Cardiopulmonary Response to Lung Injury

肺缺血/再灌注（I/R）损伤伴随着内皮细胞活化、白细胞粘附和中性粒细胞积累。临床经验也表明，肺损伤常伴有短暂的心脏功能障碍。我们假设，肺I/R损伤引发的炎症激活级联反应是本研究中观察到的心功能障碍的最终原因。我们建议采用一套互补的药理学和遗传学方法进行全动物实验，以阐明炎症在肺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，我们建立了小鼠肺I/R模型

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.