The elucidation of mechanisms underlying severe cutaneous adverse drug reactions induced by neutrophils and the establishment of early diagnostic markers
Project/Area Number |
18K16022
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 53050:Dermatology-related
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Research Institution | University of Yamanashi |
Principal Investigator |
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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Keywords | Stevens-Johnson症候群 / 中毒性表皮壊死症 / 好中球 / NETs / NETosis / 抗菌ペプチド / 表皮細胞 / SJS / TEN / 重症薬疹 / スティーブンス・ジョンソン症候群 / 表皮細胞死 / ネクロプトーシス / LL-37 |
Outline of Final Research Achievements |
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. We found a mechanism by which neutrophils trigger inflammation during early phases of SJS/TEN. Skin-infiltrating neutrophils undergoing neutrophil extracellular traps (NETs) released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1-expression rendered keratinocytes vulnerable to necroptosis. Necroptotic keratinocytes further released LL-37 to induce FPR1 expression on surrounding keratinocytes, which likely amplified the necroptotic response. This pathway may be leveraged to establish both early diagnostic markers and therapeutic targets.
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Academic Significance and Societal Importance of the Research Achievements |
薬疹は内服薬や注射薬などの投薬により発症し、全身の皮膚粘膜に障害をきたす。特に重症薬疹である SJS/TEN は、全身の表皮壊死に加え多臓器障害を伴い、ときに致死的となる。仮に救命できても、失明など重篤な後遺症を残す患者は多い。薬剤による健康障害としては、重症薬疹が最多である (医薬品医療機器総合機構の集計)。 本来、治療目的で行われる投薬による医原性疾患であること、老若男女を問わず発症しうること、急激な転機で致死的になり得ることから、その病態解明と治療確立は切迫した課題である。
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] Galectin-7 as a potential biomarker of Stevens-Johnson syndrome/ toxic epidermal necrolysis: Identification by targeted proteomics using causative drug-exposed peripheral blood cells2019
Author(s)
Natsumi Hama, Keiko Nishimura, Akito Hasegawa, Akihiko Yuki, Hideaki Kume, Jun Adachi, Manao Kinoshita, Youichi Ogawa, Saeko Nakajima, Takashi Nomura, Hideaki Watanabe, Yoshiko Mizukawa, Takeshi Tomonaga, Hiroshi Shimizu, Riichiro Abe
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Journal Title
J Allergy Clin Immunol Pract
Volume: 印刷中
Issue: 8
Pages: 2894-2897
DOI
Related Report
Peer Reviewed
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[Journal Article] Anti-depressant fluoxetine reveals its therapeutic effects via astrocytes.2018
Author(s)
M. Kinoshita, Y. Hirayama, K. Fujishita, K Shibata, Y. Shinozaki, E. Shigetomi, A. Takeda, HP Ngoc Le, H. Hayashi, M. Hiasa, Y. Moriyama, K. Ikenaka, KF Tanaka, S. Koizumi.
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Journal Title
EBioMedicine
Volume: 32
Pages: 72-83
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Presentation] Novel Markers To Diagnose Stevens-Johnson Syndrome And Toxic Epidermal Necrolysis2020
Author(s)
Manao Kinoshita, Youichi Ogawa, Natsumi Hama, Inkin Ujiie, Akito Hasegawa, Saeko Nakajima, Takashi Nomura, Takuya Sato, Shinji Shimada, Yasuyuki Fujita, Hayato Takahashi, Yoshiko Mizukawa, Keisuke Nagao, Riichiro Abe, and Tatsuyoshi Kawamura
Organizer
The 119th Annual Meeting of the Japanese Dermatological Association
Related Report
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[Presentation] Neutrophil extracellular traps initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis2019
Author(s)
Manao Kinoshita, Youichi Ogawa, Natsumi Hama, Inkin Ujiie, Jun Adachi, Shinji Shimada, Yasuyuki Fujita, Hayato Takahashi, TakeshiTomonaga, Riichiro Abe, Tatsuyoshi Kawamura
Organizer
The Japanese Society for Investigative Dermatology
Related Report
Int'l Joint Research
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