Investigation into Cold-induced Pulmonary Vascular Inflammation and Dysfunction

描述（申请人提供）：大量流行病学研究表明，居住在寒冷地区的人有较高的肺和心血管疾病发病率（见背景）。在美国，肺和心血管疾病的最高死亡率和发病率发生在寒冷的冬季。寒冷的气温会增加肺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作为心血管功能障碍的危险因素，以制定预防和治疗策略。间歇性暴露于中度寒冷（5 ℃）会导致大鼠肺血管炎症和功能障碍、肺动脉高压和右心室（RV）肥大，即冷诱导的肺动脉高压（CIPH）。动物CIPH的特点本申请的目的是研究前B细胞集落增强因子（PBEF），AMP-活化蛋白激酶（AMPK），磷酸二酯酶1B（PDE 1B）在冷-诱导肺血管功能障碍和重塑的目的，发展预防和治疗方法的PH。中心假设是，间歇暴露于寒冷增加肺血管PBEF这导致肺动脉内皮细胞（PA EC）中AMPK <$1的下调、PA SMC中PDE 1B的上调、肺血管功能障碍和重构以及PH，并且进一步地，抑制PBEF表达可以消除冷诱导的AMPK <$1和PDE 1B的失调、PH和RV肥大。这一假设是在我们实验室产生的强有力的初步数据基础上提出的。该目标将通过追求三个相互关联和互补的具体目标，使用几种新的方法，包括在体内SMC特异性和巨噬细胞特异性基因传递和实时监测RV压力（遥测）的组合来实现。这三个具体目标是：（1）确定PBEF的增加是否在冷诱导的肺动脉内皮细胞AMPK 1下调、肺动脉平滑肌细胞PDE 1B上调、肺血管功能障碍和重构以及PH中起作用。（2）研究内皮细胞AMPK 1下调是否与肺动脉内皮细胞的AMPK 1上调、肺动脉平滑肌细胞PDE 1B上调、肺动脉内皮细胞的AMPK 1下调有关。1介导PBEF在冷诱导的肺内皮功能障碍和PH中的作用。（3）确定PDE 1B和Oct-4的上调是否（一种转录因子）介导PBEF在冷诱导的PA SMC增殖、PA重塑和PH中的作用。这项工作的完成将揭示一种介导CIPH的新途径，冷暴露<$PBEF <$$> AMPK <$$> 1 <$$>，PDE 1B <$$>，Oct 4 <$CIPH。拟议研究的结果可能为PH和相关心脏病的预防策略和治疗方法提供新的见解。建议的工作对于居住在寒冷地区和冬季外出工作的人具有重要意义。

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.