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A proposed model of the Hifα/Pparα signaling axis induced by OSA (A) and a flow-chart of changes in lacrimal gland function (B). Chronic intermittent hypoxia induces an increase in Hifα expression in lacrimal gland cells. Hifα then translocates into the nucleus, combines with Hifβ, and activates downstream genes. Hif can inhibit Pparα, which leads to an increased intracellular lipid production via the regulation of Fas and a decrease in fatty acid oxidation via the regulation of Cpt1a. Upregulation of Cd36 promotes the uptake of lipid in lacrimal gland. In addition, Hifα can activate the NF-κB signaling pathway, directly or indirectly through Pparα. Activation of the NF-κB signaling pathway, intracellular lipid deposition, and inflammatory cell infiltration contribute to inflammation in the lacrimal gland microenvironment. Lipid accumulation and inflammation could induce ROS production. Inflammation, lipid deposition, ROS, increased lacrimal gland apoptosis, mitochondrial dysfunction, and impaired myoepithelial structure ultimately lead to decreased aqueous tear production.
Source publication
Purpose:
To determine the effect of obstructive sleep apnea syndrome (OSA) on lacrimal gland function and its mechanism.
Methods:
Male mice aged seven to eight weeks were housed in cages with cyclic intermittent hypoxia to mimic OSA, and the control group was kept in a normal environment. Slit-lamp observation, fluorescein staining, and corneal...
Citations
... Consistent with our findings, PPARα is also downregulated in experimental mouse models of LG inflammation induced by high-fat diets [84] or obstructive sleep apnea [85] that lead to lipid accumulation and dry eye symptoms. The latter can be alleviated by fenofibrate [84,85], an FDA-approved PPARα activator. ...
... Consistent with our findings, PPARα is also downregulated in experimental mouse models of LG inflammation induced by high-fat diets [84] or obstructive sleep apnea [85] that lead to lipid accumulation and dry eye symptoms. The latter can be alleviated by fenofibrate [84,85], an FDA-approved PPARα activator. Fenofibrate is a hypolipidemic drug that is used to treat the symptoms of high cholesterol and triglycerides in human. ...
Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren’s syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren’s syndrome models: diseased NOD.H2b compared to healthy BALBc mice and Thrombospondin-1-null (TSP-1-/-) compared to TSP-1WT C57BL/6J mice. Inflammasome activation was investigated by immunostaining using the R26ASC-citrine reporter mouse, by Western blotting, and by RNAseq. LPS/Nigericin, IL-1α and chronic inflammation induced inflammasomes in lacrimal gland epithelial cells. Acute and chronic inflammation of the lacrimal gland upregulated multiple inflammasome sensors, caspases 1/4, and interleukins Il1b and Il18. We also found increased IL-1β maturation in Sjögren’s syndrome models compared with healthy control lacrimal glands. Using RNA-seq data of regenerating lacrimal glands, we found that lipogenic genes were upregulated during the resolution of inflammation following acute injury. In chronically inflamed NOD.H2blacrimal glands, an altered lipid metabolism was associated with disease progression: genes for cholesterol metabolism were upregulated, while genes involved in mitochondrial metabolism and fatty acid synthesis were downregulated, including peroxisome proliferator-activated receptor alpha (PPARα)/sterol regulatory element-binding 1 (SREBP-1)-dependent signaling. We conclude that epithelial cells can promote immune responses by forming inflammasomes, and that sustained inflammasome activation, together with an altered lipid metabolism, are key players of Sjögren’s syndrome-like pathogenesis in the NOD.H2b mouse lacrimal gland by promoting epithelial dysfunction and inflammation.
... (A) Schematic of the OSA induction protocol. (B) Oxygen concentration was monitored in real time over 90-s cycles(27). ...
Animal experiments play an important role in the study of the pathogenesis of human diseases and new methods of diagnosis and treatment. Due to the great differences in the anatomical structure and physiology of the upper airway between animals and humans, there is currently no animal model that can fully simulate the pathological anatomy and pathophysiological characteristics of human obstructive sleep apnea (OSA) patients. Herein, we summarizes the construction methods of several OSA animal models that have been widely used in the studies published in the last 5 years, the advantages and limitations of each model as well as related evaluation techniques are described. This information has potential to provide further guide for the development of OSA related animal experiments.
... Interestingly, the incidence of multiple anti-glaucomatous medications, laser treatment and glaucoma-related surgeries was numerically lower in the OSA group than that in the non-OSA group. We speculate that the OSA itself is correlated to several ocular disorders such as floppy eyelid syndrome, dry eye disease, diabetic retinopathy and hypertensive retinopathy, which lead to ocular irritation or impaired vision [5,32,33]. Consequently, these patients may come to ophthalmic OPD for medical assistance and only the underlying early glaucoma may be found; thus, only simple management is warranted for them. ...
We try to evaluate glaucoma management numbers in patients with both glaucoma and obstructive sleep apnea (OSA) using the National Health Insurance Research Database (NHIRD) of Taiwan. A retrospective cohort study was conducted and patients with glaucoma were enrolled and divided into the OSA and non-OSA populations. A total of 11,778 participants were selected in both the OSA and non-OSA groups. The primary outcomes were the number of anti-glaucomatous medications each year and the total number of glaucoma laser and glaucoma surgeries. The Cox proportional hazard regression was utilized to produce the adjusted hazard ratios (AHR) with corresponding 95% confidence intervals (CI) between the two groups. After a study period of 18 years, 286 and 352 events of laser and surgeries for glaucoma were found in the OSA and non-OSA groups, respectively. After considering the effect of potential confounders, no significant difference concerning the numbers of laser trabeculoplasty, trabeculectomy and tube shunt surgery, cyclodestructive procedure and eyeball removal were found between the two groups (all 95% CIs included one). In addition, the multiple anti-glaucomatous medication usages were similar between the two groups (all p > 0.05) In the subgroup analyses, glaucoma patients older than 60 years and with OSA received significantly lesser trabeculectomy and tube shunt surgery compared to glaucoma patients older than 60 years without OSA (AHR: 0.774, 95% CI: 0.611–0.981) while other analyses revealed insignificant results (all 95% CIs included one). In conclusion, the presence of OSA does not increase the need for glaucoma management.
... Phantom sensations in tinnitus are similar to those in ocular neuropathic pain. Second, sleep disturbance due to the fact of tinnitus may have caused dry eye, because sleep disorders are an important risk factor for dry eye [48][49][50]. Sleep apnea accompanied with laryngopharyngeal reflux also may affect to dry eye [43,51]. Sleep disorders are associated with both tinnitus and dry eye [48][49][50]52,53]. ...
... Sleep apnea accompanied with laryngopharyngeal reflux also may affect to dry eye [43,51]. Sleep disorders are associated with both tinnitus and dry eye [48][49][50]52,53]. Third, tinnitus can lead to high levels of stress, anxiety, and depression [54,55], and medication for these psychological problems may cause dry eye [56]. ...
This study aimed to evaluate the association between dry eye and inner ear diseases in a Korean population.
Methods:
Data from the Korean National Health and Nutrition Survey (KNHANES V, 2010-2012), a national cross-sectional health examination and survey, were collected by the Korea Centers for Disease Control and Prevention. The association between dry eye and inner ear disease was determined using the chi-square test and logistic regression analysis. The individuals were divided into two age groups (<60 and ≥60 years).
Results:
In total, 17,542 individuals (n = 11,932 in the <60 years group and n = 5610 in the ≥60 years group) were enrolled. After adjusting for confounding factors, the logistic regression model revealed that the associated factors were dizziness and loss of balance experience (OR, 1.315; 95% CI, 1.143-1.513), self-awareness of abnormal voice (OR, 1.372; 95% CI, 1.120-1.679), subjective hearing discomfort (OR, 1.278; CI, 1.084-1.506), and tinnitus (OR, 1.265; 95% CI, 1.101-1.453). The inversely associated factor for dry eye was bilateral hearing loss (OR, 0.497; 95% CI, 0.367-0.672). The hearing threshold was lower in the dry eye group than in the non-dry eye group (p < 0.05).
Conclusions:
Tinnitus was associated with dry eye and bilateral hearing loss was inversely associated with dry eye. These results suggest that hypersensitivity of the senses and nerves, which is neuropathic hyperesthesia, is one of the main mechanisms of dry eye. Treatment of neuropathy may help in treating dry eye associated with dizziness or tinnitus.
