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肺上皮細胞におけるmTOR活性化が肺線維症の病態に及ぼす影響についての解析

齋藤, 美奈子 東京大学 DOI:10.15083/0002005053

2022.06.22

概要

特発性肺線維症(IPF)は原因不明で慢性かつ進行性の経過をたどり、最終的に不可逆的な線維性病変を形成し高度の拘束性換気障害を呈する極めて予後不良な疾患である。その病態については十分に解明されていない点が多いが、様々な慢性刺激による肺胞上皮細胞の傷害と異常修復の進行、そしてII型肺胞上皮細胞から産生されるサイトカイン・ケモカインや増殖因子による上皮間葉転換(EMT)の進行がIPFの重要な病態であるとされている。

近年、mTOR経路の活性化が肺線維症の病態に寄与することが示唆されてきている。しかし、これまでは、主に線維芽細胞や筋線維芽細胞におけるmTOR経路の役割を解明してきた研究がほとんどであり、肺線維症の発症への関与が示唆されている肺胞上皮傷害及びEMTとmTOR経路の関連についての研究はほとんどない。また、mTOR経路の関与の証明においても、ほとんどがmTOR阻害薬であるラパマイシンを用いた間接的なmTOR経路の関与の証明であり、mTORの直接的な活性化が肺に及ぼす研究はこれまでにない。本研究では肺上皮特異的に恒常的にキナーゼ活性を示す変異型mTORマウスを作成し、ブレオマイシン刺激肺線維症モデルを用いて、mTORの働きを直接的に解析し、IPFの病態及び、mTOR及びその下流遺伝子が治療のターゲットになる可能性について検討することとした。

まず、14週齢の活性型mTORマウスの表現型をコントロールマウスと比較した。病理学的、肺生理学的解析において明らかな違いは認めなかったが、活性型mTORマウス肺から抽出したmRNA発現量では、タイトジャンクションを構成するタンパクであるZO-1とEMTに抑制的に作用するCaveolin-1(Cav-1)の発現が、有意に活性型mTORマウスで低下していることがわかった。

次に肺胞上皮癌細胞株であるA549細胞と初代ヒト肺胞上皮細胞を用いてinvitro実験でも検証した。その結果、蛍光免疫染色において、活性型mTORベクターのトランスフェクションにより有意にZO-1及びCav-1の発現低下が認められ、マウス肺の解析と矛盾しない結果であった。さらに、mTOR活性化がタイトジャンクションを構成するZO-1の発現を低下させ、EMTの制御を抑制する可能性が示唆されたことから、活性型mTORがA549細胞において、EMTを誘導するかを検証したところ、活性型mTOR過剰発現A549細胞では、ウェスタンブロッティングにおいて、TGFβ1刺激後に有意にvimentinの発現が増強しており、EMTを促進することが示唆された。

さらに、肺上皮特異的なmTOR活性化が肺線維症を増強するかを検証するために、12週齢の活性型mTORマウス及びコントロールマウスにブレオマイシンを気管内投与し、14日後に解析した。その結果、ブレオマイシン投与により活性型mTORマウスはコントロールマウスと比較して、病理学的解析ではびまん性に線維性病変の増強を認め、肺生理学的解析では、有意に肺コンプライアンスの低下及び抵抗の上昇を認め、両肺のコラーゲン量も有意に増加しており、ブレオマイシン気管内投与によって肺線維化がより増強されることが示唆された。肺上皮細胞においてmTOR活性化によりZO-1及びCav-1の発現が低下することで、タイトジャンクションが脆弱化しEMT抑制作用が軽減しており、さらにブレオマイシンによる強い上皮傷害によって肺胞上皮細胞の異常修復が進み、再上皮化が機能せず、EMTが促進し線維化の増悪をきたしたと推察された。

肺上皮特異的なmTORの活性化が肺線維症の病態に関与していることが示されたため、さらにその分子生物学的機序を解明するために、マウスのII型肺胞上皮細胞を単離してRNAシークエンス解析による網羅的発現解析を行った。その結果、Angiopoietin-like4(ANGPTL4)の発現が活性型mTORマウスにおいて大きく発現が亢進しており、インフルエンザ感染マウスモデルの先行研究において、ANGPTL4がII型肺胞上皮細胞に発現が上昇し、肺組織透過性を亢進することが示唆されていたことから、本研究ではANGPTL4に注目してさらに解析を行った。

まず、活性型mTORで発現低下がみられたZO-1及びCav-1の発現がmTOR下流に位置するANGPTL4によって発現が制御されているかを検証した。A549細胞と初代ヒト肺胞上皮細胞においてANGPTL4過剰発現ベクターをトランスフェクションしたところ、免疫蛍光染色においてZO-1及びCav-1の発現が有意に低下していた。さらに、初代ヒト肺胞上皮細胞においてANGPTL4をノックダウンすると、ZO-1の発現量は有意な上昇を認め、Cav1は有意な増加は認めなかったが、上昇傾向を認めた。したがって、ANGPTL4の新たな機能として、ZO-1及びCav-1の発現調節に関与している可能性が示唆された。さらに、ANGPTL4過剰発現A549細胞にTGFβ1刺激をしてEMTを誘導し、ウェスタンブロッティングで解析したところ、ANGPTL4過剰発現A549細胞はコントロールと比較して有意にEcadherinの発現低下を認め、ANGPTL4がEMTを促進することが示唆された。

本研究の結果から、肺上皮細胞におけるmTOR経路の活性化が肺胞上皮のタイトジャンクションの脆弱化及び、EMT促進に関与していることが示唆され、IPFの病態に関与している可能性が示された。さらに、mTOR経路下流に位置するANGPTL4が、ZO-1及びCav1の発現調節に関与し、IPF治療のおける新規ターゲットである可能性が示唆された。

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