Study of new therapy for COPD by regulation of inflammatory cytokines and oxidant stress

2009 Fiscal Year Final Research Report

• Project/Area Number: 20790579
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Respiratory organ internal medicine
• Research Institution: Kurume University
• Principal Investigator: KINOSHITA Takashi Kurume University, 医学部, 助教 (90454917)
• Project Period (FY): 2008 – 2009
• Keywords: 閉塞性肺疾患

Research Abstract

[Background]
Caspase-1 is essential to maturity of IL-1 family cytokines IL-1beta, IL-18 and IL-33. We have recently reported that a significant correlation exists between serum levels of IL-18 and pulmonary function (%FEV_1) in COPD patients (Imaoka, ERJ 2009). Constitutive overproduction of mature IL-18 in the lungs of transgenic C57BL/6 mice resulted in severe emphysema lesions (Hoshino, AJRCCM 2007). We reported that redox-active protein thioredoxin 1 (TRX1) prevented the development and progression of elastase-induced emphysema in wild type C57BL/6 mice (Kinoshita, BBRC 2007). Both inflammatory cytokines and oxidative stress may be involved in the pathology of COPD. In this study, we investigated the roles of caspase-1 in elastase-induced COPD mouse model.
[Material and methods]
On day 0, C57BL/6 caspase-1 deficient (KO) mice and control wild type C57BL/6 mice and was anesthetized by intraperitoneal administration of thiopental (2.5 to 5 mg/mouse), and a microspray (MicroSprayer, Penn-Century, Inc., Philadelphia, PA) was inserted through its trachea. Fifty microliters of 0.9% physiological saline (vehicle) or 50 μL of purified porcine pancreatic elastase (PPE, 0.25 U) dissolved in saline was sprayed into the trachea. Mice were sacrificed on day 21. Lung tissues and bronchoalveolar lavage fluid (BALF) were histopathologically analyzed.
[Result]
A computerized color image analysis revealed that the mean alveolar chord length (30 +- 2.0μm), n = 5 for each group) was significantly reduced in elastase-treated caspase-1 KO mice, when compared with control wild type mice (39.9 +- 1.5 μm). In addition, inflammatory cells in BALF of(n = 10 for each group) was significantly prevented in elastase-treated caspase-1 KO mice.
[Conclusion]
Our results suggest that activation of caspase-1 may contribute to the pathogenesis of emphysematous changes and pulmonary inflammations in COPD patients.

Research Products

• [Journal Article] Correlation of decreased survival and IL-18 in bone metastasis (2009)
  • Author(s): Okamoto M, Azuma K, Hoshino T, Imaoka H, Ikeda J, Kinoshita T, Takamori S, Ohshima K, Edakuni N, Kato S, Iwanaga T, Aizawa H
  • Journal Title: Internal medicine (Tokyo, Japan) 2009 48(10) Pages: 763-773
• [Journal Article] Endogenous and exogenous thioredoxin 1 prevents goblet cell hyperplasia in a chronic antigen exposure asthma model (2009)
  • Author(s): Imaoka H, Hoshino T, Okamoto M, Sakazaki Y, Sawada M, Takei S, Kinoshita T, Kawayama T, Kato S, Aizawa H
  • Journal Title: Allergol Int 2009 58(3) Pages: 403-410
• [Journal Article] Interleukin-18 production and pulmonary function in COPD (2008)
  • Author(s): Imaoka H, Hoshino T, Takei S, Kinoshita T, Okamoto M, Kawayama T, Kato S, Iwasaki H, Watanabe K, Aizawa H
  • Journal Title: Eur Respir J 2008 31(2) Pages: 287-297
• [Presentation] Clinical Characteristic of Lung Cancer Patients with Interstitial Pneumonia Treated with Chemotherapy or Radiotherapy (2008)
  • Author(s): Takashi Kinoshita, Koichi Azuma, Nobutaka Edakuni, Hideo Nakao, Masaki Okamoto, Jiro Ikeda, Tomoaki Hoshino, Tomoaki Iwanaga, Hisamichi Aizawa
  • Organizer: Express IL-18 in Asthma Death Cases. European Respiratory Society Annual Congress 2008
  • Place of Presentation: Berlin, Germany
  • Year and Date: 20081004-20081008
• [Remarks]
  • URL: http://www.med.kurume-u.ac.jp/med/imed1/index.html