Veerappan Arul, Reid Alicia C, Estephan Racha, O'Connor Nathan, Thadani-Mulero Maria, Salazar-Rodriguez Mariselis, Levi Roberto, Silver Randi B
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1315-20. doi: 10.1073/pnas.0709739105. Epub 2008 Jan 17.
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 I-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(1)R). 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(1)R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and beta-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.
我们之前报道过，肥大细胞表达肾素，肾素是肾素-血管紧张素级联反应中的限速酶。我们现在评估了肥大细胞肾素释放是否会触发气道中的血管紧张素形成。在分离的大鼠支气管环中，肥大细胞脱颗粒释放出具有血管紧张素I生成活性的酶，该活性被选择性肾素抑制剂BILA2157阻断。肥大细胞肾素局部生成血管紧张素（ANG II）引发了由1型血管紧张素受体（AT(1)R）介导的支气管平滑肌收缩。在速发型超敏反应的豚鼠模型中，支气管环中的过敏性肥大细胞脱颗粒导致ANG II介导的收缩。与大鼠支气管环一样，支气管收缩（BC）被肾素抑制剂、AT(1)R阻滞剂和肥大细胞稳定剂抑制。在分离的灌注豚鼠肺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。为了将这一发现与人类联系起来，从宏观正常的人类肺废组织标本中分离出肥大细胞。对人肺肥大细胞RNA的序列分析显示，人肺肥大细胞肾素与肾外显子1和10之间的肾素具有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。我们的结果证明了由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ANG II是控制BC的关键因素，为气道疾病管理中的新型治疗靶点开辟了可能性。
