Investigation into Cold-induced Pulmonary Vascular Inflammation and Dysfunction

描述(由申请人提供)：大量流行病学研究表明，居住在寒冷地区的人患肺病和心血管疾病的几率更高(见背景资料)。在美国，肺部和心血管疾病的死亡率和发病率最高的是在寒冷的冬季。寒冷的气温会增加肺部和心血管疾病的严重程度。我们的长期目标是了解寒冷温度是心血管功能障碍的危险因素，以制定预防和治疗策略。间歇性暴露于中寒(5℃)可引起大鼠肺血管炎症和功能障碍、肺动脉高压和右室肥大，即冷源性肺动脉高压(CIPH)。动物CIPH(肺动脉高压、肺动脉肥大、丛状病变)的特点与人类特发性肺高压相似，是研究肺高压的相关而独特的模型。本研究的目的是探讨前B细胞集落增强因子(PBEF)、AMP激活的蛋白激酶(AMPK)和磷酸二酯酶1B(PDE1B)在寒性肺血管功能障碍和肺血管重塑中的作用，为肺高压的防治提供理论依据。中心假说是，间歇性冷暴露增加肺血管PBEF，导致肺血管内皮细胞(PA ECs)AMPK？1下调，PA SMCs PDE1B上调，肺血管功能障碍和重塑，以及PH。此外，抑制PBEF的表达可以消除寒冷引起的AMPK？1和PDE1B、PH和RV肥厚的失调。这一假设是基于我们实验室提供的强大的初步数据而提出的。这一目标将通过使用几种新方法的组合来实现三个相互关联和互补的特定目标，包括体内SMC特异性和巨噬细胞特异性基因传递和实时监测RV压力(遥测)。三个具体目标是：(1)确定PBEF的增加是否在寒冷诱导的PA内皮细胞AMPK？1下调、PA SMC PDE1B上调、肺血管功能障碍和重塑以及PH中起作用。(2)探讨内皮细胞AMPK下调是否参与了PBEF在冷诱导肺内皮细胞功能障碍和肺高压中的作用。(3)确定PDE1B和OCT-4(一种转录因子)的上调是否介导了PBEF在冷诱导的PA SMC增殖、PA重构和PH中的作用。这项工作的完成将揭示一种新的介导CIPH的途径，即冷暴露、PBEF、AMPK、PDE1B、10月4日CIPH。这项拟议研究的发现可能为PH和相关心脏疾病的预防策略和治疗方法提供新的见解。这项拟议的工作对生活在寒冷地区的人和冬天有户外工作的人来说意义重大。

DESCRIPTION (provided by applicant): Numerous epidemiological studies showed that people who live in cold regions have a higher incidence of pulmonary and cardiovascular diseases (see Background). In the US, the highest mortality and morbidity due to pulmonary and cardiovascular diseases occur in the cold winter season. Cold temperatures increase the severity of pulmonary and cardiovascular diseases. Our long-term goal is to understand cold temperatures as a risk factor for cardiovascular dysfunction for developing preventive and therapeutic strategies. Intermittent exposure to moderate cold (5¿C) causes pulmonary vascular inflammation and dysfunction, pulmonary arterial hypertension and right ventricular (RV) hypertrophy in rats, namely cold-induced pulmonary hypertension (CIPH). The characteristics of animal CIPH (high pulmonary arterial pressure, pulmonary artery hypertrophy, plexiform lesion) mimic those of human idiopathic PH, making it a relevant and unique model for studying PH. The objective of this application is to investigate if pre-B-cell colony enhancing factor (PBEF), AMP-activated protein kinase (AMPK), and phosphodiesterase 1B (PDE1B) play a role in cold-induced pulmonary vascular dysfunction and remodeling for the purpose to develop preventive and therapeutic approaches for PH. The central hypothesis is that intermittent exposure to cold increases pulmonary vascular PBEF which leads to downregulation of AMPK¿1 in pulmonary arterial endothelial cells (PA ECs), upregulation of PDE1B in PA SMCs, pulmonary vascular dysfunction and remodeling, and PH, and further, that inhibition of PBEF expression could abolish cold-induced dysregulation of AMPK¿1 and PDE1B, PH, and RV hypertrophy. This hypothesis is formulated on strong preliminary data produced in our laboratory. The objective will be achieved by pursuing three interrelated and complemental specific aims using a combination of several novel approaches including in vivo SMC-specific and macrophage-specific gene delivery and real-time monitoring of RV pressure (telemetry). The three specific aims are: (1) Determine if the increase in PBEF plays a role in cold-induced downregulation of AMPK¿1 in PA ECs, upregulation of PDE1B in PA SMCs, pulmonary vascular dysfunction and remodeling, and PH. (2) Investigate if the downregulation of endothelial AMPK¿1 mediates the role of PBEF in cold-induced pulmonary endothelial dysfunction and PH. (3) Determine if the upregulation of PDE1B and Oct-4 (a transcription factor) mediates the role of PBEF in cold-induced PA SMC proliferation, PA remodeling, and PH. Completion of this work will unveil a novel pathway that mediates CIPH, cold exposure ¿ PBEF¿ ¿ AMPK¿1¿, PDE1B¿, Oct4¿ ¿ CIPH. The findings from the proposed research may provide new insights into preventive strategies and therapeutic approaches for PH and related heart diseases. The proposed work is significant for people who live in cold regions and who have outside duties in winter.