Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury
Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury
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DOI：
10.3389/fphys.2020.00660
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发表时间：
2020-06-30
影响因子：
4
通讯作者：
Bates, Jason H. T.
中科院分区：
文献类型：
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作者：
Smith, Bradford J.;Roy, Gregory S.;Bates, Jason H. T.
机械通气是治疗急性呼吸窘迫综合征(ARDS)的重要救命手段。ARDS可通过肺泡力学改变、肺水肿、肺表面活性物质失活和肺损伤之间的正反馈作用而导致呼吸机相关性肺损伤(VILI)。尽管引起VILI的生物物理力已有很好的文献记载，但在实质结构改变(即肺泡萎缩和泛滥)、肺功能和VILI之间的定量联系上仍存在知识差距。这些信息对于制定诊断标准和呼吸策略以减少VILI和提高ARDS存活率至关重要。为了解决这一未得到满足的需求，我们对小鼠进行机械通风，以引起VILI。采用体视学方法测量3种充气压力下的肺结构，采用强迫振荡技术测量肺系统的机械功能。对肺表面活性物质的评估包括总表面活性物质、磷脂聚集体的分布和降低表面张力的活性。VILI诱导的表面活性变化包括大磷脂聚集体的典型功能部分的表面张力降低活性降低，以及表面不活跃的小磷脂聚集物池的显着增加。在低气道压时，肺结构的主要改变是肺泡塌陷和水淹。在较高的气道压力下，肺泡塌陷减轻，淹没的肺泡仍充满蛋白水肿性水肿。肺泡通气量减少，肺泡气体交换表面积减少。这些数据描述了小鼠VILI的三种肺泡表型：淹没的和不可招募的肺泡，不稳定的肺泡在气道压力低于5cmH(2)O时破裂，以及结构和功能相对正常的肺泡。在呼气末正压为0、3和6cmH(2)O时，肺泡各表型的比例变化反映在肺系统弹性的比例变化中。
Mechanical ventilation is an essential lifesaving therapy in acute respiratory distress syndrome (ARDS) that may cause ventilator-induced lung injury (VILI) through a positive feedback between altered alveolar mechanics, edema, surfactant inactivation, and injury. Although the biophysical forces that cause VILI are well documented, a knowledge gap remains in the quantitative link between altered parenchymal structure (namely alveolar derecruitment and flooding), pulmonary function, and VILI. This information is essential to developing diagnostic criteria and ventilation strategies to reduce VILI and improve ARDS survival. To address this unmet need, we mechanically ventilated mice to cause VILI. Lung structure was measured at three air inflation pressures using design-based stereology, and the mechanical function of the pulmonary system was measured with the forced oscillation technique. Assessment of the pulmonary surfactant included total surfactant, distribution of phospholipid aggregates, and surface tension lowering activity. VILI-induced changes in the surfactant included reduced surface tension lowering activity in the typically functional fraction of large phospholipid aggregates and a significant increase in the pool of surface-inactive small phospholipid aggregates. The dominant alterations in lung structure at low airway pressures were alveolar collapse and flooding. At higher airway pressures, alveolar collapse was mitigated and the flooded alveoli remained filled with proteinaceous edema. The loss of ventilated alveoli resulted in decreased alveolar gas volume and gas-exchange surface area. These data characterize three alveolar phenotypes in murine VILI: flooded and non-recruitable alveoli, unstable alveoli that derecruit at airway pressures below 5 cmH(2)O, and alveoli with relatively normal structure and function. The fraction of alveoli with each phenotype is reflected in the proportional changes in pulmonary system elastance at positive end expiratory pressures of 0, 3, and 6 cmH(2)O.