EXPERIMENTAL EMPHYSEMA--STUDIES ON REMEDIATION

描述（申请人摘要）：我们的长期目标是实现 分子和细胞的解释，形成肺泡， 将这些信息用于疾病的治疗目的， 肺气肿后者以肺泡破坏为特征， 美国残疾和死亡的主要原因，部分原因是 无法替换受损的肺泡。肺部的中枢性未满足挑战 研究-为治疗目的诱导和形成肺泡- 导致肺移植成为治疗肺气肿的唯一方法。 然而，一个范例-非手术廉价的可能性 肺气肿的补救-最近的三个观察提供：1） 用全反式维甲酸（RA）治疗新生大鼠引起50 肺泡数量增加百分比，但肺容量未增加; 2） 相同的治疗防止了肺泡形成的抑制， 皮质类固醇治疗引起的体重比肺泡表面积; 3)用RA治疗先前由弹性蛋白酶造成肺气肿的成年大鼠 施用消除了人肺气肿的结构特征（较大的 肺泡减少，肺容量增加，容量减少 表面积）提供肺气肿的首次非手术补救， 在人类身上产生类似效果的可能性。我们的具体目标是：（1） 使用无偏的形态测量方法来检验这一假设， RA将消除非人类中弹性蛋白酶诱导肺气肿的关键发现， 灵长类动物; 2）使用分子生物学技术启动系统的 方法来识别基因的形成负责 肺泡在非人类灵长类动物; 3）使用形态测量方法来测试， 假设，在非人类灵长类动物中， 肺泡壁，以及肺泡上皮表面积和 肺泡毛细血管表面积的变化是弹性蛋白酶诱导的肺气肿 并通过RA治疗恢复正常。我们相信我们可以 实现这些具体目标，因为我们有1）丰富的经验， 形态计量学，2）在大鼠中产生和逆转肺气肿，3）成功 具有所有必要的分子生物学程序的经验，以及4） 在非人类灵长类动物身上产生了肺气肿。

DESCRIPTION (Applicant's abstract): Our long range goal is to achieve a molecular and cellular explanation for the formation of an alveolus and to use this information for therapeutic purposes in diseases such as pulmonary emphysema. The latter, characterized by alveolar destruction, is among the leading causes of disability and death in U.S., in part, because the lung fails to replace destroyed alveoli. A central unmet challenge of lung research - the induction and formation of alveoli for therapeutic purposes - has led to lung transplantation being the only remediation for emphysema. However, a paradigm - the possibility of non-surgical inexpensive remediation of emphysema - is offered by three recent observations: 1) treatment of newborn rats with all trans retinoic acid (RA) causes a 50 percent increase in alveolar number without increasing lung volume; 2) identical treatment prevents the inhibition of alveolar formation and low body mass specific alveolar surface area caused by corticosteroid treatment; 3) treatment with RA of adult rats previously made emphysematous by elastase administration abrogates the structural features of human emphysema (larger and fewer alveoli, increased lung volume, and diminished volume corrected surface area) providing the first non-surgical remediation of emphysema and the possibility of a similar effect in humans. Our specific aims are 1) to use unbiased morphometric methods to test the hypothesis that treatment with RA will abrogate key findings of elastase induced emphysema in a non-human primate; 2) to use molecular biology techniques to initiate a systematic approach to the identification of genes responsible for the formation of alveoli in a non-human primate; 3) to use morphometric methods to test the hypothesis that, in a non-human primate, the cellular composition of the alveolar wall, and the balance between alveolar epithelial surface area and alveolar capillary surface area are changes in elastase-induced emphysema and are returned to normal by treatment with RA. We believe that we can achieve these specific aims because we have 1) considerable experience with morphometry, 2) produced and reversed emphysema in rats, 3) successful experience with all the necessary molecular biology procedures, and 4) produced emphysema in a non-human primate.