TUDCA alleviates the worsening effect of intermittent hypoxia on pulmonary fibrosis - 20/03/24

Obstructive Sleep Apnea syndrome (OSA) is frequently associated with idiopathic pulmonary fibrosis (IPF). Nocturnal Intermittent hypoxia (IH), the main pathogenic trait of OSA, has been shown to be a pejorative prognostic factor in IPF. Previous studies from our lab demonstrated that the severity of mouse pulmonary fibrosis induced by bleomycin (BLM) was more pronounced when mice were also exposed to IH, and that this effect was exacerbated when IH exposure preceded the onset of fibrosis. In the latter study, we have also shown that this effect was associated with an increase in ER stress markers ATF6 and XBP-1 1. Interestingly, the use of tauroursodeoxycholic acid (TUDCA), a chemical chaperone that reduces ER stress by facilitating proper protein folding and trafficking, suppresses IH-induced apoptosis and fibrosis in mouse pulmonary tissues 2. The aim of our study was to investigate the implication of IH-induced ER stress in the pro-fibrotic and overall worsening effect of HI on BLM-induced lung fibrosis and to decipher the specific targeted pathways involved in this effect.

C57BL/6 adult mice were exposed to IH (30 cycles/h; FiO₂ nadir: 7%; 8h/day) and treated or not with intranasal instillation of TUDCA 2.5mg/kg every 2 days. At day 14, half of the animals received intratracheal injection of low dose of BLM (2UI/g) to induce lung fibrosis. At day 28 after the beginning of the experiment, the animals were killed and the impact of TUDCA treatment on lung fibrosis was evaluated by weight loss, survival, respiratory function testing, lung histology and analysis of molecular pathways implicated in the fibrogenesis.

TUDCA significantly limits weight loss, improves survival, compliance, tailed volume and ventilatory flow rate of mice pre-exposed to IH and developing lung fibrosis. At the molecular level, TUDCA alleviates ER overload reducing ATF6 and XBP-1 functionnalization, as well as GRP78 accumulation. Interestingly, TUDCA also limits senescence-associated secreted proteins PAI-1, MMP-12, IL-8 and TGF-ß1. Intracellular expression of senescence markers (p21WAF1/p16Ink4/gamma-H₂AX are under investigation.

In this study, we demonstrate that the worsening effect of IH on BLM-induced lung fibrosis in mice could be partly due to induction of pro-fibrotic or pro-senescence markers related to ER-stress activation. Therapeutic strategies aimed to relieve ER stress in this context could represent a valuable approach to limit the worsening impact of OSA on lung fibrosis.