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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mast cell renin and a local renin-angiotensin system in the airway: Role in bronchoconstriction
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Mast cell renin and a local renin-angiotensin system in the airway: Role in bronchoconstriction

机译：气管中的肥大细胞肾素和局部肾素-血管紧张素系统：在支气管收缩中的作用

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We previously reported that mast cells express renin, the rate-limiting enzyme in the renin-angiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin l-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG Ⅱ) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG Ⅱ type 1 receptors (AT_1R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG Ⅱ-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT_1R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and β-hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway renin-angiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG Ⅱ is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease.
机译：我们先前曾报道肥大细胞表达肾素，肾素-血管紧张素级联反应中的限速酶。现在我们评估了肥大细胞肾素释放是否触发了气道中血管紧张素的形成。在分离的大鼠支气管环中，肥大细胞脱粒释放出具有血管紧张素I形成活性的酶，该酶被选择性肾素抑制剂BILA2157阻断。肥大细胞肾素局部产生血管紧张素（ANGⅡ）引起由ANGⅡ1型受体（AT_1R）介导的支气管平滑肌收缩。在立即型超敏反应的豚鼠模型中，支气管环中过敏性肥大细胞脱粒导致ANGⅡ介导的收缩。如在大鼠支气管环中一样，支气管收缩（BC）被肾素抑制剂，AT_1R阻滞剂和肥大细胞稳定剂抑制。从分离的灌注豚鼠肺的流出物中证实了肥大细胞中肾素，组胺和β-己糖胺酶的过敏性释放。为了使这一发现对人类有意义，从宏观上正常的人类肺废物组织标本中分离出肥大细胞。人肺肥大细胞RNA的序列分析显示，外显子1和10之间人肺肥大细胞肾素和肾素之间具有100％的同源性。此外，肺肥大细胞中表达的肾素蛋白具有酶活性。我们的结果证明了肥大细胞肾素释放触发的气道肾素-血管紧张素系统的存在。数据表明，局部产生的ANGⅡ是控制BC的关键因素，这为治疗气道疾病提供了新的治疗靶标。

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