Mechanical Injury to Lung Endothelium

肺内皮机械损伤

• 批准号: 6631290
• 负责人: JAMES Courtney PARKER
• 金额: $ 25.75万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631290
• 关键词: calcium flux; gadolinium; laboratory rat; lung injury; mechanical stress; microcirculation; pulmonary artery; pulmonary circulation; pulmonary stretch receptors; respirators; tissue /cell culture; vascular endothelium

Ventilator-induced lung injury represents a significant increase clinical complication for which effective therapy is lacking. This form of lung injury was initially thought to result from frank alveolar-capillary rupture that caused permeability edema. However, we have recently shown that moderate ventilatory-induced lung injury is due to stretch activated cation charmers in endothelial cells, which promote gadolinium-sensitive calcium entry sufficient increases in endothelial cell cytosolic calcium produce macrovascular and not microvascular permeability. To date, putative molecular candidates encoding stretch activated cation channels have not been identified in mammalian cells. However, the Saccharomyces cerevisiae ,ID1 gene product was recently shown to encode a stretch activated cation channel when expressed in mammalian cells. Moreover, the channel encoded by MIDI exhibited biophysical properties resembling those of endogenous human umbilical vein endothelial cell stretch activated cation channels. Therefore, we Hypothesize that stretch activated cation channel-induced calcium entry, through a MID1-like channel, is sufficient to initiate the vascular permeability response to mechanical stress in pulmonary arterial and venous endothelial cells but not in microvascular endothelial cells. Specific Aims test the related Hypotheses that: [1] Stretch activated cation channels in pulmonary arterial and venous endothelial cells have electrophysiological properties similar to those of the MID1 gene product but have a greater cation conductance or mean open frequency that do stretch activated cation channels in pulmonary microvascular endothelium; [2} Pulmonary arterial and venous endothelial cell monolayers exhibit gadolinium sensitive pressure and strain-induced increases in permeability which are presented in microvascular endothelial cell monolayers exhibit gadolinium sensitive pressure and strain-induced increases in permeability which are prevented in microvascular endothelial cell monolayers by an increased intracellular cAMP; and [3] Strain-induced segmental filtration coefficients in extra- alveolar vessels have a greater sensitivity to wall stress, oxidant enhancement and gadolinium than do microvascular vessels in intact lungs. Completion of this work will be important to further our understanding of mechanisms that underlie ventilation-induced lung injury (e.g. barotrauma and volutrauma) important for ventilatory management in patients with inflammatory lung diseases.

呼吸机所致的肺损伤是一种临床并发症，目前缺乏有效的治疗方法。这种形式的肺损伤最初被认为是由于肺泡毛细血管破裂引起的渗透性水肿。然而，我们最近发现，中度通气诱导的肺损伤是由于牵张激活的阳离子电荷在内皮细胞，这促进钆敏感的钙进入足够的增加内皮细胞胞浆钙产生大血管，而不是微血管通透性。迄今为止，尚未在哺乳动物细胞中鉴定出编码牵张激活阳离子通道的推定候选分子。然而，酿酒酵母，ID1基因产物最近被证明在哺乳动物细胞中表达时编码拉伸激活的阳离子通道。此外，通道编码的ESTA表现出类似的内源性人脐静脉内皮细胞拉伸激活的阳离子通道的生物物理特性。因此，我们假设牵张激活的阳离子通道诱导的钙离子通过MID1样通道进入肺动脉和静脉内皮细胞，但不是在微血管内皮细胞，足以启动血管通透性反应的机械应力。具体目的：验证以下相关假设：[1]肺动脉和静脉内皮细胞牵张激活的阳离子通道具有与MID1基因产物相似的电生理特性，但具有比MID1基因产物更大的阳离子电导或平均开放频率，对肺微血管内皮细胞牵张激活的阳离子通道有牵张作用;[2]肺动脉和静脉内皮细胞单层表现出钆敏感的压力和应变-在微血管内皮细胞单层中存在的诱导的渗透性增加表现出钆敏感的压力和应变，诱导的渗透性增加，这在微血管内皮细胞单层中被增加的细胞内cAMP阻止;和[3]与完整肺中的微血管相比，肺泡外血管中的应变诱导的节段性滤过系数对壁应力、氧化剂增强和钆具有更大的敏感性。这项工作的完成将是重要的，以进一步我们了解的机制，通气诱导的肺损伤（如气压伤和volutraulus）的重要性，炎症性肺病患者的辅助治疗。