Koji

  　View Summary

  The purposes of this project were to investigate the mechanisms of regulation by which lung collectins, surfactant proteins A and D (SP-A and SP-D), and Toll-like receptor (TLR) function against inflammation on the development of drug induced lung injury, and to establish the molecular basis for the clinical application of these proteins. First, the mouse model of lung injury was established using drugs, and SP-A^<-/-> mice had significantly higher mortality rates than WT mice. SP-A inhibited drug-induced inflammatory cytokine production from rat alveolar macrophages. SP-A blocked sTLR2-bleomycin binding in the dose dependent manner. These results suggest that bleomycin signals are transmitted through TLR2 dependent pathway and regulated by the molecular interaction of SP-A.

• Regulation of TLR by surfactant proteins in interstitial pneumonia

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2003

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  2004

   

  TAKAHASHI Hiroki, KUORKI Yoshio, SHIRATORI Masanori, CHIBA Hirofumi

  　View Summary

  Chronic Interstitial pneumonias involve a group showing poor prognosis including idiopathic pulmonary fibrosis (IPF). Patients with IPF occasionally complicate with infection-triggered exacerbation of respiratory disturbance and result in death. Pathologic feature of the exacerbation is diffuse alveolar damage and its molecular biology is of the basis of the upregulation of bioactive materials presented by TNF-a. Therefore, to inhibit the upregulation of TNF-a in the patients' lungs may prevent the exacerbation and then bring a good survival rate. The expression of TNF-a is upregulated by the interaction with various bacterial components and Toll-like receptor (TLR) expressed in cell membrane of inflammatory immune cells. On the other hand, surfactant protein (SP)-A is known to provide an inhibitory effect on the inflammatory reaction in vitro. We firstly investigated whether SP-A alters cellular responses by Staphylococcus aureus derived peptidoglycan (PGN). The inhibitory effect on TNF-a secretion was dependent upon SP-A concentrations in physiological range. SP-A. directly bound to a soluble form of the recombinant extracellular TLR2 domain (sTLR2). Coincubation of sTLR2 with SP-A significantly reduced the binding of sTLR2 to PGN. These results indicate that the direct interaction of SP-A with TLR2 alters PGN-induced cell signaling. We next studied interaction between SP-A and, Mycoplasma pneumoniae. SP-A enhanced the action of the lipoprotein prepared from the pathogen, increasing the release of TNF-a and NO. Only cells transfected with TLR2 or CD 14 plus TLR2 produced TNF-a. These findings directly implicate SP-A, CD 14 and TLR2 in the immediate innate response to M. pneumoniae.

• Type II pneumocytes as a protective factor against interstitial lung injury

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2001

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  2002

   

  TAKAHASHI Hiroki, SHIRATORI Masanori, KUORKI Yoshio

  　View Summary

  Interstitial lung diseases involve a group showing poor prognosis including idiopathic pulmonary fibrosis (IPF). A common pathophysiological change is irreversible fibrosis. In lung tissues injured in alveolar interstitum, to make alveolar epithelial cells regenerate is very important for repair of the injured lung. Several recent studies showed that rennin-angiotensin system induces lung fibrosis and that apoptosis of type II pneumocytes is a key factor of its mechanism. However, precise manner of this system is unknown. Aims of this study were to clarify a mechanism of interstital lung injury and following fibrosis via angiotensin II receptor 1 (AT1) and to estimate an efficacy of AT1 selective antagonist (Candesartan) as a therapeutic agent against bleomycin-induced lung injury prepared in rats. Distribution of expression of AT1 receptors in normal lungs was nonspecific for many types of cells including alveolar macrophages and type II pneumocytes. Their expression in injured lungs was more extensive in neutrophils, alveolar macrophages and fibroblasts than in other types of cells. Administration of Candesartan significantly inhibited an increased content of hydroxyproline as a quantitative indicator of fibrosis, and an increased cell number of neutrophils and alveolar macrophages, whereas it did not inhibit an increased expression of AT1. Thus, this AT1 antagonist may provide an ability to modulate a process of fibrosis in the lung. A speculated mechanism by the AT1 antagonist is based on prevention of apoptosis of type II pneumocytes.

• 急性肺傷害の遺伝子およびアポトーシスの解析とサーファクタント蛋白質による治療応用

  奨励研究(A)

  Project Year :

  2000

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  2001

   

  白鳥 正典

  　View Summary

  本研究は急性肺傷害の病態における、肺胞II型上皮細胞の動態に着目して、肺傷害出現時期の肺サーファクタント蛋白質(SP)の発現やアポトーシスの発現を評価し、肺胞構造の修復に寄与するとされている同細胞の再生・増殖の評価を行うことを目的とした。 急性肺傷害モデルとして、8週齢の雄Sprague-Dawleyラットの胸郭に20Gyの単回軟X線照射を行い放射線性急性肺傷害ラットモデルを作成した。本モデルの組織学的検討では、照射3週後より肺胞内にマクロファージを主体とする炎症細胞浸潤が出現、照射5週後には炎症細胞浸潤の増強と胞隔炎を認めた。 傷害肺組織の肺胞II型上皮細胞の細胞質内サーファクタント封入体であるlamellar body(LB)を可視化したところ、照射2週後よりLB陽性細胞が認められ、その後、それらの細胞数およびLBの数とサイズが4週後まで増加し、肺傷害後の肺サーファクタント産生の増加が示唆された。 肺組織全体からのRNA収量はサイトカインなどのmRNAの増加や炎症細胞数の増加などを反映し照射3から5週後に有意に増加した。照射4週後のSP-A,-B,-C,-DのmRNA発現は、肺組織全体で増加した。しかしながら、親水性のSPであるSP-A,-D mRNAと比較し、疎水性のSP-B,-C mRNA発現は有意に減少していた。これらの結果から、肺胞の表面張力を低下させ肺胞構造の安定化を担うSP-B、SP-Cの相対的減少がサーファクタント組成を変化させ、肺胞表面張力を上昇させ肺胞虚脱を促進し、肺の線維化(リモデリング)に関与する可能性が示唆された。 傷害に伴う肺胞II型上皮細胞のアポトーシスに関してTUNEL染色による検出を試みたが、明らかなアポトーシスは認めなかった。 急性肺傷害時の肺サーファクタント蛋白質組成の変化は、その産生の面のみならず、蛋白分解酵素などによる蛋白質構造の障害や血液中への逸脱に伴う量的減少が考えられる。量的に減少する疎水性SPを含有する人工サーファクタントの傷害肺への投与が、呼吸状態を改善させ、リモデリングを抑制する可能性が示唆された。