Table 2.
Studies assessing the association between rhinologic diseases and ER stress.
| Associated Diseases | Study Design | Species and/or Tissue Type | Detection Method | Target Gene(s) or Pathway(s) Associated with ER Stress | Results/Conclusions | |
|---|---|---|---|---|---|---|
| Sidra M Hoffman, et al. [62] | AR (induced by HDM) | In vitro cells study | Cultured primary human nasal epithelial cells | Western blotting, luminescence assay | p-IRE, GRP94, BiP, ERp57, ATF6, CHOP, caspase-3 | Seventy-two hours after exposure to HDM, cell derived from subjects exhibited increases in p-IRE as well as increases in the ER chaperone BiP, GRP94, and ERp57. Expression of the ER stress transducer ATF6α and downstream transcriptional effector CHOP was also increased after HDM exposure. Allergen exposure significantly activated caspase-3 to varying degrees in primary human nasal epithelial cells. |
| Kim YM, et al. [63] | CRSwNP | In vivo (case-control) and in vitro cell line study | Human nasal epithelial cell line | Immunohistochemical staining, Western blotting | BiP, p-eIF2α, IRE1α | SEB-positive cells were more frequent, and production of ROS was greater in the epithelial layer of EPs than in NEPs or control tissue. SEB was strongly detected in tissues from patients with CRSwNP. Induction of BiP and p47phox was significantly increased in EPs compared with NEPs or control mucosa. In RPMI 2650 cells, SEB-induced BiP was reduced by pretreatment with a ROS scavenger. |
| Lee HM, et al. [64] | CRS | In vitro study | Human (NP, IT)/A549 cell lines, PNECs | RT-PCR, immunofluorescence, Western blotting | XBP-1, BiP | TGF-β1 increased the expression of EMT markers (E-cadherin, fibronectin, vimentin, and α-SMA) and ER stress markers (XBP-1s and BiP), an effect that was blocked by 4-PBA or PP2 treatment. 4-PBA and PP2 also blocked the effect of TGF-β1 on migration of A549 cells and suppressed TGF-β1–induced expression of EMT markers in PNECs and organ cultures of the inferior turbinate. |
| Ding W, et al. [65] | OSA (CIH) | Animal model study (case-control) |
Rat | RT-PCR, Western blotting | BiP, CHOP, p-IRE1, XBP-1, pro-ATF6, PERK, eIF2α, caspase-3, caspase-9, caspase-12 | Addition of Ad increased LVF in CIH model rats (CIH + Ad group) compared with the CIH-only group. The percentage of apoptotic cells and levels of cleaved caspase-3, -9, and -12 was significantly higher in the CIH-only group compared with normal control and CIH + Ad groups. Protein Expression of cleaved caspase-3, caspase-9, and caspase-12 proteins validated TUNEL results. |
| Zhou X, et al. [66] | OSA (CIH) | Animal model study (case-control) |
Rat | Western blotting | Bax, caspase-3, cleaved caspase-12, ATF6, IRE1, BiP, CHOP | Significantly lower levels of oxidative stress, apoptosis, and ER stress were detected in the CIH + PAG group compared with the CIH-only group. |
| Bourdier G, et al. [67] | OSA (CIH) | Animal model study (case-control) |
Rat | Western blotting | p-eIF2α, eIF2α, ATF4, cleaved caspase-3, ATF6, p-PERK, PERK, CHOP, BiP | CIH induced cardiac proapoptotic ER stress, characterized by increased expression of BiP, p-PERK, ATF4, and CHOP. CIH-induced myocardial apoptosis was confirmed by increased expression of cleaved caspase-3. These CIH-associated proapoptotic alterations were associated with a significant increase in infarcts. HIT prevented both CIH-induced proapoptotic ER stress and increased myocardial infarct size. |
| Belaidi E, et al. [68] | OSA (CIH) | Animal model study (case-control) |
Mice | RT-PCR, Western blotting | BiP, p-eIF2α, eIF2α, p-PERK, PERK, ATF4, CHOP, cleaved caspase-3, ATF6, HIF-1α | CIH induced an increase in ER-Ca2+ content, ER stress markers and HIF-1α activity in mice, accompanied by an enhanced infarct size. CIH failed to increase infarct size in HIF-1α–deficient mice. TUDCA totally abolished the IH-induced increase in HIF-1α activity and infarct size. |
| Hou Y, et al. [69] | OSA (CIH) | Animal model study (case-control) |
Mice | ELISA, Western blotting | Cleaved caspase-3, cleaved caspase-9, BiP, PERK, ATF6, IRE1, CHOP, cleaved caspase-12, eIF2α, JNK | TUDCA inhibited CIH-induced ER stress in the liver, as evidenced by decreased expression of BiP, unfolded protein response transducers, and ER proapoptotic proteins. |
| Cai XH, et al. [70] | OSA (CIH) | Animal model study (case-control) |
Rat | qPCR, Western blotting | BiP, ATF4, ATF6, XBP-1, CHOP | Apoptosis was increased and phosphorylation of PERK and IRE1 was upregulated in CIH groups. Sal prevented activation of CHOP throughout hypoxia/reoxygenation exposure. |
| Perrini S, et al. [71] | OSA (CIH) | Case-control study | Human | RT-PCR | ATF4, CHOP, ERO-1 | Adipose tissue mRNA levels of ER stress markers (ATF4, CHOP, ERO-1) were decreased only in the therapeutic CPAP group compared with non-OSA and subtherapeutic CPAP groups. |
ER, endoplasmic reticulum; AR, allergic rhinitis; HDM, house dust mite; p-IRE, phosphorylation of inositol-requiring enzyme; GRP, glucose-regulated protein; BiP, immunoglobulin heavy chain-binding protein; ERp, endoplasmic reticulum protein; ATF, activating transcription factor; CHOP, C/EBP-homologous protein; CRSwNP, chronic rhinosinusitis with nasal polyp; p-eIFα, phospho-eukaryotic initiation factor-α; SEB, S. aureus enterotoxin B; ROS, reactive oxygen species; EP, eosinophilic polyp; NEP, non-eosinophilic polyp; p47phox, neutrophil cytosol factor 1 (NCF1); NP, nasal polyp; IT, inferior turbinate of the nose; PNEC, primary nasal epithelial cells; RT-PCR, reverse transcription-polymerase chain reaction; XBP1, X-box-binding protein 1; TGF, tumor growth factor; EMT, epithelial-mesenchymal transition; α-SMA, alpha-smooth muscle actin; 4-PBA, 4-phenylbutylic acid; PP2, Src and RIP2 kinase inhibitor; OSA, obstructive sleep apnea; CIH, chronic intermittent hypoxia; PERK, endoplasmic reticulum kinase; Ad, adiponectin; LVF, left ventricular function; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; Bax, BCL2-associated X; PAG, DL-propargylglycine; HIT, high intensity training; HIF-1α, hypoxia inducible factor-1α; TUDCA, tauroursodeoxycholic acid; ELISA, enzyme-linked immunosorbent assay; JNK, c-Jun N-terminal kinase; qPCR, quantitative polymerase chain reaction; Sal, salubrinal; ERO-1, endoplasmic reticulum oxidoreductin-1; CPAP, continuous positive airway pressure.