Qian Xiaoli, Jiang Ye, Jia Jianwei, Shen Weimin, Ding Yuejia, He Yuhan, Xu Peifeng, Pan Qing, Xu Ying, Ge Huiqing
Department of Respiratory Care, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Qingchun East Rd. 3, Hangzhou, 310016, China.
College of Information Engineering, Zhejiang University of Technology, Liuhe Rd. 288, Hangzhou, 310023, China.
Respir Res. 2023 Feb 13;24(1):46. doi: 10.1186/s12931-023-02356-y.
Positive end-expiratory airway pressure (PEEP) is a potent component of management for patients receiving mechanical ventilation (MV). However, PEEP may cause the development of diaphragm remodeling, making it difficult for patients to be weaned from MV. The current study aimed to explore the role of PEEP in VIDD.
Eighteen adult male New Zealand rabbits were divided into three groups at random: nonventilated animals (the CON group), animals with volume-assist/control mode without/ with PEEP 8 cmHO (the MV group/ the MV + PEEP group) for 48 h with mechanical ventilation. Ventilator parameters and diaphragm were collected during the experiment for further analysis.
There was no difference among the three groups in arterial blood gas and the diaphragmatic excursion during the experiment. The tidal volume, respiratory rate and minute ventilation were similar in MV + PEEP group and MV group. Airway peak pressure in MV + PEEP group was significantly higher than that in MV group (p < 0.001), and mechanical power was significantly higher (p < 0.001). RNA-seq showed that genes associated with fibrosis were enriched in the MV + PEEP group. This results were further confirmed on mRNA expression. As shown by Masson's trichrome staining, there was more collagen fiber in the MV + PEEP group than that in the MV group (p = 0.001). Sirius red staining showed more positive staining of total collagen fibers and type I/III fibers in the MV + PEEP group (p = 0.001; p = 0.001). The western blot results also showed upregulation of collagen types 1A1, III, 6A1 and 6A2 in the MV + PEEP group compared to the MV group (p < 0.001, all). Moreover, the positive immunofluorescence of COL III in the MV + PEEP group was more intense (p = 0.003). Furthermore, the expression of TGF-β1, one of the most potent fibrogenic factors, was upregulated at both the mRNA and protein levels in the MV + PEEP group (mRNA: p = 0.03; protein: p = 0.04).
We demonstrated that PEEP application for 48 h in mechanically ventilated rabbits will cause collagen deposition and fibrosis in the diaphragm. Moreover, activation of the TGF-β1 signaling pathway and myofibroblast differentiation may be the potential mechanism of this diaphragmatic fibrosis. These findings might provide novel therapeutic targets for PEEP application-induced diaphragm dysfunction.
呼气末正压通气（PEEP）是接受机械通气（MV）患者管理的一个重要组成部分。然而，PEEP可能导致膈肌重塑，使患者难以脱机。本研究旨在探讨PEEP在呼吸机诱导的膈肌功能障碍（VIDD）中的作用。
将18只成年雄性新西兰兔随机分为三组：非通气动物（CON组）、采用容量辅助/控制模式且不使用/使用8 cmH₂O PEEP进行48小时机械通气的动物（MV组/MV + PEEP组）。实验过程中收集呼吸机参数和膈肌样本用于进一步分析。
实验期间，三组动物的动脉血气和膈肌 excursion 无差异。MV + PEEP组和MV组的潮气量、呼吸频率和分钟通气量相似。MV + PEEP组的气道峰压显著高于MV组（p < 0.001），机械功率也显著更高（p < 0.001）。RNA测序显示，MV + PEEP组中与纤维化相关的基因富集。这一结果在mRNA表达上得到进一步证实。Masson三色染色显示，MV + PEEP组的胶原纤维比MV组更多（p = 0.001）。天狼星红染色显示，MV + PEEP组的总胶原纤维和I/III型纤维阳性染色更多（p = 0.001；p = 0.001）。蛋白质印迹结果还显示，与MV组相比，MV + PEEP组中1A1、III、6A1和6A2型胶原上调（均p < 0.001）。此外，MV + PEEP组中COL III的阳性免疫荧光更强（p = 0.003）。此外，MV + PEEP组中最有效的纤维化因子之一TGF-β1的mRNA和蛋白水平均上调（mRNA：p = 0.03；蛋白：p = 0.04）。
我们证明，在机械通气兔中应用PEEP 48小时会导致膈肌胶原沉积和纤维化。此外，TGF-β1信号通路的激活和成肌纤维细胞分化可能是这种膈肌纤维化的潜在机制。这些发现可能为PEEP应用引起的膈肌功能障碍提供新的治疗靶点。
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