Mast cell hyperactivity underpins the development of oxygen-induced retinopathy.
Mast cell hyperactivity underpins the development of oxygen-induced retinopathy.
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DOI：
10.1172/jci89893
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发表时间：
2017-11-01
期刊：
影响因子：
--
通讯作者：
Matsuda H
中科院分区：
文献类型：
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作者：
Matsuda K;Okamoto N;Kondo M;Arkwright PD;Karasawa K;Ishizaka S;Yokota S;Matsuda A;Jung K;Oida K;Amagai Y;Jang H;Noda E;Kakinuma R;Yasui K;Kaku U;Mori Y;Onai N;Ohteki T;Tanaka A;Matsuda H
肥大细胞被经典地认为在保护免受蠕虫感染和诱导过敏性疾病中起重要作用;然而，最近的研究表明，这些细胞也有助于新血管形成，这对于组织重塑、慢性炎症和癌变至关重要。在这里，我们证明了肥大细胞是必不可少的萌芽血管生成的小鼠模型氧诱导的视网膜病变（OIR）。尽管缺乏肥大细胞的小鼠品系在缺氧后未表现出视网膜新生血管形成，但这些小鼠在输注肥大细胞或注射肥大细胞类胰蛋白酶（MCT）后发生了OIR。相对缺氧通过瞬时受体电位锚蛋白1刺激肥大细胞脱颗粒。随后的MCT激增刺激视网膜内皮细胞产生单核细胞趋化蛋白-1（MCP 1）和血管生成因子，导致出芽血管生成。肥大细胞稳定剂以及特异性类胰蛋白酶和MCP 1抑制剂可防止WT小鼠发生OIR。患有早期早产儿视网膜病变的早产儿血浆MCT水平明显高于年龄匹配的无疾病婴儿，这表明肥大细胞与人类疾病有关。总之，这些结果表明，抑制肥大细胞活性的疗法应进一步探索作为预防眼部疾病和随后的失明诱导的新血管形成的潜在选择。
Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization.