Cardiopulmonary Response to Lung Injury

肺的缺血/再灌注（I/R）损伤伴随着内皮活化、白细胞粘附和中性粒细胞积聚。临床经验还表明，肺损伤往往伴随着短暂的心脏功能缺陷。我们推测，肺I/R损伤引发的炎性激活级联反应最终导致了这种情况下观察到的心功能不全。我们建议，整个动物实验采用一套互补的药理学和遗传学方法将有助于阐明炎症在肺I/R损伤后心功能不全中的作用，并确定有效的治疗策略。在初步研究中，我们已经建立了一个小鼠肺I/R模型， 损伤，并使用心脏磁共振成像（MRI）来评估完整小鼠的心脏功能。在本项目中，将使用特定的药理学试剂、基因操作小鼠和过继转移技术阐明I/R损伤后肺炎症激活的作用。将采用跨外科、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领域的多学科方法。具体目的是：1）表征肺移植后小鼠肺和心脏中炎症活化的持续时间和程度。I/R损伤，我们最近发现抗炎剂可以逆转由肺I/R损伤引起的心功能障碍。使用小鼠模型，我们将测试假设i） 对一个肺的I/R损伤诱导另一个肺中的炎性活化，和ii）由对肺的I/R损伤引起的心功能障碍是由于炎性活化。 2)明确肺损伤后心功能不全的信号通路。T细胞缺陷小鼠和过继转移技术将用于检验T细胞在肺损伤的心肺反应中起重要作用的假设。此外，我们假设，由于I/R肺损伤导致的心功能不全将被干扰炎症激活的药物减弱。3)使用31 P NMR光谱表征A2 a-腺苷受体刺激对肺I/R损伤后心肌能量学的影响。我们假设A2 A-腺苷受体刺激将改善小鼠肺I/R损伤的心肌能量。

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.