Abstract
BackgroundObstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues. Chronic intermittent hypoxia (IH) is considered to be the primary player in OSA, but the mechanisms underlying its effect on pulmonary tissues are unknown. Endoplasmic reticulum (ER) stress induced by IH treatment plays an important role in accelerating the process of fibrosis and induction of apoptosis.MethodsMice were placed in IH chambers for 4 weeks with an oscillating oxygen (O2) concentration between 5 and 21%, cycling every 90s for 8 h daily. Mice were randomly divided into four groups: control group (normal oxygen), tauroursodeoxycholic acid (TUDCA) group (normal oxygen intraperitoneally injected with TUDCA), IH group and IH + TUDCA group. After 4 weeks, the proteins in three branch signaling pathways of ER stress, including protein kinase RNA (PKR)-like/Pancreatic ER kinase (PERK), activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1), were evaluated. The cleaved caspase-3, caspase-12 and TUNNEL staining was assessed. Furthermore, the expression of transforming growth factor-β1 (TGF-β1) and thrombospondin-1(TSP-1), two extracellular matrix proteins that play critical role in fibrosis, were examined. Finally, Masson’s trichrome staining was performed to detect the expression of collagen.ResultsAfter 4 weeks of IH treatment, the expressions of two ER stress markers, glucose regulated protein-78 (Grp78) and transcription factor C/EBP homologous protein (CHOP) were increased which was prevented by administration of the ER stress attenuator, TUDCA. The expressions of PERK, but not those of ATF-6 and IRE-1, were increased. The effects of IH were accompanied by an increased number of apoptotic cells and increased expressions of cleaved caspase-3 and caspase-12 in pulmonary tissues. In addition, histological examination suggested the presence of fibrosis after chronic IH treatment, indicated by increased expression of collagen, which was associated with the up-regulation of TGF-β1 and TSP-1 that are known to promote fibrosis. Similarly, TUDCA could reduce the extent of fibrotic area and the expression levels of these proteins.ConclusionsIt reveals the roles of ER stress, especially the PERK pathway, in IH induced apoptosis and fibrosis in pulmonary tissues that might underlie the pulmonary complications observed in OSA.
Highlights
Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues
Shi et al BMC Pulmonary Medicine (2020) 20:92 (Continued from previous page). It reveals the roles of endoplasmic reticulum (ER) stress, especially the Pancreatic ER kinase (PERK) pathway, in intermittent hypoxia (IH) induced apoptosis and fibrosis in pulmonary tissues that might underlie the pulmonary complications observed in OSA
Chronic IH induces ER stress in pulmonary tissue To test whether ER stress could be triggered in pulmonary tissue by chronic IH, mice were subject to 4 weeks of IH exposure, which consisted of daily 8 h of fluctuating O2 level between 21 and 5% in every 90s in the ambient environment
Summary
Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues. Several previous reports have indicated that the morphology and function of the lung are altered in OSA patients and IH animal models, including reductions in lung volumes and induction of pulmonary hypertension [1,2,3]. These symptoms were associated with pulmonary fibrosis and endothelial apoptosis [4,5,6]. These three pathways activate pro-apoptotic via the induction of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) [14, 15]
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