Haine Liasmine, Bravais Juliette, Yegen Céline-Hivda, Bernaudin Jean-Francois, Marchant Dominique, Planès Carole, Voituron Nicolas, Boncoeur Emilie
UMR INSERM U1272 Hypoxie & Poumon, Université Sorbonne Paris Nord, 93017 Bobigny, France.
Faculté de Médecine, Sorbonne Université, 75012 Paris, France.
Life (Basel). 2021 Sep 15;11(9):973. doi: 10.3390/life11090973.
High prevalence of obstructive sleep apnea (OSA) is reported in incident and prevalent forms of idiopathic pulmonary fibrosis (IPF). We previously reported that Intermittent Hypoxia (IH), the major pathogenic element of OSA, worsens experimental lung fibrosis. Our objective was to investigate the molecular mechanisms involved.
Impact of IH was evaluated on C57BL/6J mice developing lung fibrosis after intratracheal instillation of Bleomycin (BLM). Mice were Pre-exposed 14 days to IH before induction of lung fibrosis or Co-challenged with IH and BLM for 14 days. Weight loss and survival were daily monitored. After experimentations, lungs were sampled for histology, and protein and RNA were extracted.
Co-challenge or Pre-exposure of IH and BLM induced weight loss, increased tissue injury and collagen deposition, and pro-fibrotic markers. Major worsening effects of IH exposure on lung fibrosis were observed when mice were Pre-exposed to IH before developing lung fibrosis with a strong increase in sXBP1 and ATF6N ER stress markers.
Our results showed that IH exacerbates BLM-induced lung fibrosis more markedly when IH precedes lung fibrosis induction, and that this is associated with an enhancement of ER stress markers.
据报道，在特发性肺纤维化（IPF）的发病和流行形式中，阻塞性睡眠呼吸暂停（OSA）的患病率很高。我们之前报道过，OSA的主要致病因素间歇性缺氧（IH）会加重实验性肺纤维化。我们的目的是研究其中涉及的分子机制。
评估IH对经气管内注入博来霉素（BLM）后发生肺纤维化的C57BL/6J小鼠的影响。在诱导肺纤维化前，将小鼠预先暴露于IH环境14天，或者将小鼠同时暴露于IH和BLM环境14天。每天监测体重减轻情况和存活率。实验结束后，采集肺组织进行组织学检查，并提取蛋白质和RNA。
IH与BLM同时暴露或预先暴露于IH环境，均会导致体重减轻、组织损伤增加、胶原蛋白沉积增加以及促纤维化标志物增多。当小鼠在发生肺纤维化之前预先暴露于IH环境时，观察到IH暴露对肺纤维化有更明显的恶化作用，同时内质网应激标志物sXBP1和ATF6N显著增加。
我们的结果表明，当IH在肺纤维化诱导之前出现时，IH会更明显地加重BLM诱导的肺纤维化，并且这与内质网应激标志物的增强有关。
