Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
Department of Critical Care Medicine, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China.
Am J Physiol Lung Cell Mol Physiol. 2018 May 1;314(5):L808-L821. doi: 10.1152/ajplung.00510.2017. Epub 2018 Jan 25.
Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO) mice, and CD44 gene-deficient (CD44) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44 resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO mice. Isolated perfused lungs of HCl instilled WT but not of CD44 mice had elevated values of the filtration coefficient ( K). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( R). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of K and R as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.
在麻醉过程中，酸（HCl）吸入可能导致急性肺损伤。目前尚无有效的治疗方法。我们假设，在 C57BL/6 小鼠的气管内滴注 HCl 会导致低分子量透明质酸（L-HA）的形成，从而激活 RhoA 和 Rho 激酶（ROCK），导致气道高反应性（AHR）和通透性增加。此外，高分子量透明质酸（H-HA；Yabro）的滴注将逆转肺损伤。我们在 C57BL/6 野生型（WT）、髓过氧化物酶基因缺失（MPO）小鼠和 CD44 基因缺失（CD44）小鼠中滴注 HCl。WT 小鼠还在 HCl 滴注后 1 和 23 小时接受 H-HA（Yabro）的鼻腔内滴注。所有测量均在 HCl 滴注后 1、5 或 24 小时进行。在 WT 中而不是在 CD44 中滴注 HCl 会导致炎症增加、AHR、肺损伤和 BALF 中的 L-HA 在 HCl 滴注后 24 小时增加；在 HCl 滴注的 MPO 小鼠中，L-HA 水平和肺损伤明显降低。HCl 滴注的 WT 而非 CD44 小鼠的离体灌注肺具有较高的滤过系数（K）值。在人原代支气管上皮细胞单层的顶表面添加 L-HA 会降低屏障阻力（R）。HCl 滴注后 24 小时，H-HA 显著减轻炎症、AHR 和肺血管渗漏，并减轻 K 和 R 以及 ROCK2 磷酸化的增加。在机械通气患者的 BALF 中发现了增加的 H-和 L-HA 水平，但在健康志愿者中未发现。HCl 诱导的肺损伤是由 L-HA-CD44-RhoA-ROCK2 信号通路介导的，H-HA 是一种治疗酸吸入性肺损伤的潜在新型治疗药物。
