Department of Medicine, National Jewish Health, Denver, Colorado;
Department of Cell and Developmental Biology, University of Colorado, Aurora, Colorado.
Am J Physiol Lung Cell Mol Physiol. 2014 Jul 1;307(1):L94-105. doi: 10.1152/ajplung.00233.2013. Epub 2014 Apr 18.
There are 190,600 cases of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) each year in the United States, and the incidence and mortality of ALI/ARDS increase dramatically with age. Patients with ALI/ARDS have alveolar epithelial injury, which may be worsened by high-pressure mechanical ventilation. Alveolar type II (ATII) cells are the progenitor cells for the alveolar epithelium and are required to reestablish the alveolar epithelium during the recovery process from ALI/ARDS. Lung fibroblasts (FBs) migrate and proliferate early after lung injury and likely are an important source of growth factors for epithelial repair. However, how lung FBs affect epithelial wound healing in the human adult lung has not been investigated in detail. Hepatocyte growth factor (HGF) is known to be released mainly from FBs and to stimulate both migration and proliferation of primary rat ATII cells. HGF is also increased in lung tissue, bronchoalveolar lavage fluid, and serum in patients with ALI/ARDS. Therefore, we hypothesized that HGF secreted by FBs would enhance wound closure in alveolar epithelial cells (AECs). Wound closure was measured using a scratch wound-healing assay in primary human AEC monolayers and in a coculture system with FBs. We found that wound closure was accelerated by FBs mainly through HGF/c-Met signaling. HGF also restored impaired wound healing in AECs from the elderly subjects and after exposure to cyclic stretch. We conclude that HGF is the critical factor released from FBs to close wounds in human AEC monolayers and suggest that HGF is a potential strategy for hastening alveolar repair in patients with ALI/ARDS.
美国每年有 190600 例急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS），ALI/ARDS 的发病率和死亡率随年龄增长而显著增加。ALI/ARDS 患者存在肺泡上皮损伤，高压机械通气可能使其恶化。肺泡 II 型（ATII）细胞是肺泡上皮的祖细胞，在 ALI/ARDS 恢复过程中需要重建肺泡上皮。肺成纤维细胞（FB）在肺损伤后早期迁移和增殖，可能是上皮修复的重要生长因子来源。然而，肺成纤维细胞如何影响成人肺部的上皮伤口愈合尚未得到详细研究。已知肝细胞生长因子（HGF）主要由 FB 释放，并刺激原代大鼠 ATII 细胞的迁移和增殖。HGF 也在 ALI/ARDS 患者的肺组织、支气管肺泡灌洗液和血清中增加。因此，我们假设 FB 分泌的 HGF 会增强肺泡上皮细胞（AEC）的伤口闭合。使用划痕愈合测定法在原代人 AEC 单层和与 FB 的共培养系统中测量伤口闭合。我们发现，FB 主要通过 HGF/c-Met 信号加速伤口闭合。HGF 还恢复了老年患者和暴露于周期性拉伸后的 AEC 受损的伤口愈合。我们得出结论，HGF 是 FB 释放的关键因子，可促进人 AEC 单层的伤口闭合，并表明 HGF 是加速 ALI/ARDS 患者肺泡修复的潜在策略。
