MECHANISMS OF AIRWAY RESPONSES TO ENDOTOXEMIA

在最初的提议中，我们能够描述 内毒素血症对未麻醉绵羊肺力学的影响 成人呼吸窘迫综合征（ARDS）。 我们定义了两种可能 相互关联的机制，可能负责，至少部分， 观察到以下肺力学变化 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 内毒素血症急性增加肺对气雾剂组胺的反应性 而粒细胞耗竭降低肺对气雾剂的反应性， 组胺 这些结果产生了一个新的假设， 竞争性更新 我们假设肺部炎症介导了 与两种相关临床症状相关的肺力学改变 问题--如在哮喘中观察到的ARDS和气道反应性改变。 在这个建议中，我们扩展了我们的肺损伤模型， 肺部炎症与内毒素血症以外的两种新模型--佛波醇 肉豆蔻酸乙酸酯（PMA）和酵母聚糖活化血浆（ZAP）输注。 我们 建议通过使用新的方法来解决我们的具体目标和假设， 这些技术可以让我们更准确地测量肺部的变化， 力学、肺血流动力学和肺液体和溶质交换 （包括逆行气道导管和上皮渗透性， 改进的分析方法和定量形态测量学）。 我们将 继续努力阐明造成这一现象的重要机制， 与内毒素血症、PMA、ZAP和气道改变相关的病理变化 通过检测潜在的介质，使用特定的 阻断剂、粒细胞和血小板耗竭和输注， 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.