CELLS AND EXTRACELLULAR MATRIX IN PULMONARY HYPERTENSION

慢性肺动脉高压的血管重塑被认为是 包括详细阐述刺激细胞增殖的介质和 肺动脉(PA)中基质蛋白的合成。小才是 然而，已知的是导致退化的过程 PA压力降低后的重塑。我们观察到 令人惊讶地迅速恢复到正常结构的主要PA以下 大鼠缺氧性肺动脉高压的恢复。我们假设 PA压力的降低刺激血管中的蛋白酶 壁来降解细胞和细胞外基质蛋白，并且 这些过程类似于调节从胎儿 到新生儿的成年PA结构。这一假设的胜利在 从缺氧性肺动脉高压恢复的成年大鼠(10天和30天 暴露于10%02)，在新生大鼠和分离的PA环中 墙壁的张力突然降低了。有证据表明，肥大细胞 是分解胶原蛋白的关键效应细胞，肥大的作用 将在肥大细胞缺陷小鼠和肥大细胞中研究退化的细胞 培养中的细胞。我们建议确定蛋白质分解途径， 降解细胞内和细胞外基质蛋白以及 金属蛋白酶组织抑制因子(TIMP)在生物化学和生物化学中的应用 分子生物学的方法。我们还将描述一个明显的 使用分子遗传学方法的血管特异性弹性蛋白酶，以及 用免疫组织化学和免疫组织化学方法确定蛋白酶的细胞来源 原位杂交技术。肿瘤坏死因子的作用 α、白介素1和一种促进合成的脱粒剂 或从培养的肥大细胞释放胶原酶将被测试。我们 将确定与蛋白质降解有关的特定蛋白酶 由于壁面突然减小而受到刺激的孤立PA环 紧张。这些实验可能表明PAS在壁上的感觉减少。 血压降低时的张力，并通过激活 来自PA壁特定细胞的蛋白水解酶。这些研究可能 引发关于肺血管重构的新的病理概念 这可能与慢性肺动脉高压有关。

Vascular remodeling in chronic pulmonary hypertension is thought to involve elaboration of mediators that stimulate cell proliferation and synthesis of matrix proteins in the pulmonary artery (PA). Little is known, however, about the processes which lead to regression of remodeling following lowering of PA pressure. We have observed surprisingly rapid retum to normal structure of the main PA following recovery from hypoxic pulmonary hypertension in the rat. We postulate that reduction in PA pressure stimulates proteases in the blood vessel wall to degrade cellular and extracellular matrix proteins, and that these processes are similar to those regulating the transition from fetal to adult PA structure in the neonate. This postulate win be tested in adult rats recovering from hypoxic pulmonary hypertension (10 and 30 day exposure to 10% 02), in neonatal rats and in isolated PA rings in which wall tension is abruptly reduced. Evidence suggests that the mast cells are a key effector cell in breakdown of collagen, and the role of mast cells in regression will be studied in mast cell deficient mice and mast cells in culture. We propose to identify the proteolytic pathways which degrade intracellular and extracellular matrix proteins as well as the tissue inhibitor of metalloprotease (TIMP) using biochemical and molecular biology approaches. We will also characterize an apparently vascular-specific elastase using molecular genetics methods, and determine the cellular sources of proteases using immunohistochemical and in situ hybridization techniques. The role of tumor necrosis factor alpha, interleukin-1 and a degranulating agent in stimulating synthesis or release of collagenase from cultured mast cells will be tested. We will identify specific proteases involved in degradation of proteins in isolated PA rings which are stimulated by abrupt reduction in wall tension. These experiments may show that PAs sense reduction in wall tension when blood pressure is lowered and "involute" by activation of proteases derived from specific cells in the PA wall. These studies may lead to new pathogenetic concepts about pulmonary vascular remodeling which may be pertinent to chronic pulmonary hypertension.