Cardiopulmonary Response to Lung Injury

肺缺血再灌注(I/R)损伤伴有内皮细胞活化、白细胞黏附和中性粒细胞聚集。临床经验还表明，肺损伤通常伴有一过性心功能障碍。我们假设，在这种情况下观察到的心功能不全最终是由肺I/R损伤引发的炎症激活级联反应所致。我们建议，采用一套互补的药理学和遗传学方法的整体动物实验将有助于阐明炎症在肺I/R损伤后心功能障碍中的作用，并确定有效的治疗策略。在初步研究中，我们建立了一种小鼠肺I/R模型 并使用心脏磁共振成像(MRI)来评估完好小鼠的心功能。在这个项目中，将使用特定的药理学药物、基因操纵的小鼠和过继转移技术来阐明肺I/R损伤后炎症激活的作用。将使用多学科方法，跨越外科、生物医学工程、放射学、心血管生理学、药理学、免疫病理学、细胞生物学和分子遗传学等领域。其具体目的是：1)研究小鼠肺损伤后心肺组织炎症激活的持续时间和程度。I/R损伤，我们最近证明抗炎药可以逆转因肺I/R损伤而导致的心功能障碍。使用老鼠模型，我们将检验假设：i) 一个肺的I/R损伤导致另一个肺的炎症激活，II)肺的I/R损伤导致的心功能不全是炎症激活所致。 2)明确肺损伤后心功能障碍的信号转导途径。T细胞缺陷小鼠和过继转移技术将被用来检验T细胞在肺损伤的心肺反应中发挥重要作用的假设。此外，我们假设肺I/R损伤引起的心功能障碍将通过干扰炎症激活的药物来减轻。3)用31P核磁共振波谱研究刺激A2a-腺苷受体对肺I/R损伤后心肌能量学的影响。我们假设A2A腺苷受体刺激将改善肺I/R损伤小鼠的心肌能量。

Ischemia / reperfusion (I/R) injury to the lung is accompanied by endothelial activation, leukocyte adhesion and neutrophil accumulation. Clinical experience also indicates that pulmonary injury is often accompanied by a transient deficit in cardiac performance. We hypothesize that the cascade of inflammatory activation initiated by I/R injury to the lung is ultimately responsible for the cardiac dysfunction observed in this setting. We propose that whole animal experiments employing a complementary set of pharmacologic and genetic approaches will serve to elucidate the role of inflammation in cardiac dysfunction after lung I/R injury and to identify effective treatment strategies. In preliminary studies, we have developed a mouse model of lung I/R injury and have used cardiac magnetic resonance imaging (MRI) to evaluate cardiac function in intact mice. In this project, the role of inflammatory activation after I/R injury to the lung will be elucidated using specific pharmacologic agents, genetically-manipulated mice and adoptive transfer techniques. A multidisciplinary approach will be used that spans the fields of surgery, biomedical engineering, radiology, cardiovascular physiology, pharmacology, immunopathotogy, cell biology and molecular genetics. The specific aims are to: 1) Characterize the duration and extent of inflammatory activation in the mouse lung and heart after pulmonary. I/R injury, We have recently shown that an anti-inflammatory agent can reverse the cardiac dysfunction that results from I/R injury to the lung. Using a mouse model, we will test the hypotheses that i) I/R injury to one lung induces inflammatory activation in the other lung, and ii) the cardiac dysfunction that results from I/R injury to the lung is due to inflammatory activation. 2) Define the signaling pathways responsible for cardiac dysfunction after lung injury. T-cell deficient mice and adoptive transfer techniques will be used to test the hypothesis that T-cells participate importantly in the cardiopulmonary response to lung injury. Furthermore, we hypothesize that cardiac dysfunction as a result of I/R injury to the lung will be attenuated by agents that interfere with inflammatory activation. 3) Characterize the effects of A2a-adenosine receptor stimulation on myocardial energetics after I/R injury to the lung using 31P NMR spectroscopy. We hypothesize that A2A-adenosine receptor stimulation will improve myocardial energetics in mice subjected to pulmonary I/R injury.