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Toll様受容体9番の慢性抑制はラットにおいて肺高血圧症を改善させる

石川, 智一 ISHIKAWA, Tomohito イシカワ, トモヒト 九州大学

2022.09.22

概要

背景:Toll様受容体9番(toll-like receptor9:TLR9)が心血管病の原因に関与していることが近年多く報告されているが、肺高血圧症におけるTLR9の役割は依然として未解決のままである。我々はTLR9が肺高血圧症の進展に寄与していると仮説を立てた。

方法と結果:モノクロタリン(monocrotaline: MCT)誘発性肺高血圧ラットモデルを用いてTLR9が血行動態パラメーターに与える影響を調べた。MCT暴露ラットは14日目に、血漿ミトコンドリアDNAマーカーが上昇しておりそれらがTLR9によって認識された結果、肺におけるTLR9の活性化とIL-6mRNAの上昇を来した。さらに21日目には右室収縮期圧と総肺血管抵抗が上昇し、肺血管リモデリング、マクロファージ集簇を来した。予防プロトコールにおいて、選択的TLR9阻害薬(E6446)もしくは非選択的TLR9阻害薬(クロロキン)の投与(MCT投与3日前からMCT投与後21日目まで)によって、右室収縮期圧・総肺血管抵抗・肺血管リモデリング・マクロファージ集簇の上昇が軽減された。2つの阻害薬はまたNF-κB活性化やIL-6mRNA上昇を同程度軽減させた。短期治療プロトコールにおいて、E6446治療(MCT投与後14日目から17日目)によりNF-κB活性化とIL-6mRNA上昇をほぼ正常化し、マクロファージ集簇を低下させた。さらに治療期間を延長させたプロトコールにおいて、E6446治療(MCT投与後14日目から24日目)により総肺血管抵抗や肺血管リモデリングを改善し、さらに生存率を改善した。

結論:TLR9はNF-κB-IL-6経路を介した肺高血圧症の進展に寄与しており、TLR9阻害は肺高血圧症の新たな治療戦略となりうる。

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