CELLS AND EXTRACELLULAR MATRIX IN PULMONARY HYPERTENSION

慢性肺动脉高压的血管重构被认为是 包括精心制作刺激细胞增殖的介质， 肺动脉（PA）中基质蛋白的合成。 之甚少 然而，我们知道，导致退化的过程 降低PA压力后的重塑。 我们观察到 令人惊讶地快速恢复到主PA的正常结构， 大鼠缺氧性肺动脉高压的恢复。 我们推测 肺动脉压的降低会刺激血管中的蛋白酶 壁降解细胞和细胞外基质蛋白， 这些过程类似于那些调节从胎儿 与新生儿的成人肺动脉结构相对应。 这一假设可以在 成年大鼠缺氧性肺动脉高压（10和30天 暴露于10%O2），在新生大鼠和分离的PA环中，其中 壁张力突然降低。 有证据表明肥大细胞 是胶原分解的关键效应细胞，肥大细胞的作用是 将在肥大细胞缺陷小鼠和肥大细胞中研究退化的细胞。 细胞培养。 我们建议确定蛋白水解途径， 降解细胞内和细胞外基质蛋白以及 金属蛋白酶组织抑制剂（TIMP）使用生化和 分子生物学方法。 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，和 使用免疫组织化学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、白细胞介素-1和脱粒剂刺激合成 或从培养的肥大细胞释放胶原酶。 我们 将确定参与蛋白质降解的特定蛋白酶， 孤立的PA环，其由壁的突然减小刺激 张力 这些实验可能表明，PA感觉到壁中的减少， 当血压降低和“渐开线”的激活紧张 来源于PA壁中特定细胞的蛋白酶。 这些研究可能 提出了肺血管重构发病机制新概念 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.