Rationale:Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema and poor gas exchange resulting from severe inflammatory lung injury. Neutrophilic infiltration and increased pulmonary vascular permeability are hallmarks of early ARDS and precipitate a self-perpetuating cascade of inflammatory signaling. The biochemical processes initiating these events remain unclear. Typically associated with extracellular matrix degradation, recent data suggests MMP's are regulators of pulmonary inflammation. Objectives:To demonstrate that inhalation of a broad MMP inhibitor attenuates LPS induced pulmonary inflammation. Methods:Nebulized CGS27023AM was administered to LPS injured mice. Pulmonary CGS27023A levels were examined by mass spectroscopy. Inflammatory scoring of H&E sections, examination of vascular integrity via lung wet:dry and BAL:serum FITC-albumin ratios were performed. Cleaved caspase 3 levels were also assessed. Differential cell counts and pulse-chase labeling were utilized to determine the effects of CGS27023AM on neutrophil migration. The effects of CGS27023AM on human neutrophil migration and viability were examined using Boyden chambers and MTT assays. Measurements and Main Results:Nebulization successfully delivered CGS27023AM to the lungs. Treatment decreased pulmonary inflammatory scores, edema and apoptosis in LPS treated animals. Neutrophil chemotaxis was reduced by CGS27023AM treatment, with inhalation causing significant reductions in both the total number as well as newly produced BrdU positive cells infiltrating the lung. Mechanistic studies on cells isolated from humans demonstrate that CGS treated neutrophils exhibit decreased chemotaxis. Conclusions:MMP's mediate the development of pulmonary edema and neutrophil infiltration. Inhaled MMP inhibitors are a potential new therapeutic avenue for treating of acute lung injury.

中文翻译：

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内毒素肺损伤模型中吸入 MMP 抑制剂减轻肺损伤

基本原理：急性呼吸窘迫综合征 (ARDS) 的特征是肺水肿和严重的炎症性肺损伤导致的气体交换不良。中性粒细胞浸润和肺血管通透性增加是早期 ARDS 的标志，并会引发炎症信号的自我延续级联反应。引发这些事件的生化过程仍不清楚。通常与细胞外基质降解有关，最近的数据表明 MMP 是肺部炎症的调节剂。目的：证明吸入广泛的 MMP 抑制剂可减轻 LPS 诱导的肺部炎症。方法：将雾化的 CGS27023AM 给予 LPS 损伤的小鼠。通过质谱检查肺CGS27023A水平。H&E 切片的炎症评分，通过肺湿：干和 BAL：血清 FITC-白蛋白比率检查血管完整性。还评估了裂解的半胱天冬酶 3 水平。利用差异细胞计数和脉冲追踪标记来确定 CGS27023AM 对中性粒细胞迁移的影响。CGS27023AM 对人类嗜中性粒细胞迁移和活力的影响使用博伊登室和 MTT 测定进行了检查。测量和主要结果：雾化成功地将 CGS27023AM 输送到肺部。治疗降低了 LPS 治疗动物的肺部炎症评分、水肿和细胞凋亡。CGS27023AM 治疗降低了嗜中性粒细胞的趋化性，吸入导致总数量和新产生的 BrdU 阳性细胞浸润肺的显着减少。对从人类分离的细胞进行的机制研究表明，CGS 处理的中性粒细胞表现出降低的趋化性。结论：MMP介导肺水肿和中性粒细胞浸润的发展。吸入 MMP 抑制剂是治疗急性肺损伤的潜在新治疗途径。