Effects of sulfur dioxide on hypoxic pulmonary vascular structural remodeling
Effects of sulfur dioxide on hypoxic pulmonary vascular structural remodeling
复制标题
二氧化硫对缺氧肺血管结构重塑的影响
DOI：
10.1038/labinvest.2009.102
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发表时间：
2010-01-01
影响因子：
5
通讯作者：
Du, Junbao
中科院分区：
文献类型：
--
作者：
Sun, Yan;Tian, Yue;Du, Junbao
低氧性肺动脉高压是多种心肺疾病发生发展的重要病理生理过程。最近，我们发现二氧化硫可以由肺血管内源性产生，并显示出血管调节功能。本文探讨了二氧化硫在低氧性肺血管结构重建中的作用。将48只Wistar大鼠分为6组。低氧组、低氧+二氧化硫组、低氧+异羟肟酸组大鼠置于低氧条件下，对照组、对照+二氧化硫组、对照+异羟肟酸组大鼠置于空气中。对于每个组，我们测量了大鼠的肺动脉压、血浆和肺组织中的二氧化硫含量、谷草转氨酶1和谷草转氨酶2 mRNA、肺动脉的显微和超微结构变化、肺平滑肌细胞增殖、血管胶原代谢、肺内皮细胞炎症反应和肺血管内皮素-1的产生。低氧组大鼠血浆和肺组织中二氧化硫含量较对照组显著降低，肺动脉高压明显，肺血管结构重构，血管炎症反应增强。SO2供体显著下调Raf-1、丝裂原活化蛋白激酶激酶-1（MEK-1）和p-ERK/ERK，抑制肺血管平滑肌细胞增殖、胶原重塑和肺血管内皮细胞核因子-κ B（NF-kappaB）、细胞间粘附分子-1（ICAM-1）表达。它还防止肺动脉高压和肺血管结构重塑与上调二氧化硫/谷氨酸草酰乙酸转氨酶途径。然而，羟肟酸可导致肺动脉高压、肺血管结构重塑和肺动脉炎症反应，并与二氧化硫/谷氨酸草酰乙酸转氨酶途径下调有关。结果表明，SO2可显著抑制低氧诱导的肺动脉平滑肌细胞（PASMC）增殖，并抑制Raf-1、MEK-1和细胞外信号调节激酶（ERK）的磷酸化。二氧化硫/谷草转氨酶途径下调可能参与了肺动脉高压和肺血管结构重建的机制。
Hypoxic pulmonary hypertension is a pathophysiological process important in the development of various cardiopulmonary diseases. Recently, we found that sulfur dioxide could be produced endogenously by pulmonary vessels, and that it showed vascular regulatory capabilities. In this paper, we examined the role of sulfur dioxide in hypoxic pulmonary vascular structural remodeling (HPVSR). A total of 48 Wistar rats were divided into six groups. Rats in the hypoxic group, hypoxic+sulfur dioxide group, and hypoxic+hydroxamate group were left under hypoxic conditions, whereas the control group, control+sulfur dioxide group, and control+hydroxamate group rats were left in room air. For each group, we measured the pulmonary arterial pressure, sulfur dioxide content in plasma and lung tissue, glutamate oxaloacetate transaminase 1 and 2 mRNAs, micro- and ultra-structural changes in pulmonary arteries, proliferation of pulmonary smooth muscle cells, vascular collagen metabolism, pulmonary endothelial cell inflammatory response, and pulmonary vascular endothelin-1 production in the rats. In hypoxic rats, the content of sulfur dioxide in plasma and lung tissue decreased significantly in comparison with those in the control groups, and significant pulmonary hypertension, pulmonary vascular structural remodeling, and increased vascular inflammatory response were also observed in hypoxic rats. Sulfur dioxide donor significantly downregulated Raf-1, mitogen-activated protein kinase kinase-1 (MEK-1) and p-ERK/ERK, and inhibited pulmonary vascular smooth muscle cell proliferation, collagen remodeling and pulmonary vascular endothelial cell nuclear factor-kappaB (NF-kappaB), and intercellular adhesion molecule 1 (ICAM-1) expressions. It also prevented pulmonary hypertension and pulmonary vascular structural remodeling in association with the upregulated sulfur dioxide/glutamate oxaloacetate transaminase pathway. Hydroxamate, however, advanced pulmonary hypertension, pulmonary vascular structural remodeling, and inflammatory response of the pulmonary artery in association with a downregulated sulfur dioxide/glutamate oxaloacetate transaminase pathway. The results suggested that sulfur dioxide markedly inhibited Raf-1, MEK-1, and the phosphorylation of extracellular signal-regulated kinase (ERK), and then inhibited pulmonary arterial smooth muscle cell (PASMC) proliferation induced by hypoxia. The downregulated sulfur dioxide/glutamate oxaloacetate transaminase pathway may be involved in the mechanisms responsible for pulmonary hypertension and pulmonary vascular structural remodeling.