Sunday M E, Hua J, Torday J S, Reyes B, Shipp M A
Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts 02115.
J Clin Invest. 1992 Dec;90(6):2517-25. doi: 10.1172/JCI116145.
The cell membrane-associated enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) functions in multiple organ systems to downregulate responses to peptide hormones. Recently, CD10/NEP was found to hydrolyze bombesin-like peptides (BLP), which are mitogens for normal bronchial epithelial cells and small cell lung carcinomas. Growth of BLP-responsive small cell lung carcinomas was potentiated by CD10/NEP inhibition, implicating CD10/NEP in regulation of BLP-mediated tumor growth. BLP are also likely to participate in normal lung development because high BLP levels are found in fetal lung, and bombesin induces proliferation and maturation of human fetal lung in organ cultures and murine fetal lung in utero. To explore potential roles for CD10/NEP in regulating peptide-mediated human fetal lung development, we have characterized temporal and cellular patterns of CD10/NEP expression and effects of CD10/NEP inhibition in organ cultures. Peak CD10/NEP transcript levels are identified at 11-13 wk gestation by Northern blots and localized to epithelial cells and mesenchyme of developing airways by in situ hybridization. CD10/NEP immunostaining is most intense in undifferentiated airway epithelium. In human fetal lung organ cultures, inhibition of CD10/NEP with either phosphoramidon or SCH32615 increases thymidine incorporation by 166-182% (P < 0.025). The specific BLP receptor antagonist, [Leu13-psi(CH2NH)Leu14]bombesin abolishes these effects on fetal lung growth, suggesting that CD10/NEP modulates BLP-mediated proliferation. CD10/NEP expression in the growing front of airway epithelium and the effects of CD10/NEP inhibitors in lung explants implicate the enzyme in the regulation of peptide-mediated fetal lung growth.
细胞膜相关酶CD10/中性内肽酶24.11（CD10/NEP）在多个器官系统中发挥作用，以下调对肽类激素的反应。最近，发现CD10/NEP可水解蛙皮素样肽（BLP），而BLP是正常支气管上皮细胞和小细胞肺癌的促有丝分裂原。CD10/NEP抑制可增强BLP反应性小细胞肺癌的生长，这表明CD10/NEP参与调节BLP介导的肿瘤生长。BLP也可能参与正常肺发育，因为在胎儿肺中发现高BLP水平，并且蛙皮素在器官培养中可诱导人胎儿肺以及子宫内小鼠胎儿肺的增殖和成熟。为了探究CD10/NEP在调节肽介导的人胎儿肺发育中的潜在作用，我们已对CD10/NEP表达的时间和细胞模式以及CD10/NEP抑制在器官培养中的作用进行了表征。通过Northern印迹法在妊娠11 - 13周时鉴定出CD10/NEP转录本水平的峰值，并通过原位杂交将其定位到发育中气道的上皮细胞和间充质。CD10/NEP免疫染色在未分化的气道上皮中最为强烈。在人胎儿肺器官培养中，用磷酰胺脒或SCH32615抑制CD10/NEP可使胸腺嘧啶核苷掺入增加166 - 182%（P < 0.025）。特异性BLP受体拮抗剂[Leu13 - psi(CH2NH)Leu14]蛙皮素消除了这些对胎儿肺生长的影响，表明CD10/NEP调节BLP介导的增殖。气道上皮生长前沿的CD10/NEP表达以及CD10/NEP抑制剂在肺外植体中的作用表明该酶参与调节肽介导的胎儿肺生长。
