Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Radiat Res. 2019 Aug;192(4):367-379. doi: 10.1667/RR15356.1. Epub 2019 Aug 2.
Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive complication of therapeutic irradiation of the thorax. It has been suggested that senescence of type II pneumocytes (AECIIs), an alveolar stem cell, plays a role in the development of RIPF through loss of replicative reserve and via senescent AECII-driven release of proinflammatory and profibrotic cytokines. Within this context, we hypothesized that arachidonate 12-lipoxygenase (12-LOX) is a critical mediator of AECII senescence and RIPF. Treatment of wild-type AECIIs with 12S-hydroxyeicosateraenoic acid (12S-HETE), a downstream product of 12-LOX, was sufficient to induce senescence in a NADPH oxidase 4 (NOX4)-dependent manner. Mice deficient in 12-LOX exhibited reduced AECII senescence, pulmonary collagen accumulation and accumulation of alternatively activated (M2) macrophages after thoracic irradiation (5 × 6 Gy) compared to wild-type mice. Conditioned media from irradiated or 12S-HETE-treated primary pneumocytes contained elevated levels of IL-4 and IL-13 compared to untreated pneumocytes. Primary macrophages treated with conditioned media from irradiated AECII demonstrated preferential M2 type polarization when AECIIs were derived from wild-type mice compared to 12-LOX-deficient mice. Together, these data identified 12-LOX as a critical component of RIPF and a therapeutic target for radiation-induced lung injury.
放射性肺纤维化（RIPF）是胸部治疗性照射的一种慢性、进行性并发症。有人认为，Ⅱ型肺泡上皮细胞（AECII）的衰老，作为一种肺泡干细胞，通过丧失复制储备以及衰老的 AECII 驱动的促炎和促纤维化细胞因子的释放，在 RIPF 的发展中起作用。在这种情况下，我们假设花生四烯酸 12-脂氧合酶（12-LOX）是 AECII 衰老和 RIPF 的关键介质。用 12S-羟基二十碳四烯酸（12S-HETE），即 12-LOX 的下游产物，处理野生型 AECII，足以以 NADPH 氧化酶 4（NOX4）依赖性方式诱导衰老。与野生型小鼠相比，缺乏 12-LOX 的小鼠在胸部照射（5×6Gy）后，AECII 衰老、肺胶原积累和选择性激活（M2）巨噬细胞积累减少。与未经处理的肺细胞相比，照射或 12S-HETE 处理的原代肺细胞的条件培养基中含有更高水平的 IL-4 和 IL-13。与来自 12-LOX 缺陷型小鼠的 AECII 相比，用来自野生型小鼠的 AECII 的条件培养基处理的原代巨噬细胞显示出优先的 M2 型极化。这些数据共同确定 12-LOX 是 RIPF 的关键组成部分，也是辐射性肺损伤的治疗靶点。
