LOCAL EXPRESSION OF ALPHA-1-ANTITRYPSIN IN EMPHYSEMA

肺气肿中 ALPHA-1-抗胰蛋白酶的局部表达

• 批准号: 3353771
• 负责人: David H Perlmutter
• 金额: $ 10.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3353771
• 关键词: Xenopus; alpha 1 antitrypsin; alpha 1 antitrypsin deficiency; alveolar macrophages; bone marrow; cell type; corticosteroids; elastase inhibitor; elastases; emphysema; extracellular matrix; fibroblasts; gel electrophoresis; gene expression; genetic manipulation; human milk; human subject; laboratory mouse; liver transplantation; lymphokines; macrophage; monocyte; sex hormones; tissue /cell culture; transfection

Homozygous PiZZ Alpha1PI deficiency is associated with reduction in serum concentrations of Alpha1PI and with the development of pulmonary emphysema. Nevertheless, a number of PiZZ individuals do not develop clinical lung involvement. There is also wide variability in the extent of destructive lung disease in the affected Alpha1PI-deficient population even when the absolute serum level of Alpha1PI and cigarette smoking are taken into consideration. We have recently identified expression of Alpha1PI in human mononuclear phagocytes, including alveolar macrophages, raising the possibility that local alveolar expression of Alpha1PI is a determinant in development of lung disease. We will examine cellular and extracellular variables that determine net Alpha1PI expression in normal (PiMM) and deficient (PiZZ, PiSZ) individuals. Since the integrity of the lung is thought to be maintained by a balance of elastase and anti-elastase in a microenvironment that is constantly confronted by elastase, these enzymes must be considered among the variables that affect net local Alpha1PI expression. In preliminary experiments, we have demonstrated a substantial dose-dependent increase in Alpha1PI expression in blood monocytes and alveolar macrophages incubated in medium containing serine elastase. The effects of elastase on Alpha1PI expression in mononuclear phagocytes will be the major focus of this project, but this effect will also be examined in the context of other potential variables including cellular maturation, tissue specificity, other products of mononuclear phagocytes, products elaborated by other cells locally (lymphokines) and remotely (sex steroid hormones, adrenal corticosteroids) and constituents of the extracellular matrix.

纯合子 PiZZ Alpha1PI 缺乏与血清减少有关 Alpha1PI 的浓度和肺部疾病的发展 气肿。 然而，许多 PiZZ 个体并没有发展 临床肺部受累。 程度也存在很大差异 受影响的 Alpha1PI 缺陷人群甚至会患上破坏性肺部疾病 当测量 Alpha1PI 的绝对血清水平和吸烟情况时 考虑在内。 我们最近发现 Alpha1PI 在 人类单核吞噬细胞，包括肺泡巨噬细胞，提高 Alpha1PI 的局部肺泡表达可能是一个决定因素 肺部疾病的发展。 我们将检查细胞和细胞外 决定正常 (PiMM) 和 有缺陷的（PiZZ，PiSZ）个体。 由于肺的完整性被认为是通过平衡来维持的 弹性蛋白酶和抗弹性蛋白酶处于不断变化的微环境中 面对弹性蛋白酶，这些酶必须被视为 影响网络局部 Alpha1PI 表达的变量。 在初步 实验中，我们已经证明了显着的剂量依赖性增加 孵育的血液单核细胞和肺泡巨噬细胞中的 Alpha1PI 表达 在含有丝氨酸弹性蛋白酶的培养基中。 弹性蛋白酶对Alpha1PI的影响 单核吞噬细胞的表达将是本次研究的重点 项目，但这种影响也将在其他项目的背景下进行检验 潜在的变量包括细胞成熟、组织特异性、 单核吞噬细胞的其他产品，其他人精心制作的产品 细胞局部（淋巴因子）和远程（性类固醇激素、肾上腺 皮质类固醇）和细胞外基质的成分。