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THE ROLE OF INTERLEUKIN,TUMOR NECROSIS FACTOR-ALPHA AND PROTEINASES IN THE DEVELOPMENT OF ACUTE LUNG INJURY IN SHEEP

Research Project

Project/Area Number 08457179
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionSHINSHU UNIVERSITY

Principal Investigator

KUBO Keishi  SHINSHU UNIVERSITY SCHOOL OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (80143965)

Co-Investigator(Kenkyū-buntansha) SHIBAMOTO Toshishige  SHINSHU UNIVERSITY SCHOOL OF MEDICINE,ASSOCIATE PROFESSOR, 医学部, 助教授 (90178921)
HONDA Takayuki  SHINSHU UNIVERSITY SCHOOL OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (80238815)
KOIZUMI Tomonobu  SHINSHU UNIVERSITY HOSPITAL,ASSISTANT, 医学部附属病院, 助手 (20273097)
FUJIMOTO Keisaku  SHINSHU UNIVERSITY HOSPITAL,ASSISTANT, 医学部附属病院, 助手 (70242691)
KOBAYASHI Toshio  SHINSHU UNIVERSITY HOSPITAL,ASSISTANT PROFESSOR, 医学部附属病院, 講師 (80020775)
松沢 幸範  信州大学, 医学部・附属病院, 助手 (40219423)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1997: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsEndotoxin-induced lung injury / Acute lung injury / Interleukin / Tumor necrosis factor / Proteinase / Sheep / VEGF,VPF / 蛋白分解酵素阻害剤 / 気道上皮液 / グルタチオン
Research Abstract

We investigated effects of JTE-607, a synthetase inhibitor of cytokines, especially tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) -1 and IL-6, on endotoxin-induced lung dysfunction in awake sheep with chronic lung lymph fistula. The pretreatment of JTE-607 (10mg/kg) did not prevent the dysfunctions induced by intravenous infustion of E.coli endotoxin (1 mug/kg) including pulmonary hypertension, circulating leukocyte depletion and hypoxemia during the early phase, and increased permeability edema during the late phase. The endotoxemia led to a significant increase in the serum concentration of TNF-alpha which was measured by bioassay (Yoshie et al.J Biochem 100 : 531,1986), but JTE-607 did not suppress the increased TNF levels.
Since secretary leukoprotease inhibitor (SLPI), which is a 12KDa serine antiproteasae and physiologically exist in the epithelial surface of upper airways significantly increases the levles of glutathione of lung epithelial lining layr and lung lymph i … More n sheep (Gillissen et al.J Appl Physiol 75 : 825,1993), we tried the effects of recombinant half-sized SLPI (1/2 SLPI ; TEI-7361) on the levels of glutathione in bronchoalveolar lavage fluid (BALF) and lung lymph in awake sheep. Intravenous administration of TEI-7361 of 15mg/kg into awake sheep did not change the glutathione levels in BALF,lung lymph and serum. Therefore, it seems that 1/2 SLPI does not have the ability to increase the levels of glutathione of lung epithelial lining layr.
High altitude pulmonary edema (HAPE) is a non cardiogenic pulmonary edema, a typical disorder as acute lung injury, occurs in the Japan Alps. The pathogenesis of HAPE is unclear. We investigated the levels of ILs, TNF-alpha and P-selectin in BALF performed at early period of 7 patients with HAPE and the relations between these values and pulmonary hemodynamics. The proinflammatory cytokines such as IL-1 beta, IL-6, IL-8 and TNF-alpha were remarkably increased, but IL-10 and P-selection did not increase. However, these values were not detected or within low levels in BALF at recovery. The increased levels of IL-6 and TNF-alpha were related to driving pressure. The proinflammatory cytokines play an important role of the development of HAPE,although the role is transient. Furthermore, pulmonary hypertension is related to the changes of proinflammatory cytokines. On the other hand, we measured the levels of vascular endothelial growth factor (VEGF), a new chemotactic factor related to increasing permeability, in BALF at its early period of HAPE.The values were increased, but we need further studies to see the role of VEGF in HAPE. Less

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Kubo, K.et al: "Inflammatory cytokines in the BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema" Respir Physiol. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Koizumi, T.et al: "Neutrophils pretreated with granulocyte colony-stimu lating factor(G-CSF)are not related to the severity of endotoxin-induced lung injary" Exp Lung Res. 23. 393-404 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hanaoka, M.et al: "Effect of post-treatment with granulocyte colony-stimulating factor on endotoxin-induced lung injury in sheep" Exp Lung Res. 24. 15-25 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hanaoka, M.et al: "Association of high-altitude pulmonary edema with the major histocom pathbility complex" Circulation. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ge, R-L, et al: "Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochontona Curzonide(Pika)at high altitude" Am J Physiol(Heart Circ Physiol). (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Miyahara, T.et al: "Lecithinized superoxide dismutase attenuates Phorbol myristate acetate-Induced injury in isolated dog lung" Eur J Pharmacol. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Fujimoto, K.et al.: "Effect of the 21-aminosteroid U-74006F on antigen-induced bronchoconstriction and bronchoalveolar eosinophilia in allergic sheep" Eur Respir J. 9. 2044-2049 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Miyahara, T.et al.: "Specific neutrophil elastase inhibitor does not attenuate acute lung injury induced by air embolism in awake sheep." Exp Lung Res. 22. 613-625 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Droma, Y.et al.: "Endothelin-1 and interleukin-8 in high altitude pulmonary edema." Eur Respir J. 9. 1947-1949 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Droma, Y.et al.: "Acute hypoxic pulmonary vascular response does not accompany plasma endothelin-1 elevation in subjects susceptible to high altitude pulmonary edema." Intern Medicine. 35. 257-260 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Koizumi, T.et al.: "Nitric oxide and nitroglycerin reversal of pulmonary vasoconstriction induced by alpha-activation during exercise" Am J Physiol. 270 (Heart Circ Physiol 39). H875-H880 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Koizumi, T.et al.: "Neutrophils pretreated with granulocyte colony-stimulating factor (G-CSF) are not related to the severity of endotoxin-induced lung injury." Exp Lung Res. 23. 393-404 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ge, R-L.et al.: "Low pulmonary diffusing capacity in subjects with acute mountain sickness." Chest. 111. 58-64 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hanaoka, M.et al.: "Effect of post-treatment with granulocyte colony-stimulating factor on endotoxin-induced lung injury in sheep." Exp Lung Res. 24. 15-25 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hanaoka, M.et al.: "Association of high-altitude pulmonary edema with the major histocompatibility complex." Circulation. (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kubo, K.et al.: "Inflammatory cytokines in the BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema." Respir Physiol. (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ge, R-L.et al.: "Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochontona Curzoniae (Pika) at high altitude." Am J Physiol (Heart Circ Physiol). (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Miyahara, T., et al.: "Lecithinized superoxide dismutase attenuates phorbol myristate acetate-induced injury in isolated dog lung." Eur J Pharmacol. (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kubo,K.et al: "Inflammatory cytokines in the BAL fluid and pulmonary hemodynamics in high-altitude pulmonary ddema" Respir Physiol. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Hanaoka,M.et al: "Effect of post-treatment with granulocyte colony-stimulating factor on endotoxin-induced lung injury in sheep" Exp Lung Res. 24. 15-25 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hanaoka,M.et al: "Association of high-altitude pulmonary edema with the major histocompatibility complex" Circulation. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Ge,R-L.et al: "Blunted hypoxic pulmonary vasoconstriction respone in the rodent Ochontona Curzonide(Pika)at high altitude" Am J Physiol(heart Cire physiol). (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Miyahara,T.et al: "Lecithinzed superoxide dismutase attenuates phorbol myristate acetate-induced injury in isolated dog lung" Eur J Pharmacol. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Kubo K et al: "Cytokines in bronchoalveolar lavage fluid in patients with high attitude and manaryedeals at moderate altitude in Japan" chest. 51. 739-742 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Fujimoto K et al: "Effect of the 21-aminosteroid U-74006F on autigen-induced bronchoalveolar eosinophillia in allevgic sheep" Enr Respir J. 9. 2044-2049 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 久保恵嗣 他: "肺傷害とchemical mediators" 日胸学会誌(増刊号). 33. 231-238 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 久保恵嗣 他: "高地肺水腫の臨床" 日本内科専門医会誌. 8(1). 56-60 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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