肺動脈高血圧の治療標的としてCCR5
Valérie Amsellem1, Larissa Lipskaia1, Shariq Abid1
1Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
Circulation
|July 5, 2014
まとめ
マラビロックの標的であるCCR5経路は,滑らかな筋肉細胞の増殖と炎症を促進することによって,肺動脈高血圧 (PH) に重要な役割を果たします. CCR5を阻害することは,HIVに関連した症例を含むPHに対する潜在的な新しい治療法を提供します.
科学分野:
- 心血管科学の研究について
- 免疫学 免疫学とは
- 細胞生物学 細胞生物学
背景:
- 肺動脈高血圧 (PH) は,肺動脈の滑らかな筋肉細胞 (PA-SMC) の増殖と炎症を含む複雑な血管改造を伴う.
- HIVの侵入に関与する受容体であるCCR5は,血管細胞とマクロファージに発現し,PHの病原化に寄与する可能性があります.
研究 の 目的:
- 肺動脈高血圧 (PH) の発症におけるCCR5の役割を調査する.
- 実験的なPHモデルにおけるCCR5アンタゴニズムの治療の可能性を評価する.
主な方法:
- CCR5遺伝子ノックアウトマウスとヒト-CCR5ノックインマウスを,CCR5アンタゴニストのマラビロックによる薬理学研究に使用した.
- 低酸素状態でのPA-SMCの増殖,マクロファージの徴募,PHの発達を評価した.
- CCR5リガンド (CCL5,HIV-1gp120) とマラビロックのPA-SMCおよびマクロファージ条件付け媒体に対する効果を調査した.
主要な成果:
- CCR5の発現はPH肺に上昇し,PA-SMCに局限していた.
- CCR5欠乏症またはマラビロックによるブロックは,低酸素誘発PHモデルにおけるPA-SMCの増殖とマクロファージの募集を減少させた.
- CCL5とHIV-1 gp120によって刺激されたCCR5シグナル伝達媒介のPA-SMC成長,maravirocによって抑制された効果.
結論:
- CCL5-CCR5シグナル伝達経路はPHの病原化に関与しています.
- マラビロックのようなCCR5抗体でCCL5-CCR5経路を標的にすることは,HIV関連症例を含むPHの有望な治療戦略です.
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