Albert Karolin, Krischer Jeanne-Marie, Pfaffenroth Alexander, Wilde Sabrina, Lopez-Rodriguez Elena, Braun Armin, Smith Bradford J, Knudsen Lars
Institute of Functional and Applied Anatomy, Hannover Medical School, Hanover, Germany.
Fraunhofer Institute for Toxicology and Experimental Medicine, Hanover, Germany.
Front Physiol. 2020 Sep 18;11:530485. doi: 10.3389/fphys.2020.530485. eCollection 2020.
Mechanical ventilation of lungs suffering from microatelectases may trigger the development of acute lung injury (ALI). Direct lung injury by bleomycin results in surfactant dysfunction and microatelectases at day 1 while tissue elastance and oxygenation remain normal. Computational simulations of alveolar micromechanics 1-day post-bleomycin predict persisting microatelectases throughout the respiratory cycle and increased alveolar strain during low positive end-expiratory pressure (PEEP) ventilation. As such, we hypothesize that mechanical ventilation in presence of microatelectases, which occur at low but not at higher PEEP, aggravates and unmasks ALI in the bleomycin injury model. Rats were randomized and challenged with bleomycin (B) or not (H = healthy). One day after bleomycin instillation the animals were ventilated for 3 h with PEEP 1 (PEEP1) or 5 cmHO (PEEP5) and a tidal volume of 10 ml/kg bodyweight. Tissue elastance was repetitively measured after a recruitment maneuver to investigate the degree of distal airspace instability. The right lung was subjected to bronchoalveolar lavage (BAL), the left lung was fixed for design-based stereology at light- and electron microscopic level. Prior to mechanical ventilation, lung tissue elastance did not differ. During mechanical ventilation tissue elastance increased in bleomycin-injured lungs ventilated with PEEP = 1 cmHO but remained stable in all other groups. Measurements at the conclusion of ventilation showed the largest time-dependent increase in tissue elastance after recruitment in B/PEEP1, indicating increased instability of distal airspaces. These lung mechanical findings correlated with BAL measurements including elevated BAL neutrophilic granulocytes as well as BAL protein and albumin in B/PEEP1. Moreover, the increased septal wall thickness and volume of peri-bronchiolar-vascular connective tissue in B/PEEP1 suggested aggravation of interstitial edema by ventilation in presence of microatelectases. At the electron microscopic level, the largest surface area of injured alveolar epithelial was observed in bleomycin-challenged lungs after PEEP = 1 cmHO ventilation. After bleomycin treatment cellular markers of endoplasmic reticulum stress (p-Perk and p-EIF-2α) were positive within the septal wall and ventilation with PEEP = 1 cmHO ventilation increased the surface area stained positively for p-EIF-2α. In conclusion, hidden microatelectases are linked with an increased pulmonary vulnerability for mechanical ventilation characterized by an aggravation of epithelial injury.
患有微小肺不张的肺进行机械通气可能会引发急性肺损伤（ALI）的发展。博来霉素所致的直接肺损伤在第1天会导致表面活性剂功能障碍和微小肺不张，而组织弹性和氧合仍保持正常。博来霉素注射后1天的肺泡微观力学计算模拟预测，在整个呼吸周期中微小肺不张持续存在，并且在低呼气末正压（PEEP）通气期间肺泡应变增加。因此，我们假设在存在微小肺不张（在低PEEP时出现，而在高PEEP时不出现）的情况下进行机械通气会加重并暴露博来霉素损伤模型中的ALI。将大鼠随机分组，用博来霉素（B）进行攻击或不进行攻击（H = 健康组）。在博来霉素滴注后1天，动物用PEEP 1（PEEP1）或5 cmH₂O（PEEP5）以及10 ml/kg体重的潮气量通气3小时。在进行肺复张操作后重复测量组织弹性，以研究远端气腔不稳定的程度。对右肺进行支气管肺泡灌洗（BAL），将左肺固定用于光镜和电镜水平的基于设计的体视学研究。在机械通气之前，肺组织弹性没有差异。在机械通气期间，用PEEP = 1 cmH₂O通气的博来霉素损伤肺组织弹性增加，但在所有其他组中保持稳定。通气结束时的测量结果显示，在B/PEEP1组中肺复张后组织弹性随时间的增加最大，表明远端气腔的不稳定性增加。这些肺力学结果与BAL测量结果相关，包括B/PEEP1组中BAL中性粒细胞以及BAL蛋白和白蛋白升高。此外，B/PEEP1组中增厚的间隔壁和支气管周围血管结缔组织体积增加表明，在存在微小肺不张的情况下通气会加重间质性水肿。在电镜水平，在PEEP = 1 cmH₂O通气后，在博来霉素攻击的肺中观察到受损肺泡上皮的最大表面积。在博来霉素治疗后，间隔壁内内质网应激的细胞标志物（p-Perk和p-EIF-2α）呈阳性，并且用PEEP = 1 cmH₂O通气增加了p-EIF-2α阳性染色的表面积。总之，隐匿的微小肺不张与机械通气时肺易损性增加有关，其特征是上皮损伤加重。
