肺血管性肺高血圧の突然変異感受性とDNA損傷

論文No662

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

Chiara Federici, Kylie M. Drake, Christina M. Rigelsky, Lauren N. McNelly, Sirena L. Meade, Suzy A. A. Comhair, Serpil C. Erzurum, and Micheala A. Aldred

American Journal of Respiratory and Critical Care Medicine, Vol. 192, No. 2 (2015), pp. 219-228.

アメリカからの報告．
＜背景＞
肺動脈性肺高血圧（PAH）は肺細動脈の血管リモデリングで特徴づけられる重篤な肺疾患である．
PAH患者の肺血管細胞では染色体異常とDNA損傷の増加が指摘されているが，そのタイミングと病態への役割については不明である．

＜目的＞
DNA損傷がPAHに先行するとしたら，病気になった肺以外でおこる内因性細胞の特性かもしれないと考えた．

＜方法＞
グループ１のPAH患者の肺，血液細胞のDNA損傷，突然変異感受性，活性酸素種(ROS)を測定し，正常人のものと比較した．

＜結果＞
ベースラインのDNA損傷は肺動脈内皮細胞，末梢血単核球（PBMC）ともにPAH患者で高かった．
PAHと診断されていない親戚でもPBMCで同様のDNA損傷があり，PAH治療とは関係ないことがわかった．
ROSレベルもPAH患者で高かった．
DNA損傷はROS産生物と相関しており，抗酸化物質により抑制された．
患者，親戚のPBMCは２つの化学物質（ブレオマイシン，エトポシド）に強く感受性が増加していた．
これらの結果は特発性，遺伝性，関連PAHを問わなかった．

＜感想＞
PAHになるような患者さんは，遺伝的にもともとDNA損傷が強く起こっており，ROSが関連しているようです．
ハイリスクの人には抗酸化物質を投与するとPAH発症を遅らすことができる可能性があるように感じました．

Rationale: Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown.

Objectives: We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung.

Methods: We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects.

Measurements and Main Results: Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P < 0.05) and peripheral blood mononuclear cells (PBMC) (P < 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P < 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P < 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P < 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups.

Conclusions: Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management.