Key Points Rapid reductions in oxygen tension triggered the degranulation of mast cells. Oxygen-induced activation of mast cells was mediated via TRPA1 channels. Rapid reductions in oxygen tension induced anaphylactic shock. Extensive activation of mast cells is the major switch that triggers systemic anaphylaxis, resulting in the subsequent release of anaphylactic mediators into circulation. We previously demonstrated that rapid changes in oxygen tension lead to mast cell degranulation, and the released tryptase triggers retinal angiogenesis in a murine oxygen-induced retinopathy model. However, whether a rapid shift from hyperoxia to normoxia (relative hypoxic stress) is a risk factor for systemic anaphylaxis remains unknown. In this study, we demonstrated that the relative hypoxia stress induces systemic mast cell activation via transient receptor potential ankyrin 1 (TRPA1) channels, which immediately leads to hypothermia and increased vascular permeability in adult mice. Although mast cell–deficient or TRPA1-deficient mice did not exhibit anaphylactic symptoms following a rapid sift to normoxia, preinjection with bone marrow–derived cultured mast cells (BMCMCs) derived from wild-type TRPA1-expressing mice restored anaphylactic responses. In addition, we found that the rapid reductions in oxygen tension in a culture atmosphere triggered the degranulation of BMCMCs derived from wild-type TRPA1-expressing mice but not that of BMCMCs derived from TRPA1-deficient mice. In human LAD2 mast cells, the relative hypoxic stress led to the degranulation, which was suppressed by the addition of a TRPA1 inhibitor. Gradual reductions from hyperoxia to normoxia led to no anaphylactic symptoms. Our results demonstrated that TRPA1-triggered mast cell degranulation is a novel pathway that induces anaphylactic shock without Ag–Ab reactions. These findings introduce a potential role for oxygen in inducing mast cell–dependent anaphylaxis and highlight the need to reconsider chronic pure oxygen therapy for anoxic diseases.

中文翻译：

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从慢性高氧到常氧的快速转变通过肥大细胞上的瞬时受体电位锚蛋白 1 通道诱导全身性过敏反应

要点 氧张力的快速降低引发了肥大细胞的脱粒。氧诱导的肥大细胞活化是通过 TRPA1 通道介导的。氧张力的快速降低引起过敏性休克。肥大细胞的广泛激活是触发全身性过敏反应的主要开关，导致随后过敏介质释放到循环中。我们之前已经证明氧张力的快速变化会导致肥大细胞脱颗粒，并且释放的类胰蛋白酶在小鼠氧诱导的视网膜病变模型中触发视网膜血管生成。然而，从高氧到常氧（相对缺氧应激）的快速转变是否是全身性过敏反应的危险因素仍然未知。在这项研究中，我们证明了相对缺氧应激通过瞬时受体电位锚蛋白 1 (TRPA1) 通道诱导全身肥大细胞活化，这立即导致成年小鼠体温过低和血管通透性增加。虽然肥大细胞缺陷或 TRPA1 缺陷小鼠在快速筛选至常氧后没有表现出过敏症状，但预注射源自野生型 TRPA1 表达小鼠的骨髓衍生培养肥大细胞 (BMCMC) 恢复了过敏反应。此外，我们发现培养环境中氧张力的快速降低引发了野生型表达 TRPA1 小鼠的 BMCMC 的脱粒，但不会引发来自 TRPA1 缺陷小鼠的 BMCMC 的脱粒。在人 LAD2 肥大细胞中，相对缺氧应激导致脱颗粒，通过添加 TRPA1 抑制剂来抑制。从高氧到常氧的逐渐减少导致没有过敏症状。我们的结果表明，TRPA1 触发的肥大细胞脱颗粒是一种新途径，可在没有 Ag-Ab 反应的情况下诱导过敏性休克。这些发现介绍了氧气在诱导肥大细胞依赖性过敏反应中的潜在作用，并强调需要重新考虑慢性纯氧治疗缺氧性疾病。