小分子イオンチャネルは,システィック線維症の呼吸道上皮質における宿主防御を強化する

Katrina A Muraglia¹, Rajeev S Chorghade², Bo Ram Kim³

¹Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Nature

|March 15, 2019

まとめ

アンフォテリシンBは,イオンチャネルを作り出し,CFTR変異とは無関係に pHと機能を回復します. 胞性線維症の患者にとって新たな治療法となる可能性があります

科学分野:

細胞生物学
呼吸器医学
薬理学について

背景:

細胞膜伝導性調節器 (CFTR) の機能喪失による突然変異は,上皮のイオン輸送を阻害し,呼吸道表面液体のpHを低下させ,細胞膜結晶症の呼吸器の防御を損なう.
現在の治療法ではしばしばCFTRを標的にしますが,多くの変異は機能的なタンパク質を生じさせず,代替治療方法が必要になります.

研究の目的:

選択的でないイオンチャネルを形成する小さな分子であるアンフォテリシンBが,システィック線維症の呼吸道上皮質における上皮質機能と宿主防御を回復できるかどうかを調査する.
この治療効果がCFTRの存在または機能に依存するかどうかを判断する.

主な方法:

胞性線維症患者の培養された呼吸道上皮質は,アピカルアンフォテリシンBで治療された.
イオン輸送回復のメカニズムを理解するために,基礎側Na+,K+-ATPaseの活性が評価されました.
呼吸道表面液体pHに対するアンフォテリシンBの影響を評価するために,CFTR- nullの豚を用いてin vivo試験を実施した.

主要な成果:

アピカルアンフォテリシンBは,HCO3の分泌を回復し,気道表面液体のpHを気道上皮質に増加させた.
これらの効果は,基底側Na+,K+-ATPaseの活性に依存し,内生性イオン輸送による機能的統合を示した.
アンフォテリシンBは,呼吸道表面液体の粘度と抗菌活性を改善し,CFTR- nullの豚の体内液体のpHを増加させた.

結論:

アンフォテリシンBのような非選択的小分子イオンチャネルは,気道上皮質における宿主防御を回復することができる.
この治療メカニズムはCFTRの機能と遺伝子型とは無関係であり,すべてのシスティック線維症患者のための潜在的な治療戦略を提供します.
アンフォテリシンBは,呼吸道表面液体ホメオスタシスを回復し,システィック線維症の呼吸器の健康を改善するための有望な治療候補である.

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