Regulation of the coagulation cascade as a new therapeutic strategy for pulmonary injury following traumatic brain injury

2021 Fiscal Year Annual Research Report

• Project/Area Number: 18K16535
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: 安井 秀樹 浜松医科大学, 医学部, 特任講師 (60804937)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 頭部外傷 / 肺障害 / 凝固障害

Outline of Annual Research Achievements

頭部外傷患者では遠隔臓器において全身性合併症をきたすことが報告されており、中でも肺障害は重症頭部外傷において比較的高率に合併し、予後に直結する重要な合併症であることがよく知られている。しかしながら、頭部外傷後の肺障害に関する発症機序は不明点が多い。ノルエピネフリンなどのカテコラミンの過剰産生が主因であると考えられてきたが、我々の先行研究において、頭部外傷動物モデルにおいて血漿中のノルエピネフリン上昇は確認されず (Yasui H, et al. Am J Physiol Lung Cell Mol Physiol 2016)、臨床の現場においてもノルエピネフリン上昇を伴わない頭部外傷後の肺障害症例を経験した (Yasui H, et al. Inten Med 2018)。
一方で、頭部外傷直後に肺障害を合併した重症症例において、頭部外傷直後から肺障害と同時に、血漿中に過剰なトロンビン産生ならびに凝固カスケードの活性化が確認された。頭部外傷後の肺障害の発症機序として、脳内に多量に含まれる組織因子 (TF) が血液脳関門の破綻により、全身に流入し、TFを開始因子とした外因系凝固カスケードの活性化が主因であることが推測された。本仮説の証明のために頭部外傷患者の血漿を用いて凝固線溶系マーカーの測定を実施している。
また、凝固カスケードや凝固カスケードの下流に位置するトロンビンの活性化と肺障害との関連性を証明するために、ラットを用いて、頭部外傷モデルを2つの方法で作成した。1つは、麻酔下にドリルを用いて鋭的に頭部外傷を与えるモデル、もう１つは、麻酔下に分銅を一定の高さより落とす鈍的頭部外傷モデルを作成した。鋭的外傷モデルと比べ、鈍的頭部外傷モデルで肺障害が顕著であり、鈍的外傷モデルを用いて肺障害と凝固障害の評価を実施した。

Research Products

• [Journal Article] Association of the Geriatric Nutritional Risk Index with the survival of patients with non-small-cell lung cancer after platinum-based chemotherapy (2021)
  • Author(s): Masato Karayama, Yusuke Inoue, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Tomoyuki Fujisawa, Noriyuki Enomoto, Yutaro Nakamura, Naoki Inui, Takafumi Suda
  • Journal Title: BMC Pulm Med . Volume: 21(1) Pages: 409
  • DOI: 10.1186/s12890-021-01782-2.
  • Peer Reviewed / Open Access
• [Journal Article] Prophylactic granulocyte-colony stimulating factor in patients with lung neuroendocrine carcinoma receiving platinum agents plus etoposide. (2021)
  • Author(s): Watanabe H, Karayama M, Yasui H, Inoue Y, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: Cancer Treat Res Commun. Volume: 29 Pages: 100493
  • DOI: 10.1016/j.ctarc.2021.100493.
  • Peer Reviewed / Open Access
• [Journal Article] MET Amplification and Efficacy of Nivolumab in Patients With NSCLC. (2021)
  • Author(s): Yoshimura K, Inoue Y, Inui N, Karayama M, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Sugimura H, Suda T.
  • Journal Title: JTO Clin Res Rep. Volume: 2(11) Pages: 100239
  • DOI: 10.1016/j.jtocrr.2021.100239.
  • Peer Reviewed / Open Access
• [Journal Article] Radiological pleuroparenchymal fibroelastosis-like lesion in idiopathic interstitial pneumonias. (2021)
  • Author(s): Fujisawa T, Horiike Y, Egashira R, Sumikawa H, Iwasawa T, Matsushita S, Sugiura H, Kataoka K, Hashisako M, Yasui H, Hozumi H, Karayama M, Suzuki Y, Furuhashi K, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: Respir Res. Volume: 22(1) Pages: 290
  • DOI: 10.1186/s12931-021-01892-9.
  • Peer Reviewed / Open Access
• [Journal Article] Comparative assessment of NOIR-SS and ddPCR for ctDNA detection of EGFR L858R mutations in advanced L858R-positive lung adenocarcinomas. (2021)
  • Author(s): Akahori D, Inoue Y, Inui N, Karayama M, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Suda T.
  • Journal Title: Sci Rep. Volume: 11(1) Pages: 14999
  • DOI: 10.1038/s41598-021-94592-9.
  • Peer Reviewed / Open Access
• [Journal Article] Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis. (2021)
  • Author(s): Tanaka K, Enomoto N, Hozumi H, Isayama T, Naoi H, Aono Y, Katsumata M, Yasui H, Karayama M, Suzuki Y, Furuhashi K, Fujisawa T, Inui N, Nakamura Y, Suda T.
  • Journal Title: Respir Investig. Volume: 59(6) Pages: 827-836
  • DOI: 10.1016/j.resinv.2021.05.008.
  • Peer Reviewed
• [Journal Article] Prognostic and Clinical Value of Cluster Analysis in Idiopathic Pleuroparenchymal Fibroelastosis Phenotypes. (2021)
  • Author(s): Nakamura Y, Mori K, Enomoto Y, Kono M, Sumikawa H, Johkoh T, Colby TV, Yasui H, Hozumi H, Karayama M, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Inui N, Kaida Y, Yokomura K, Koshimizu N, Toyoshima M, Imokawa S, Yamada T, Shirai T, Nakamura H, Hayakawa H, Suda T.
  • Journal Title: J Clin Med. Volume: 10(7) Pages: 1498
  • DOI: 10.3390/jcm10071498.
  • Peer Reviewed / Open Access
• [Journal Article] Impact of bronchoalveolar lavage lymphocytosis on the effects of anti-inflammatory therapy in idiopathic non-specific interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, and unclassifiable idiopathic interstitial pneumonia (2021)
  • Author(s): Yamagata A, Arita M, Tachibana H, Tokioka F, Sugimoto C, Sumikawa H, Tanaka T, Yasui H, Fujisawa T, Nakamura Y, Suda T, Ishida T.
  • Journal Title: Respir Res. Volume: 22(1) Pages: 115
  • DOI: 10.1186/s12931-021-01726-8.
  • Peer Reviewed / Open Access
• [Journal Article] Simple method for detecting idiopathic interstitial pneumonias by measuring vertical lung length on chest X-ray (2021)
  • Author(s): Karayama M, Aoshima Y, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: Sci Rep. Volume: 11(1) Pages: 7669
  • DOI: 10.1038/s41598-021-87452-z.
  • Peer Reviewed / Open Access
• [Journal Article] Conventional type 2 lung dendritic cells are potent inducers of follicular helper T cells in the asthmatic lung (2021)
  • Author(s): Sakurai S, Furuhashi K, Horiguchi R, Nihashi F, Yasui H, Karayama M, Suzuki Y, Hozumi H, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T.
  • Journal Title: Allergol Int . Volume: 70(3) Pages: 351-359
  • DOI: 10.1016/j.alit.2021.01.008.
  • Peer Reviewed / Open Access
• [Journal Article] Cluster analysis-based clinical phenotypes of idiopathic interstitial pneumonias: associations with acute exacerbation and overall survival. (2021)
  • Author(s): Aoshima Y, Karayama M, Horiike Y, Mori K, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: BMC Pulm Med. Volume: 21(1) Pages: 63
  • DOI: 10.1186/s12890-021-01428-3.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Significance of Interstitial Lung Disease and Its Acute Exacerbation in Microscopic Polyangiitis. (2021)
  • Author(s): Hozumi H, Kono M, Hasegawa H, Yasui H, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Yokomura K, Nakamura H, Suda T.
  • Journal Title: Chest. Volume: 159(6) Pages: 2334-2345
  • DOI: 10.1016/j.chest.2021.01.083.
  • Peer Reviewed
• [Journal Article] Predictors for bronchoalveolar lavage recovery failure in diffuse parenchymal lung disease. (2021)
  • Author(s): Koda K, Hozumi H, Yasui H, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Suda T.
  • Journal Title: Sci Rep. Volume: 11(1) Pages: 1682
  • DOI: 10.1038/s41598-021-81313-5.
  • Peer Reviewed / Open Access
• [Journal Article] Pneumothorax in Patients with Idiopathic Pleuroparenchymal Fibroelastosis: Incidence, Clinical Features, and Risk Factors. (2021)
  • Author(s): Kono M, Nakamura Y, Enomoto Y, Yasui H, Hozumi H, Karayama M, Suzuki Y, Furuhashi K, Miki Y, Hashimoto D, Fujisawa T, Enomoto N, Inui N, Kaida Y, Yokomura K, Koshimizu N, Toyoshima M, Imokawa S, Yamada T, Shirai T, Hayakawa H, Nakamura H, Suda T.
  • Journal Title: Respiration. Volume: 100(1) Pages: 19-26
  • DOI: 10.1159/000511965.
  • Peer Reviewed
• [Journal Article] Prednisolone and tacrolimus versus prednisolone and cyclosporin A to treat polymyositis/dermatomyositis-associated ILD: A randomized, open-label trial. (2021)
  • Author(s): Fujisawa T, Hozumi H, Kamiya Y, Kaida Y, Akamatsu T, Kusagaya H, Satake Y, Mori K, Mikamo M, Matsuda H, Yokomura K, Koshimizu N, Toyoshima M, Imokawa S, Yasui H, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: Respirology. Volume: 26(4) Pages: 370-377
  • DOI: 10.1111/resp.13978.
  • Peer Reviewed
• [Journal Article] Erlotinib and bevacizumab in elderly patients =and>75 years old with non-small cell lung cancer harboring epidermal growth factor receptor mutations. (2021)
  • Author(s): Aoshima Y, Karayama M, Inui N, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Mikamo M, Matsuura S, Kusagaya H, Kaida Y, Uto T, Hashimoto D, Matsui T, Asada K, Suda T.
  • Journal Title: Invest New Drugs. Volume: 39(1) Pages: 210-216
  • DOI: 10.1007/s10637-020-00988-1.
  • Peer Reviewed