Tetenev Konstantin, Cloutier Mary E, von Reyn Jessica A, Ather Jennifer L, Candon James, Allen Gilman B
Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont; Siberian State Medical University, Tomsk, Russia; and.
Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont;
Am J Physiol Lung Cell Mol Physiol. 2015 Nov 15;309(10):L1103-11. doi: 10.1152/ajplung.00197.2014. Epub 2015 Sep 25.
Aspiration is a common cause of lung injury, but it is unclear why some cases are self-limited while others progress to acute respiratory distress syndrome (ARDS). Sporadic exposure to more than one insult could account for this variable progression. We investigated whether synergy between airway acid and endotoxin (LPS) amplifies injury severity in mice and whether LPS levels in human patients could corroborate our experimental findings. C57BL/6 mice aspirated acid (pH 1.3) or normal saline (NS), followed by LPS aerosol or nothing. Bronchoalveolar lavage fluid (BALF) was obtained 2 to 49 h later. Mice were injected with FITC-dextran 25 h after aspiration and connected to a ventilator, and lung elastance (H) measured periodically following deep inflation (DI). Endotracheal and gastric aspirates were also collected from patients in the intensive care unit and assayed for pH and LPS. Lung instability (ΔH following DI) and pressure-volume hysteresis in acid- or LPS-exposed mice was greater than in controls but markedly greater in the combined acid/LPS group. BALF neutrophils, cytokines, protein, and FITC-dextran in the acid/LPS mice were geometrically higher than all other groups. BALF from acid-only mice markedly amplified LPS-induced TNF-α production in cultured macrophages. Human subjects had variable endotracheal LPS levels with the highest burden in those at higher risk of aspiration. Acid aspiration amplifies LPS signaling in mice to disrupt barrier function and lung mechanics in synergy. High variation in airway LPS and greater airway LPS burden in patients at higher risk of aspiration could help explain the sporadic progression of aspiration to ARDS.
误吸是肺损伤的常见原因，但尚不清楚为何有些病例是自限性的，而另一些则会进展为急性呼吸窘迫综合征（ARDS）。偶尔暴露于不止一种损伤因素可能解释了这种不同的进展情况。我们研究了气道酸与内毒素（LPS）之间的协同作用是否会加重小鼠的损伤严重程度，以及人类患者的LPS水平是否能证实我们的实验结果。C57BL/6小鼠吸入酸（pH 1.3）或生理盐水（NS），随后吸入LPS气雾剂或不吸入任何东西。2至49小时后获取支气管肺泡灌洗液（BALF）。小鼠在误吸后25小时注射异硫氰酸荧光素标记的葡聚糖，并连接到呼吸机上，在深度充气（DI）后定期测量肺弹性（H）。还从重症监护病房的患者中收集气管内和胃吸出物，检测其pH值和LPS。酸或LPS暴露小鼠的肺不稳定性（DI后的ΔH）和压力-容积滞后大于对照组，但酸/LPS联合组明显更大。酸/LPS小鼠的BALF中性粒细胞、细胞因子、蛋白质和异硫氰酸荧光素标记的葡聚糖在几何上高于所有其他组。仅酸处理小鼠的BALF显著增强了培养巨噬细胞中LPS诱导的TNF-α产生。人类受试者的气管内LPS水平各不相同，误吸风险较高者的负担最重。酸误吸会增强小鼠体内的LPS信号传导，协同破坏屏障功能和肺力学。气道LPS的高度变化以及误吸风险较高患者的气道LPS负担加重，可能有助于解释误吸向ARDS的散发性进展。
