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肺内尿酸値の上昇により肺動脈性肺高血圧症は増悪する

渡邊, 高徳 WATANABE, Takanori ワタナベ, タカノリ 九州大学

2022.10.31

概要

近年の研究では尿酸が内皮細胞においてアルギナーゼ活性を亢進させ、一酸化窒素を減少させることが報告されている。しかしながら、肺動脈性肺高血圧症(PAH)における肺組織尿酸値の役割は未だに明らかとなっていない。我々は、肺組織尿酸値の上昇がPAHの進行に寄与すると仮説を立てた。

 ヒト肺動脈内皮細胞において、尿酸トランスポーターの一つであるURATv1が発現しており、肺動脈内皮細胞への尿酸曝露によりアルギナーゼ活性が亢進することを確認した。SU5416/低酸素/常酸素曝露PAHモデルラットにおける還流肺実験において、正常ラット群への尿酸投与時と比較してPAHモデルラット群への尿酸投与で有意に肺動脈圧が上昇し、肺組織のcGMP値低下が見られた。尿酸による肺動脈圧上昇は尿酸トランスポーター阻害薬であるベンズブロマロンや、アルギナーゼ阻害薬であるL-ノルバリンの前処置により抑制された。PAHモデルラットにおいて2%オキソン酸投与により高尿酸血症を合併させると、高尿酸血症非合併PAHモデルラットと比較して肺組織尿酸値が有意に上昇し、右室収縮期圧(RVSP)が有意に上昇すると共に小肺動脈の閉塞病変が有意に増悪した。高尿酸血症合併PAHモデルラットへのベンズブロマロン投与によりキサンチン酸化還元酵素(XOR)活性は変化せずに肺組織尿酸値は有意に低下し、RVSPの上昇及び閉塞病変の増加が抑制された。PAHモデルラットにXOR阻害薬であるトピロキソスタットを投与すると、肺組織XOR活性は有意に低下したがRVSP、Ea(右室の後負荷の指標)、閉塞病変の改善は見られなかった。低酸素誘発性PAHモデルマウスにおいてXORノックアウトはRVSPの上昇や筋性化血管の増加に影響を与えなかった。

 以上より、肺組織尿酸値の上昇自体がPAHを増悪させる一方で、XORはPAHの病態に影響を与えなかった。高尿酸血症を合併したPAHにおいて肺組織尿酸値上昇は新規治療標的となりうると考えられた。

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