Reticulocalbin 3 Deficiency in Alveolar Epithelium Exacerbated Bleomycin-induced Pulmonary Fibrosis
Reticulocalbin 3 Deficiency in Alveolar Epithelium Exacerbated Bleomycin-induced Pulmonary Fibrosis
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肺泡上皮 Reticulocalbin 3 缺乏加剧博来霉素诱导的肺纤维化
DOI：
10.1165/rcmb.2017-0347oc
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发表时间：
2018-09-01
影响因子：
6.4
通讯作者：
Ma, Runlin Z.
中科院分区：
文献类型：
--
作者：
Jin, Jiawei;Shi, Xiaoqian;Ma, Runlin Z.
网状钙结合蛋白3(Rcn3)是一种定位于分泌途径的内质网(ER)管腔蛋白。我们已经报道，Rcn3在围生期肺发育过程中对肺泡上皮II型细胞的成熟起关键作用，但它在成人肺中的生物学作用尚不清楚。在本研究中，我们发现在博莱霉素诱导的肺纤维化过程中，肺泡上皮细胞中Rcn3的表达显著增加，在肺泡上皮细胞(AECII S)中最为明显。为了进一步研究Rcn3在肺损伤重塑中的作用，我们培育了转基因小鼠，在成年后选择性地删除AECIIs中的Rcn3。虽然Rcn3缺失没有引起肺结构和力学的明显异常，但Rcn3缺失的小鼠暴露在博莱霉素中会导致肺纤维化加剧和肺力学降低。这些Rcn3缺失的小鼠在博莱霉素处理后也表现出肺泡上皮细胞(AEC)凋亡和内质网应激，这一点在原代AECII和小鼠肺上皮细胞中的体外研究中都得到了证实。同样，Rcn3缺乏也加强了内质网应激和由内质网应激诱导剂、衣霉素和thapsigargin诱导的细胞凋亡。此外，Rcn3缺乏可钝化血管内皮细胞的闭合能力，但不改变其增殖和博莱霉素诱导的上皮-间充质转化过程。总之，这些发现表明博莱霉素诱导的AECII细胞中Rcn3的上调似乎有助于AECII细胞的存活和伤口愈合。这些观察首次提示了Rcn3在调节肺损伤重塑中的新作用，并进一步阐明了特发性肺纤维化的机制。
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.