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Specialized pro-resolving lipid meditators agonistic to formyl peptide receptor type 2 attenuate ischemia-reperfusion injury in rat lung

Oda, Hiromi 京都大学 DOI:10.14989/doctor.k23760

2022.03.23

概要

背景：
終末期呼吸器疾患において肺移植は唯一の治療手段であるが、術後急性期の初期移植肺機能不全の発症は臨床経過に大きく影響し、長期予後をも悪化させる要因として問題となる。初期移植肺機能不全の原因の一つとしては虚血再灌流障害（ischemia-reperfusion injury; IRI）が知られている。肺のIRI は、非特異的な肺胞障害と強固な炎症による肺水腫を特徴とする急性肺障害の一形態である。
近年、様々な炎症性疾患の緩和に ω3 および ω6 系多価不飽和脂肪酸の代謝産物が有効であるとの報告がなされている。これらの代謝産物はリゾルビンやリポキシンに代表され、特異的炎症収束性脂質メディエーター（specialized pro-resolving lipid mediators;SPMs）と呼ばれている。今日まで 肺のIRI における内因性SPMs の動態とその作用については殆ど知られていない。本研究では、肺のIRI の開始から解消に至る期間において内因性SPMs の動的変化を評価し、SPMs の補充が肺のIRI に及ぼす影響を明らかにすることを目的とした。

方法：
ラット左肺門クランプモデルを用い、９０分間の虚血に続いて種々の時間で再灌流を行った。次に肺組織の内因性 SPMs の動的変化を液体クロマトグラフィー・タンデム式質量分析により評価した。また、虚血再灌流の前後における SPMs 受容体の遺伝子発現を評価した。また、再灌流時に SPMs の投与、あるいは SPMs 受容体拮抗薬と SPMs の併用投与を行い、再灌流後に呼吸機能、動脈血液ガス分析、肺湿乾重量比、肺組織の炎症性サイトカイン濃度の計測と病理学的評価を行った。

結果：
肺の内因性 SPMs は再灌流１時間後には減少する傾向を示した。再灌流後３日から７日の間に呼吸機能は改善したが、内因性SPMs は正常時に比較して低値のままであった。SPMs 受容体のうち、肺組織ではホルミルペプチド受容体２(formyl peptide receptor type2; ALX/FPR2)遺伝子の発現が再灌流３時間後に増加していた。また肺組織に認められた炎症細胞は免疫組織化学的にALX/FPR2 に陽性であった。ALX/FPR2 のアゴニストであるアスピリン誘発リゾルビン D1（aspirin-triggered resolvin D1; AT-RvD1）およびアスピリン誘発リポキシンA4（aspirin-triggered lipoxin A4; AT-LXA4）を再灌流時に投与すると、再灌流３時間後において呼吸機能の改善、肺水腫の軽減、炎症性サイトカイン濃度の低下、肺胞内出血の軽減と好中球浸潤の減少が認められた。一方で、AT-RvD1 および AT-LXA4のこれらの効果は、ALX/FPR2 拮抗薬の併用下では認められなかった。

結論：
ラット左肺門クランプモデルにおいて肺組織の内因性 SPMs は再灌流後に低下し、肺機能の回復後も低値を維持していた。 SPMs 受容体である ALX/FPR2 は肺 IRI の開始期で上昇していた。AT-RvD1 およびAT-LXA4の投与はALX/FPR2 を介してラット肺のIRI の増悪を緩和していた。これらのSPMs は IRI の新たな予防および治療方法の開発の一助となる可能性があると考えられた。

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