Dry eye disease (DED) or keratoconjunctivitis sicca is a common multifactorial disease characterized by ocular surface discomfort, redness, light sensitivity, and variable visual disturbances accompanied by ocular surface inflammation and hyperosmolarity of tears.1 Moderate to severe DED is accompanied by corneal pain, which may cause a decline in the quality of life and work,2,3 and even depression and other psychological problems due to long-term illness.4–6 The disease has become a serious social and public health problem.7–9 Recently, ocular surface inflammation,10 oxidative stress injury,11 and extracellular DNA damage12 have become the most prevalent research topics in the pathology of DED. In general, chronic inflammation of the ocular surface is a widely recognized key factor in the pathogenesis of DED and the difficulty in treatment.13
Medical therapy is currently the primary treatment for DED, but the use of eye drops is still insufficient to alleviate DED.14 Several limitations of the current treatment should be considered. First, the supplement of artificial tears and anti-inflammatory eye drops cannot completely replace the normal components of tears.15 Second, because of various economic levels, educational levels, and degrees of treatment compliance, many patients are unable to adhere to the treatment program for a long time.5 Third, for moderate and severe DED, the use of artificial tears and anti-inflammatory treatment can only partially relieve the symptoms but not cure the disease.16 Fourth, the long-term abuse of over-the-counter eye drops with preservatives will not only fail to achieve therapeutic effects but may also aggravate the syndrome and its symptoms.17 Therefore, it is crucial to explore a new treatment strategy for DED.
Aerobic exercise (AE) has been used as an effective complement of systemic disease therapy in recent years. Recent studies have mainly focused on the changes that exercise causes on intraocular pressure, ocular blood flow, and the physiological parameters of the anterior chamber, but no study on AE and human ocular surface has been conducted.18,19 Previous animal studies have suggested that a 5-day per week AE for 8 weeks can increase tear secretion of type-2 diabetic mice.20 However, the documentation on the effect of exercise on both healthy subjects and DED patients is still sparse.21 To investigate the effect of AE on the adults who mainly work at office, we performed the current study.
This study was performed in compliance with the requirements of the Declaration of Helsinki, and the protocol was approved by the Ethical Review Committee of the Zhongshan Ophthalmic Center. Written informed consent was obtained from the participants before they were enrolled.
The inclusion criteria were as follows: 18 to 40 years of age; 15% to 85% body mass index, and no history of eye diseases, such as DED, ocular trauma, and so on. The exclusion criteria include: breakup time <5 s; ocular surface staining with fluorescein was positive according to the Tear Film & Ocular Surface Society Dry Eye Workshop II22; spherical equivalent between −6.0 and +6.0 D, use of eye drops within a month, previous history of ocular surgeries, use of contact lenses, pregnant or lactating women, and electrocardiogram abnormalities or other serious systemic diseases. The participants underwent detailed eye examination procedures to exclude eye diseases or contact lens use history before enrollment.
This study was composed of 2 sections. The first part aimed to study correlation effects of AE on tear secretion. The second section enrolled 13 healthy subjects in total to explore the effect of AE on production of inflammatory cytokines. A single subject will participate in only 1 section.
AE was processed with a 30-minute running on a treadmill in a room. The room temperature was controlled at 22°C, and the humidity was controlled at 60% by central air conditioning. The exercise protocol was set at 30-minute moderate running, with a speed of 6 kph for females and 7 kph for males, according to previous studies.23,24 The maximum heart rate was defined as 220 minus the age, and the heart rate (HR) standard was set at 60% to 80% of the maximum heart rate.25,26 Fitbit charge 2 (Fitbit, San Francisco, CA), a wrist-worn HR monitor that had been manually corrected, was used to track the HR continuously throughout the running progress.27
Axial Length Measurement
Axial length (AL) was measured by IOL Master (Version 5.0, Carl Zeiss Meditech Ltd, Jena, Germany). After the instrument was calibrated, the patients were instructed to fix their eyes on the forward red spot. AL was accurately measured 5 times (with the difference between the maximum and the minimum values being <0.03 mm), and the average value was taken as the subject's AL.
Swept-Source Optical Coherence Tomography Imaging
Swept-source optical coherence tomography (SS-OCT) (Casia SS-1000, Tomey, Nagoya, Japan) was used with customized vertical Raster V scans before and 0, 10, and 20 minutes after the exercise. This customized scan mode was used to obtain a total of 256 cross-sectional images of the anterior segment within a 12 × 12-mm area. Each optical coherence tomography (OCT) scan was taken within 30 seconds in a dark room with light intensity of 0.16 lux. Lower tear menisci (LTM) was visualized as vertical through the scan mode. The acquisition time for a single scan was 2.6 s. The image consisted of 256 × 256 scans. The subjects were asked to look at the green dot sign located in infinity at a fixation light with no background illumination and allowed to blink spontaneously during the examination. All patients were asked to keep their eyes closed when examinations were paused so as to avoid eye irritation and tearing.
LTM Parameters Measurement
Graders were masked until the measurement of LTM parameters was finished. Images with the following issues were excluded: images with unclear boundary of tear meniscus thus preventing an image analysis, and the images taken when the participants yawned autonomously. All the above images were removed to ensure the accuracy of the data and to avoid possible bias.
Area of lower tear meniscus (LTMA) and volume of lower tear meniscus (LTMV) were measured manually, as described in previous studies.28–30 The central slice of OCT images, which is located on the 128th of 256 slices, was chosen for measurement. Each LTM parameter was measured twice independently by 2 graders, and the average of the first and second measurement was used in statistical analysis for each grader. The average of 2 graders’ results was taken as the result. We performed an intraobserver and interobserver test to check the consistency between the measurements of the 2 graders. LTMA was measured with the original OCT scans at the center of the pupil, magnified by 300% (Fig. 1). The outlines of the LTM at the central cornea, which consisted of the corneal surface, the lid margin, and the tear meniscus surface, were plotted manually by using calipers. The area within the plotted lines, the LTMA, was calculated automatically by the program, and the resulting tear menisci area value was divided by the refractive index of the balanced salt solution (1.343) to correct the refraction at the air–meniscus interface. LTMV was measured by using the central 63 images of 3-mm width. The LTMA of each image was identified as mentioned above, and the LTMA of the 63 consecutive images was integrated automatically by the program to calculate the LTMV. Again, the calculated value was corrected by dividing it by 1.343. LTMA and LTMV were outlined manually and calculated by the built-in software of SS-OCT. Each LTM parameter was measured twice by the same observer, and the mean value of these 2 measurements was taken as the final value. Because the presence of eyelashes rendered it difficult to visualize the entire upper tear menisci adequately, the upper tear menisci volume could not be evaluated.
Tear Sample Collection and Cytokines Concentration Analysis
Thirteen subjects participated in this section. Subjects who underwent tear collection did not receive OCT scans to avoid influence on LTM parameters caused by tear collection. A total of 10 μL tear samples were collected separately from the inferior tear meniscus of each eye of subjects using 0.5 μL capillary micropipette (Drummond, Broomall, PA) at baseline and 0, 20, and 60 minutes after AE, respectively. All samples were stored at −80°C. Tear samples were diluted to 50 μL before analysis and 25-μL samples were enough to analyze inflammatory cytokines.31 Cytokine concentrations were analyzed using a commercial multiplex bead immunoassay kit (Milliplex Human Cytokine kit; Millipore Corp., Billerica, MA). The assays were performed according to the manufacturer's instructions and analyzed by Bio-Plex suspension array system (Bio-Plex200; Bio-Rad, Hercules, CA). A set of 15 inflammatory cytokines including interferon-γ, tumor necrosis factor-α, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12P70, IL-13, IL-15, IL-17A, IL-21, IL-27, and CCL20/MIP3a were analyzed simultaneously in the same 96-microwell plate.
The data were presented as the mean ± SD. The Shapiro-Wilk test was used for the normality of variables. Comparison between LTM parameters at baseline and after AE was analyzed by a paired student t test using generalized estimating equation model by Stata software (V.14, StataCorp, College Station, TX). The paired t test was used to analyze the changes of inflammatory cytokines in tear fluid before and after exercise. The statistical significance was accepted at P < 0.05.
Demographic Characteristics of Healthy Participants
The first part of the study was designed to investigate the effect of AE on tear secretion. In total, 60 eyes of 30 healthy participants were included in this part. In this step, LTMA and LTMV were respectively measured with SS-OCT before the AE and 0, 10, and 20 minutes after 30-minute moderate running on a treadmill. The subjects had a mean age of 23.3 ± 3.6 years, a mean spherical equivalent of −2.85 ± 1.93 D, and a mean AL of 24.8 ± 1.2 mm (as shown in Table 1).
LTMA and LTMV changes after AE
This step included 60 eyes in the analysis of LTMA and 59 eyes in the analysis of LTMV. One eye was excluded from the analysis of LTMV because the LTM image was obscured by eyelashes. LTMA and LTMV showed significant increases 10 minutes after the AE (Data were presented in Table 2). The LTMA values at baseline, 0, 10, and 20 minutes after the AE were 0.019 ± 0.008 mm2, 0.020 ± 0.009 mm2, 0.024 ± 0.017 mm2, and 0.021 ± 0.010 mm2, respectively. An increase of 0.005 mm2 was found between the baseline and at 10 minutes (P = 0.008). However, the LTMA at the other time points showed no statistical significant difference (P > 0.05). The LTMV values at the corresponding time points were 0.0247 ± 0.0081 mm3, 0.0273 ± 0.0129 mm3, 0.0289 ± 0.0117 mm3, and 0.0276 ± 0.0148 mm3, respectively. The statistical analysis showed that the LTMV increased by 0.0042 mm3 (P = 0.002) after 10 minutes of exercise, whereas no statistical significant difference was observed at the other time points (P > 0.05) (Fig. 2).
Change of Inflammatory Cytokines Before and After AE
Thirteen healthy volunteers were recruited in this second section. Demographic characters of these volunteers were shown in Table 3. Concentration of inflammatory cytokines at different time points were shown in Supplemental Table S1, https://links.lww.com/APJO/A58. Inflammatory cytokines decreased immediately after exercise, reaching minimal concentration within 20 minutes, and then returned to baseline levels after about 60 minutes. Among them, interferon-γ (P = 0.003), tumor necrosis factor-α (P < 0.001), IL-1β (P = 0.007), IL-4 (P < 0.001), IL-5 (P = 0.006), IL-6 (P = 0.001), IL-10 (P = 0.002), IL-12P70 (P = 0.012), IL-13 (P = 0.006), IL-15 (P = 0.004), IL-17A (P = 0.001), IL-21 (P = 0.007), and IL-27 (P = 0.005) were significantly lower at 20 minutes after AE than that of baseline (P < 0.01). CCL/MIP-3α persisted to decrease after exercise, and statistically significant difference (P = 0.031) was found compared with 60 minutes after AE with baseline. However, there was no significant difference of IL-2 between baseline and any time point after exercise (P > 0.05) (Fig. 3, Supplemental Table S2, https://links.lww.com/APJO/A59).
AE on tear secretion and inflammatory cytokines have not been investigated so far and the present study makes up for the gaps in ocular surface health research. This study finds out that a 30-minute running indoor can promote tear secretion and decrease inflammatory cytokines, which indicates that AE indoor could be a complementary treatment for DED apart from medication and lacrimal surgeries.
It is widely known that AE can result in reduced risks of systemic diseases. Additionally, previous studies have demonstrated that AE has positive effects on various eye diseases, such as myopia,32,33 proliferative diabetic retinopathy,34 glaucoma,35 and age-related macular degeneration.36 However, few studies have considered the influence of AE on DED.37,38 The present study focuses on the relationship between AE and healthy subjects’ tear secretion and inflammatory cytokines change, in the hope of providing a new therapy for DED.
Current study improves the methodology of using SS-OCT to measure LTM. A previous study calculated LTMV only using 11 B-scans of LTM, and the interval between B-scans was too wide to assure accurate measurements of LTMV.28 Through observation and analysis of the tear menisci in normal subjects, our study finds that it is feasible to measure LTMV in the central 3-mm area, which is stable and takes the largest portion of the tear volume.
Previous studies have used SS-OCT to measure tear menisci.30,39 Tear meniscus volume, especially LTMV, is known to constitute 75% to 90% of the aqueous tear volume and to decrease as DED progresses.40 This present study's results show increased tear secretion after AE, which is consistent with previous research findings.20,41 Based on the current study's results, it is suggested that 30-minute daily running may be appropriate for the treatment of DED. A previous study has shown that tear secretion is mainly regulated by the sympathetic and parasympathetic autonomic nervous system,42 and exercise could stimulate this system to promote tear secretion. Some researchers believe that epithelial sodium channels, which mediate the first step of active Na+ reabsorption, play a major role in the maintenance of electrolytes and water homeostasis,43 and exist in all vertebrates, may contribute to tear secretion.44,45 However, the exact mechanism remains unclear, and further research is required to elucidate the mechanism.
This study's major outcome is the increase in LTMA and LTMV due to AE. We suggest a significant increase in LTMV and LTMA after AE. A dynamic change in tear secretion is found after AE, which gradually increases after the exercise, reaching its peak at 10 minutes and then gradually decreasing. Tear capacity is directly related to the severity of DED, which had been difficult to visualize until SS-OCT appeared. Through the analysis of LTMV and LTMA, this study finds that LTMV may be a more accurate assessment method for tear menisci, followed by LTMA. This study's measurement method is more reasonable than those of previous studies,30,39 and it could accurately assess the amount of tear fluid of patients through a customized LTMV measurement method.
Chronic inflammation of the ocular surface is critically important in dry eye treatment.10,46 Conventional medications, especially over-the-counter drugs, can only temporarily control inflammation, but the preservatives may lead to further damage to the cornea in long-term applications, increasing the difficulty of dry eye treatment.8,17 Our present study found after AE, concentration of inflammatory cytokines decreased, which might be due to regulatory effect of AE on ocular surface microenvironment or increased secretion of tears. Further research is needed to clarify the exact reason for decrease in cytokine concentration.
This study also has some limitations. First, the current study had a relatively small sample size to draw any definitive conclusions. Second, the follow-up time is too short to observe the long-term relationship between AE and tear secretion. Third, this study is on indoor AE, which the environmental conditions can be well controlled through central air conditioning. In the future, the relationship between outdoor AE and human tear secretion and inflammatory factors can be studied to clarify the real effect of outdoor AE. At last, whether the lowering of inflammatory cytokines concentration after AE happens in DED patients is still unknown and needs further investigation.
This study demonstrates that indoor AE can increase the secretion of tears and reduce the expression of inflammatory cytokines in tears, suggesting that indoor AE may be a supplementary treatment of dry eyes. Long-term studies are still needed to focus on the impact of AE on healthy population and dry eye.
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