REGULATORS OF CLARA CELL DIFFERENTIATION IN LUNG

在成年哺乳动物中，无纤毛细支气管上皮细胞（Clara） 细胞是细胞毒性和代谢的主要场所。 肺环境毒物，需要通过激活 细胞色素P-450单加氧酶系统，无论这些化合物 通过吸入或摄入进入机体。 最近的一些 研究表明，那些母亲被 受到环境毒素的影响， 这些曝光。 胎儿气道细胞 分化为功能性Clara细胞是一种前 产后现象 因为几乎没有任何信息 哪些因子调节Clara细胞的分化， 关于生物活化的肺细胞毒素如何调节这一过程， 我们建议评估对Clara细胞的影响 一系列化合物的分化， 细胞色素P-450系统。 我们的总体假设是 测试是，改变肺细胞色素P- 450系统作为Clara细胞的刺激因子 在胎儿和新生动物中的分化和成熟。 我们评估了激素的作用，这些激素已经被证明是 调节肺发育的其他方面（糖皮质激素和 孕酮），成人肝P-450的诱导剂（钠 苯巴比妥，Arochlor，β-萘酮），生物活化的克拉拉 细胞特异性毒物（4-异戊烯醇）和细胞色素抑制剂 P-450活性（SKF 525-A和氨基苯并三唑）。 实现 由分化的克拉拉细胞组成的成体细胞器将 通过超微结构形态测定法进行评估。 此外，这三个 将评估Clara细胞的主要功能： 细支气管上皮细胞的祖细胞，细胞色素P- 450-介导的代谢，以及细支气管粘液分泌的来源 proteins. 3 H-胸苷掺入和细胞周转将 通过放射自显影和细支气管上皮细胞群估计 将对密度进行定量评估。 免疫细胞化学， 免疫化学、分光光度和酶活性测定 将用于测量细胞色素P-450系统。 免疫细胞化学和免疫化学方法将用于 评估分泌功能的改变。 该提案提供 一个独特的机会来评估面临的危险程度， 暴露于环境毒素的母亲的新生儿和胎儿， 来确定环境毒素对肺细胞类型的影响 这是许多正常肺功能的关键， 鉴定可作为Clara细胞调节剂化合物 分化

In adult mammals, the nonciliated bronchiolar epithelial (Clara) cell is the principal site for cytotoxicity and metabolism of pulmonary environmental toxicants which require activation via the cytochrome P-450 monooxygenase system, whether these compounds enter the organism via inhalation or ingestion. A number of recent studies suggest that the lungs of fetuses whose mothers have been subjected to environmental toxins also may be at risk as a result of these exposures. The process by which fetal airway cells differentiate into functional Clara cells is both a pre- and postnatal phenomenon. Because there is virtually no information on which factors regulate differentiation of the Clara cell, nor on how bioactivated pulmonary cytotoxins may modulate this process, we have proposed to evaluate the effects on Clara cell differentiation of a series of compounds which inhibit or induce the cytochrome P-450 system. The overall hypothesis we will be testing is that compounds which alter the pulmonary cytochrome P- 450 system in the adult function as stimulators of Clara cell differentiation and maturation in the fetal and neonatal animal. We we evaluate the effects of hormones which have been shown to regulate other aspects of lung development (glucocorticoids and progesterone), inducers of hepatic P-450s in adults (sodium phenobarbital, Arochlor, beta-naphthoflavone), a bioactivated Clara cell-specific toxicant (4-ipomeanol) and inhibitors of cytochrome P-450 activity (SKF 525-A and aminobenzotriazole). The attainment of adult organelle composition by differentiated Clara cells will be assessed by ultrastructural morphometry. In addition, all three major functions of the Clara cell will be assessed: role as progenitor of bronchiolar epithelial cells, site of cytochrome P- 450-mediated metabolism, and source of bronchiolar mucosecretory proteins. 3H-Thymidine incorporation and cell turnover will be estimated by autoradiography, and bronchiolar epithelial population densities will be assessed quantitatively. Immunocytochemical, immunochemical, spectrophotometric and enzymatic activity assays will be used to measure the cytochrome P-450 system. Immunocytochemical and immunochemical methods will be used to evaluate alterations in secretory function. This proposal offers a unique opportunity to assess the degree of hazard faced by neonates and fetuses of mothers exposed to environmental toxins, to define the impact of environmental toxins on a lung cell type which is pivotal for a number of normal lung functions and to identify compounds which may serve as regulators of Clara cell differentiation.