1 The Clinical Research Center, and.
4 Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Am J Respir Cell Mol Biol. 2018 Sep;59(3):320-333. doi: 10.1165/rcmb.2017-0347OC.
Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum (ER) lumen protein localized to the secretory pathway. We have reported that Rcn3 plays a critical role in alveolar epithelial type II cell maturation during perinatal lung development, but its biological role in the adult lung is largely unknown. In this study, we found marked induction of Rcn3 expression in alveolar epithelium during bleomycin-induced pulmonary fibrosis, which is most obvious in alveolar epithelial type II cells (AECIIs). To further examine Rcn3 in pulmonary injury remodeling, we generated transgenic mice to selectively delete Rcn3 in AECIIs in adulthood. Although Rcn3 deletion did not cause obvious abnormalities in the lung architecture and mechanics, the exposure of Rcn3-deleted mice to bleomycin led to exacerbated pulmonary fibrosis and reduced lung mechanics. These Rcn3-deleted mice also displayed enhanced alveolar epithelial cell (AEC) apoptosis and ER stress after bleomycin treatment, which was confirmed by in vitro studies both in primary AECIIs and mouse lung epithelial cells. Consistently, Rcn3 deficiency also enhanced ER stress and apoptosis induced by ER stress inducers, tunicamycin and thapsigargin. In addition, Rcn3 deficiency caused blunted wound closure capability of AECs, but not altered proliferation and bleomycin-induced epithelial-mesenchymal transition process. Collectively, these findings indicate that bleomycin-induced upregulation of Rcn3 in AECIIs appears to contribute to AECII survival and wound healing. These observations, for the first time, suggest a novel role of Rcn3 in regulating pulmonary injury remodeling, and shed additional light on the mechanism of idiopathic pulmonary fibrosis.
网钙蛋白 3（Rcn3）是一种内质网（ER）腔蛋白，定位于分泌途径。我们曾报道过，Rcn3 在围生期肺发育过程中肺泡上皮细胞 II 型（AECII）成熟过程中发挥关键作用，但在成人肺中其生物学作用在很大程度上仍是未知的。在这项研究中，我们发现在博来霉素诱导的肺纤维化过程中，Rcn3 在肺泡上皮中表达明显上调，在 AECII 中最为明显。为了进一步研究 Rcn3 在肺损伤重塑中的作用，我们生成了在成年期选择性删除 AECII 中 Rcn3 的转基因小鼠。尽管 Rcn3 缺失并未导致肺结构和力学的明显异常，但 Rcn3 缺失小鼠暴露于博来霉素中会导致更严重的肺纤维化和肺力学降低。这些 Rcn3 缺失小鼠在博来霉素处理后还显示出增强的肺泡上皮细胞（AEC）凋亡和内质网应激，这在原代 AECII 和小鼠肺上皮细胞的体外研究中得到了证实。一致地，Rcn3 缺失还增强了内质网应激诱导剂，衣霉素和他普西龙诱导的 ER 应激和凋亡。此外，Rcn3 缺失导致 AEC 的伤口闭合能力减弱，但对增殖和博来霉素诱导的上皮-间充质转化过程没有改变。总之，这些发现表明，博来霉素诱导的 AECII 中 Rcn3 的上调似乎有助于 AECII 的存活和伤口愈合。这些观察结果首次表明 Rcn3 在调节肺损伤重塑中具有新的作用，并为特发性肺纤维化的机制提供了更多的认识。
