Puthusseri Bijesh, Bhagavath Ashoka Kumar, Korir Daniel, Shetty Rashmi, Johnson Gretchen A, Stankowska Dorota L, Konduru Nagarjun V, Tang Hua, Bolla Sudhir, Criner Gerald J, Marchetti Nathaniel, Das Durgesh Nandini, Shetty Sreerama
The University of Texas Health Science Center at Tyler, Tyler, Texas, United States.
University of North Texas Health Science Center, Fort Worth, Texas, United States.
Am J Respir Cell Mol Biol. 2024 Sep 13;72(1):97-108. doi: 10.1165/rcmb.2023-0453OC.
Impaired alveolar epithelial regeneration in patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) is attributed to telomere dysfunction in type II alveolar epithelial cells (ACs). Genetic susceptibility, aging, and toxicant exposures, including tobacco smoke (TS), contribute to telomere dysfunction in ACs. Here we investigated whether improvement of telomere function plays a role in CSP7-mediated protection of ACs against ongoing senescence and apoptosis during bleomycin (BLM)-induced pulmonary fibrosis (PF) as well as alveolar injury caused by chronic TS exposure. We found a significant telomere shortening in ACs isolated from IPF and COPD lungs in line with other studies. These cells showed increased in addition to its post-translational modification with induction of activated and , suggesting a -mediated loss of AC renewal. Further, we found increased expression of , a -inducible E3 ubiquitin ligase known to down-regulate telomere repeats binding factor 2 (). Consistent with the loss of and upregulation of , telomerase reverse transcriptase () was downregulated in ACs. ACs from fibrotic lungs of mice either repeatedly instilled with BLM or isolated from chronic TS exposure-induced lung injury model showed reduced telomere length along with induction of , , and as well as loss of and , which were reversed in wild-type mice after treatment with CSP7. Interestingly, mice, or those lacking microRNA-34a expression in ACs, resisted telomere dysfunction, while mice failed to respond to CSP7 treatment, suggesting feed-forward induction and pathway contributes to telomere dysfunction.
特发性肺纤维化（IPF）和慢性阻塞性肺疾病（COPD）患者的肺泡上皮再生受损归因于II型肺泡上皮细胞（ACs）中的端粒功能障碍。遗传易感性、衰老以及包括烟草烟雾（TS）在内的有毒物质暴露均会导致ACs中的端粒功能障碍。在此，我们研究了端粒功能的改善是否在CSP7介导的对博来霉素（BLM）诱导的肺纤维化（PF）过程中ACs持续衰老和凋亡以及慢性TS暴露引起的肺泡损伤的保护作用中发挥作用。我们发现，与其他研究一致，从IPF和COPD肺中分离出的ACs存在明显的端粒缩短。这些细胞除了其翻译后修饰增加并诱导活化的 和 外，还显示出 增加，提示 介导的AC更新丧失。此外，我们发现 表达增加， 是一种已知可下调端粒重复结合因子2（ ）的 诱导型E3泛素连接酶。与 的丧失和 的上调一致，端粒酶逆转录酶（ ）在ACs中下调。反复注入BLM的小鼠纤维化肺中的ACs或从慢性TS暴露诱导的肺损伤模型中分离出的ACs显示端粒长度缩短，同时诱导 、 、 和 以及丧失 和 ，在用CSP7治疗后野生型小鼠中这些情况得到逆转。有趣的是， 小鼠或ACs中缺乏微小RNA - 34a表达的小鼠抵抗端粒功能障碍，而 小鼠对CSP7治疗无反应，提示 前馈诱导和 途径导致端粒功能障碍。
