MECHANISMS OF AIRWAY RESPONSES TO ENDOTOXEMIA

在最初的提案中，我们能够描述以下效果： 内毒素血症对未麻醉绵羊肺力学的影响（动物模型 成人呼吸窘迫综合征（ARDS）。 我们定义了两个可能的 相互关联的机制可能至少部分负责 以下观察到的肺力学变化 内毒素血症--花生四烯酸代谢的环氧合酶产物 炎症细胞（尤其是粒细胞）。 我们还证明了 内毒素血症急剧增加肺部对气溶胶组胺的反应性 而粒细胞消耗降低了肺部对气溶胶的反应性 组胺。 这些结果产生了一个对此至关重要的新假设 竞争更新。 我们推测肺部炎症介导 与两个相关临床相关的肺力学变化 问题——ARDS 和气道反应性改变，如哮喘中观察到的那样。 在这项提案中，我们扩展了与以下疾病相关的肺损伤模型： 肺部炎症对内毒素血症以外的两种新模型——佛波醇 醋酸肉豆蔻酸酯（PMA）和酵母聚糖活化血浆（ZAP）输注。 我们 提议通过使用新的方法来解决我们的具体目标和假设 使我们能够更准确地测量肺部变化的技术 力学、肺血流动力学以及肺液体和溶质交换 （包括逆行气道导管和上皮通透性， 改进的分析方法和定量形态测量）。 我们会 继续努力阐明负责的重要机制 与内毒素血症、PMA、ZAP 和气道改变相关的病理变化 通过潜在介质的分析、使用特定的 阻断剂、粒细胞和血小板去除和输注以及通过 研究注入的潜在介质的影响。

In the original proposal, we were able to describe the effects of endotoxemia on lung mechanics in the unanesthetized sheep (an animal model of the adult respiratory distress syndrome--ARDS). We defined two possibly interrelated mechanisms that may be responsible, at least in part, for the alterations in lung mechanics observed following endotoxemia--cyclooxygenase products of arachidonate metabolism and inflammatory cells (especially granulocytes). We also demonstrated that endotoxemia acutely increased pulmonary responsiveness to aerosol histamine while granulocyte depletion decreased pulmonary responsiveness to aerosol histamine. These results generated a new hypothesis central to this competing renewal. We hypothesize that pulmonary inflammation mediates the alterations in lung mechanics associated with two interrelated clinical problems--ARDS and altered airway responsiveness as is observed in asthma. In this proposal, we expand our models of lung injury associated with pulmonary inflammation to two new models other than endotoxemia--phorbol myristate acetate (PMA) and zymosan activated plasma (ZAP) infusions. We propose to address our specific goals and hypotheses through the use of new techniques which allow us to more accurately measure changes in lung mechanics, pulmonary hemodynamics and lung fluid and solute exchange (including retrograde airway catheters and epithelial permeability, improved analytic methods and quantitative morphometrics). We will continue to try to elucidate important mechanisms responsible for the pathologic changes associated with endotoxemia, PMA, ZAP and altered airway responsiveness through assays of potential mediators, the use of specific blocking agents, granulocyte and platelet depletion and infusions and by studying the effects of infused potential mediators.