Elucidation of the pathophysiology of eosinophilic chronic rhinosinusitis focused on nasal NO and its application to new treatments

• Project/Area Number: 19K18801
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: University of Fukui
• Principal Investigator: Yoshida Kanako 福井大学, 学術研究院医学系部門(附属病院部), 医員 (00773706)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 好酸球性副鼻腔炎 / 鼻腔一酸化窒素(NO) / 鼻茸 / LRP-1 / 内臓脂肪 / 鼻腔一酸化窒素（NO)

Outline of Research at the Start

好酸球性副鼻腔炎は難治再発性の鼻茸を特徴とし、喘息を高率に合併する慢性副鼻腔炎であり、指定難病に定められている。鼻茸形成と難治化の病態を解明し、術後再発の可能性が高い症例を早期に見出し、適切に介入することが今後の最大の課題と考えられる。我々はこれまでの研究により、鼻腔一酸化窒素（鼻腔NO）が好酸球性副鼻腔炎のバイオマーカーとなる可能性を見出した。
本研究では、鼻副鼻腔におけるNO産生メカニズムを解明し、好酸球性副鼻腔炎の病態形成への関与とバイオマーカーの確立、治療への応用を目的とする。

Outline of Final Research Achievements

To elucidate the mechanism of NO production in the sinonasal mucosa and the mechanism of nasal NO involved in the pathogenesis of eosinophilic chronic rhinosinusitis, this study focused on two NO production pathways. (1) In the LRP-1 (Low density lipoprotein receptor-related protein-1) cell membrane receptor-mediated pathway; we investigated the relationship between LRP-1 expression localization in the nasal mucosa and NO production. As a result, we found that low LRP-1 expression may be involved in the pathophysiology of eosinophilic chronic rhinosinusitis and low nasal NO production. (2) In the adipocytokine-mediated pathway produced by visceral adipose tissue；we found that the visceral fat area may be involved in the pathophysiology of eosinophilic chronic rhinosinusitis and NO production.

Academic Significance and Societal Importance of the Research Achievements

本研究により、鼻腔NOの低値が好酸球性副鼻腔炎の病態形成に関与することがわかった。そして、LRP-1発現が低値であること、内臓脂肪面積が高値であることが、鼻腔NO低値に関与し、鼻腔NO産生にはLRP-1の発現、内臓脂肪が関与する可能性が示唆された。
鼻・副鼻腔におけるNO産生メカニズムと好酸球性副鼻腔炎の病態形成への関与機序を解明できれば、鼻腔NOを好酸球性副鼻腔炎のバイオマーカーとして確立できると考える。また、鼻副鼻腔においてNOを誘導することが新規治療につながる可能性があると考える。

Research Products

• [Journal Article] Baicalin suppresses type 2 immunity through breaking off the interplay between mast cell and airway epithelial cell (2021)
  • Author(s): Yoshida K, Takabayashi T, Kaneko A, Takiyama M, Sakashita M, Imoto Y, Kato Y, Narita N, Fujieda S.
  • Journal Title: Journal of Ethnopharmacology Volume: 1;267 Pages: 113492-113492
  • DOI: 10.1016/j.jep.2020.113492
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of sensitization and prevalence of Japanese cedar pollen and mite-induced perennial allergic rhinitis between 2006 and 2016 in hospital workers in Japan (2021)
  • Author(s): Sakashita M, Tsutsumiuchi T, Kubo S, Tokunaga T, Takabayashi T, Imoto Y, Kato Y, Yoshida K, Kimura Y, Kato Y, Kanno M, Ogi K, Okamoto M, Narita N, Fujieda S.
  • Journal Title: Allergology International Volume: 70 Issue: 1 Pages: 89-95
  • DOI: 10.1016/j.alit.2020.07.004
  • NAID: 130007966780
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced 15-Lipoxygenase 1 Production is Related to Periostin Expression and Eosinophil Recruitment in Eosinophilic Chronic Rhinosinusitis (2020)
  • Author(s): Imoto Y, Takabayashi T, Sakashita M, Kato Y, Yoshida K, Kidoguchi M, Koyama K, Adachi N, Kimura Y, Ogi K, Ito Y, Kanno M, Okamoto M, Narita N, Fujieda S.
  • Journal Title: Biomolecules Volume: 18;10(11) Issue: 11 Pages: 1568-1568
  • DOI: 10.3390/biom10111568
  • Peer Reviewed / Open Access
• [Journal Article] Association between the NOS2 pentanucleotide repeat polymorphism and risk of postoperative recurrence of chronic rhinosinusitis with nasal polyps in a Japanese population. (2020)
  • Author(s): Kidoguchi M, Yoshida K, Noguchi E, Nakamura T, Morii W, Haruna T, Okano M, Yamashita Y, Haruna S, Hasegawa M, Yoshida N, Ninomiya T, Imoto Y, Sakashita M, Takabayashi T, Fujieda S.
  • Journal Title: Allergology International Volume: 69(4) Issue: 4 Pages: 619-621
  • DOI: 10.1016/j.alit.2020.04.005
  • NAID: 130007926244
  • Peer Reviewed / Open Access
• [Journal Article] Reduced nasal nitric oxide levels in patients with eosinophilic chronic rhinosinusitis (2019)
  • Author(s): Yoshida K, Takabayashi T, Imoto Y, Sakashita M, Narita N, Fujieda S
  • Journal Title: Allergology International Volume: 68 Issue: 2 Pages: 225-232
  • DOI: 10.1016/j.alit.2018.09.005
  • NAID: 130007633635
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Eosinophilic chronic rhinosinusitis (2019)
  • Author(s): Fujieda S, Imoto Y, Kato Y, Ninomiya T, Tokunaga T, Tsutsumiuchi T, Yoshida K, Kidoguchi M, Takabayashi T
  • Journal Title: Allergology International Volume: 68 Issue: 4 Pages: 403-412
  • DOI: 10.1016/j.alit.2019.07.002
  • NAID: 130007733129
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Increased expression of L‐plastin in nasal polyp of patients with nonsteroidal anti‐inflammatory drug‐exacerbated respiratory disease (2018)
  • Author(s): Takabayashi Tetsuji、Tanaka Yukie、Susuki Dai、Yoshida Kanako、Tomita Kaori、Sakashita Masafumi、Imoto Yoshimasa、Kato Yukinori、Narita Norihiko、Nakayama Tsugihisa、Haruna Shinichi、Schleimer Robert P.、Fujieda Shigeharu
  • Journal Title: Allergy Volume: 印刷中 Issue: 7 Pages: 1307-1316
  • DOI: 10.1111/all.13677
  • Peer Reviewed
• [Presentation] 好酸球性副鼻腔炎の病態解明と新たな治療戦略 (2020)
  • Author(s): 藤枝重治、高林哲司、坂下雅文、意元義政、加藤幸宣、木戸口正典、吉田加奈子、小山佳祐、足立直人
  • Organizer: 第121回日本耳鼻咽喉科学会総会・学術講演会
  • Invited
• [Presentation] Thrombin activatable fibrinolysis inhibitor(TAFI)がアレルギー炎症に与える影響の検討 (2020)
  • Author(s): 吉田加奈子、高林哲司、坂下雅文、意元義政、加藤幸宣、成田憲彦、藤枝重治
  • Organizer: 第38回日本耳鼻咽喉科免疫アレルギー学会
• [Presentation] 好酸球性副鼻腔炎における鼻腔一酸化窒素濃度（NO)測定の可能性 (2019)
  • Author(s): 吉田加奈子、高林哲司、加藤幸宣、意元義政、坂下雅文、成田憲彦、藤枝重治
  • Organizer: 第120回日本耳鼻咽喉科学会総会・学術講演会
• [Presentation] 黄ごん成分（Baicalin）が好酸球性副鼻腔炎の病態に与える影響の検討 (2019)
  • Author(s): 吉田加奈子、高林哲司、坂下雅文、意元義政、成田憲彦、藤枝重治
  • Organizer: 第68回日本アレルギー学会
• [Presentation] Baicalinが好酸球性副鼻腔炎の病態に与える影響の検討 (2019)
  • Author(s): 吉田加奈子、高林哲司、坂下雅文、意元義政、加藤幸宣、成田憲彦、藤枝重治
  • Organizer: 第58回日本鼻科学会総会・学術講演会
• [Patent(Industrial Property Rights)] 医薬組成物 (2020)
  • Inventor(s): 藤枝重治、高林哲司、吉田加奈子
  • Industrial Property Rights Holder: 藤枝重治、高林哲司、吉田加奈子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Acquisition Date: 2020
  • Overseas
• [Patent(Industrial Property Rights)] アンジオテンシン変換酵素2の発現抑制剤、および、アンジオテンシン変換酵素2を受容体とするウイルスに対する抗ウイルス剤 (2020)
  • Inventor(s): 高林哲司、吉田加奈子、意元義政、藤枝重治
  • Industrial Property Rights Holder: 高林哲司、吉田加奈子、意元義政、藤枝重治
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-146169
  • Filing Date: 2020
  • Acquisition Date: 2020