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Association of Meibum Oleic Acid with Meibomian Seborrhea
Abstract
We sought to determine whether patient meibum fatty acid unsaturation is associated with meibomian gland secretion consistency.
Meibomian gland secretions were dissolved in chloroform and separated into lipid classes by thin-layer chromatography. Fatty acids in individual lipid classes were characterized by gas chromatography after transmethylation.
Meibum from patients with meibomian seborrhea was higher, and meibum from patients with meibomian keratoconjunctivitis (meibomianitis) was lower in the monounsaturated fatty acid, oleic acid, than that of other disease groups and normal subjects.
Our results strongly suggest that the melting characteristics of meibum, influenced primarily by the amount of oleic acid in wax and sterol esters and free fatty acids, greatly influence the consistency of meibomian gland secretions.
... Shine et al. [298] used gas chromatography to show that unsaturated fatty acids comprise only a small percentage of the meibum in MGD, while in seborrheic MGD this percentage was higher. They report that the percentage of unsaturated fatty acids was related to the viscosity of the meibum. ...
... All the studies comparing the meibum of patients with MGD and healthy individuals were crosssectional in nature. Diagnostic methods for MGDs of interest varied among the studies that used the Japanese diagnostic criteria [23,297], Foulks and Bron diagnostic criteria [50,295,296,299,305], unique diagnostic criteria [298,[300][301][302][303][304], and unknown [306]. Serious inconsistencies were identified in participants' selection. ...
... Serious inconsistencies were identified in participants' selection. Various lipid analysis methods have been used including NMR spectroscopy [50,295,296], infrared spectroscopy [299], gas chromatography [298,300,301,304], liquid chromatography [23,297,302,303], Raman spectroscopy [305], and hot stage cross-polarized light microscopy with immunohistochemical approach [306]. These variations among the studies make it difficult to directly compare the obtained results. ...
... Tiffany determined that there is "no typical" meibum composition, meaning that there is a great variation among normal subjects, 32 but multiple investigators have found significant differences in the meibum obtained from normal subjects when compared to subjects with blepharitis and/or dry eye syndrome. 10,12,13,15,22,30,[33][34][35][36][37][38][39][40][41][42] These differences are thought to disrupt the lipid layer of the tear film leading to tear film evaporation. ...
... 38 Shine determined that fatty acid unsaturation is associated with meibomian gland secretion consistency. 39 Shine determined that the major unsaturated fatty acid in the meibum that is associated with wax esters, cholesterol esters, and free fatty acids was oleic acid (C 18 ), and determined that total unsaturated fatty acids of 18 carbons or shorter were best correlated with meibum associated with the meibomian keratoconjunctivitis and seborrheic with meibomian seborrhea disease groups. Shine's data indicateds that meibum from the meibomian keratoconjunctivitis group has low levels of oleic acid and is paste-like; however, meibum from the seborrheic with meibomian seborrhea group has high levels of oleic acid is liquid-like. ...
... Shine's data indicateds that meibum from the meibomian keratoconjunctivitis group has low levels of oleic acid and is paste-like; however, meibum from the seborrheic with meibomian seborrhea group has high levels of oleic acid is liquid-like. 39 Building out of this work, Dougherty compared free fatty acids in normal subjects and the six blepharitis groups. 12 Dougherty determined that the free fatty acids make up 0.2% to 1.3% (normal and abnormal subjects) of the total meibum, and that the fatty acids chains ranged between C 12 and C 29 with C 16:0 , C 18:0 , and C 18:1 making up the majority of the free fatty acid secretions. ...
... To determine what specific lipids are found in the meibomian secretions, the glands can be compressed, forcing the lipid to be excreted onto the lid margin, where it can be collected for analysis. [46][47][48] Subsequent analysis by various forms of chromatography has determined the lipid types and relative amounts (Table 1). 21,41,44,49,50 The meibum has been found to contain over 45 types of lipids. ...
... For example, subjects with obstructive meibomian gland dysfunction are seen to have decreased amounts of triglycerides 50 and monounsaturated fatty acids like oleic acid. 46 There are differences in the cause and consequences of blepharitis, meibomian gland obstruction, and androgen hormone deficiency. These differences are shown in ...
... The principal method used to collect lipid from the meibomian glands involves wiping the lid clean with a sterile swap, compressing the eyelid to gently squeeze out the lipids, and collecting the lipid. 166 The lid can be compressed between a lid conformer and a swab 44,46,47,166 or between the clinician's fingers (Figure 13), 21,48,55,70 with or without the use of an anaesthetic. The meibomian gland secretions can then be collected using a spatula 44,46,47,166 or a curette. ...
... 37,40,41 Tiffany determined that there is "no typical" meibum composition, meaning that there is a great variation among normal subjects, 42 but many investigators have found significant differences between the meibum obtained from normal subjects and that obtained from subjects with blepharitis and/or dry eye disease. [16][17][18]20,26,39,[43][44][45][46][47][48][49][50][51][52] These differences may disrupt the lipid layer of the tear film, leading to tear film evaporation. In 1961, Mishima and Maurice found that the meibomian glands produce the lipids that are responsible for maintaining tear film stability, while the other ocular glands do not have an effect on preventing tear film degradation (lacrimal, Harderian, goblet cells). ...
... Investigators have used the spatula procedure with 17,18,39,[46][47][48][49]65 and without 6,[19][20][21]28,32,45,[50][51][52][58][59][60][61][62][63][64],66 a drop of topical anesthetic (eg, lidocaine) applied to the ocular surface. Significant pressure is required to express the meibum, and the use of an anesthetic allows for better patient comfort and less reflex tearing; however, theoretically, anesthetic could alter the sample. ...
... Investigators have also attempted to clean the eyelid margins prior to sample collection. 17,39,[46][47][48][49][50][51][52]59 Each eyelid is then squeezed between two devices (eg, lid conformer and cotton swab, spatula and thumb, two cotton tip applicators), and the lipids are collected with a sterile spatula. The sample is then transferred to a storage container, dried, and frozen until the time of analysis. ...
The meibum is a lipid-rich secretion that is the primary component of the external layer of the tear film. The meibomian glands produce the meibum, and meibomian gland dysfunction can lead to degradation of the tear film. Such dysfunction can result in ocular irritation, inflammation, and clinical disease. Understanding this relationship is critical to preventing ocular disease; therefore, a search of peer-reviewed literature focusing on the collection, quantification, and analysis of normal and abnormal meibum and tear lipids was conducted. Numerous collection and quantification techniques are described, including their advantages and disadvantages. Studies indicate that the meibum and tear lipids consist of a large array of polar and nonpolar lipids; individual lipids or their classes can be correlated to pathology. Significant amounts of lipids are deposited on contact lenses, depending on the nature of their polymer chemistry. These findings taken together indicate that normal meibum and tear lipids are essential for normal ocular health. Additional studies are required to provide a better understanding of the meibum and tear film biomolecules so that more effective treatments for blepharitis, dry eye disease, and tear film-related contact lens complications can be devised.
... In a related publication, the same authors evaluated the content of oleic acid in human MGS [77]. It was re-confirmed that oleic acid was the major unsaturated FA of MGS detected in WE, CE, and TAG, and as a FFA. ...
... However, statistically significant decreases in the presence of DAG and FFA were reported, which allowed the authors to conclude that minocycline inhibited lipolytic activity of enzymes present on the ocular surface, possibly lipases excreted by the ocular microflora. Later on, the same authors estimated the TAG content of meibum to be ~6% with oleic acid being their major FA (up to 48%) [77]. From the structural and quantitative standpoints, meibomian DAG remain extremely poorly understood, and even their existence in normal meibum has not been reliably proven yet. ...
... : Meibomian FFA were discussed on numerous occasions as compounds that could possibly stabilize TFLL [7, 49, 58, 77, 94, 125, 126]. Nicolaides et al. [7]] estimated their content to be ~2% of whole meibum sample weight. ...
Human Meibomian gland secretions (MGS) are a complex mixture of diverse lipids that are produced by Meibomian glands that are located in the upper and the lower eyelids. During blinking, MGS are excreted onto the ocular surface, spread and mix with aqueous tears that are produced by lachrymal glands, and form an outermost part of an ocular structure called "the tear film" (TF). The main physiological role of TF is to protect delicate ocular structures (such as cornea and conjunctiva) from desiccating. Lipids that are produced by Meibomian glands are believed to "seal" the aqueous portion of TF by creating a hydrophobic barrier and, thus, retard evaporation of water from the ocular surface, which enhances the protective properties of TF. As lipids of MGS are interacting with underlying aqueous sublayer of TF, the chemical composition of MGS is critical for maintaining the overall stability of TF. There is a consensus that a small, but important part of Meibomian lipids, namely polar, or amphiphilic lipids, is of especial importance as it forms an intermediate layer between the aqueous layer of TF and its upper (and much thicker) lipid layer formed mostly of very nonpolar lipids, such as wax esters and cholesteryl esters. The purpose of this review is to summarize the current knowledge on the lipidomics of human MGS, including the discussions of the most effective modern analytical techniques, chemical composition of MGS, biophysical properties of Meibomian lipid films, and their relevance for the physiology of TF. Previously published results obtained in numerous laboratories, as well as novel data generated in the author's laboratory, are discussed. It is concluded that despite a substantial progress in the area of Meibomian glands lipidomics, there are large areas of uncertainty that need to be addressed in future experiments.
... The balanced composition of meibum is important for maintenance of the stability of the tear film [38,41]. The oleic acid content of meibum was shown to be higher in patients with meibomian seborrhea than in those with meibomianitis or in healthy individuals [41]. ...
... The balanced composition of meibum is important for maintenance of the stability of the tear film [38,41]. The oleic acid content of meibum was shown to be higher in patients with meibomian seborrhea than in those with meibomianitis or in healthy individuals [41]. Fatty acids in meibum of MGD patients were found to include a higher proportion of branched-chain fatty acids and a lower proportion of SFAs, especially of palmitic (C16) and stearic (C18) acids, compared with those in healthy meibum [38]. ...
Intervention studies have shown that n-3 polyunsaturated fatty acid (PUFA) supplementation is effective for the treatment of meibomian gland dysfunction (MGD). Ointment containing an analog of vitamin D has also been found to improve symptoms and signs of MGD. We have now evaluated the relation of MGD prevalence to dietary intake of fatty acids (FAs) and vitamin D among a Japanese population. Subjects comprised 300 adults aged 20 to 92 years residing on Takushima Island. MGD was diagnosed on the basis of subjective symptoms, lid margin abnormalities, and meibomian gland obstruction. Dietary FA and vitamin D intake was estimated with a brief-type self-administered diet history questionnaire. MGD prevalence was 35.3%. Multivariate adjusted odds ratios (95% confidence intervals) between extreme quintiles of intake for MGD prevalence were 0.40 (0.16–0.97) for total fat, 0.40 (0.17–0.97) for saturated FAs, 0.40 (0.17–0.97) for oleic acid, 0.52 (0.23–1.18) for n-3 PUFAs, 0.63 (0.27–1.49) for n-6 PUFAs, 1.32 (0.59–2.95) for the n-6/n-3 PUFA ratio, and 0.38 (0.17–0.87) for vitamin D. Total fat, saturated FA, oleic acid, and vitamin D intake may thus be negatively associated with MGD prevalence in the Japanese.
... Meibomian gland lipid can be obtained by squeezing the eyelid margin to express meibum, [164][165][166] by gently sucking meibum out of each glandular orifice 162 or collecting tear samples. 152,167 These samples are then dissolved in an organic solvent and separated into their various lipid classes. ...
... Analysis of lipid components has shown a considerable decrease in triglycerides and cholesterol, and monounsaturated fatty acids (specifically oleic acid), in patients with obstructive meibomian gland dysfunction, chronic blepharitis and viscous meibum. 165,169 These changes in the lipid composition may be associated with tear film instability. Polar lipids may define the structural organization of the overlying non-polar lipids and loss of these constituents are believed to result in decreased tear breakup time and increased aqueous tear evaporation. ...
... The authors reported that a common, moderately long FFA oleic acid (OA) (a C 18:1-FA) was a predominant monounsaturated fatty acid in the meibomian lipids in all study groups (Joffre et al., 2008). Interestingly, McCulley and Shine reported that the amount of FFA is increased in the meibomian lipids from patients with chronic blepharitis, probably due to the activity of bacterial hydrolases (Butovich et al., 2007;Shine and McCulley, 2000). ...
... Thus, it appears that the amounts of FFA in (aqueous) tears might be more important to the stability of the MLF and TFLL than their amounts in meibum itself, as it is very unlikely that meibum will ever contain enough FFA to cause self-solubilization. Shine and McCulley suggested that unsaturated fatty acids, especially those with a carbon chain length of ≤18 carbons, may be important in determining meibum consistency (Shine and McCulley, 2000). However, our in vitro experiments demonstrated that the presence of such FFA at concentration higher than 2.5 μM in the aqueous subphase might not be beneficial for the TFLL. ...
The purpose of this study was to evaluate the impact of free fatty acids (FFA), namely oleic (OA) and linoleic (LA) ones, on meibomian lipid films (MLF) using a Langmuir trough (LT) and a Brewster angle microscope (BAM). Human meibum was collected from healthy volunteers. A Tris-buffered saline (TBS, pH 7.4) was used as the control aqueous subphase for LT experiments. Then, varying amounts of OA and LA were dissolved in TBS to make FFA-containing subphases. Predetermined amounts of meibum were loaded onto the surface of the (TBS/±FFA) subphases to form MLF. Then, surface pressure-area (π/A) isotherms of MLF were recorded. Standard rheological parameters such as rigidity, elasticity, and hysteresis, were computed. In a separate experiment, OA and LA were pre-mixed with meibum at different weight ratios prior their spreading onto the control TBS subphase, and the (π/A) isotherms of the resulting mixed films of meibum and FFA were studied and analyzed in the same fashion as described above. When studied at the normal corneal temperature of 34 °C with the (TBS/-FFA) subphase, meibum formed stable films. When (TBS/+FFA) subphase was used, both FFA quickly disrupted the MLF, acting in a similar fashion. BAM revealed that the most dramatic changes in the structure of MLF occurred in the range of OA concentrations between 5 and 15 μM. However, this effect was apparent even with 2.5 μM OA. When OA was pre-mixed with meibum, but was absent from the subphase, it caused gradual concentration-dependent changes in the (π/A) isotherms, but the MLF did not disappear from the surface. Thus, tested FFA showed a remarkable ability to disrupt, and/or prevent the formation of, human MLF, which could contribute to the onset of those forms of dry eye disease that are associated with enhanced activity of lipolytic enzymes, such as chronic blepharitis.
... 105 Qualitative lipid changes may result in an increased viscosity of meibum, as observed in the decrease in monounsaturated fatty acid, specifically oleic acid, in patients with chronic blepharitis. 438 Since a decreased desaturation of lipid raises its melting point and hence leads to its thickening, 407 this phenomenon can reinforce an obstructive process and explains an elevated rate of obstruction in blepharitis. A loss of the polar lipids that are assumed to maintain the adherence of the superficial nonpolar lipid layer to the aqueous tear film 2,102,439 may contribute to an increase in tear film instability and evaporation in patients with MGD. ...
... 148 In patients with chronic blepharitis and seborrhea, qualitative changes in lipid composition were observed, including a higher amount of monounsaturated fatty acids that lead to a decreased melting point and hence explain the fluid appearance of oil on the lid margin in this condition. 438 Seborrheic blepharitis, similar to obstructive MGD, is also associated with increased bacterial growth and hence shares the presence of bacterial lipid-modifying enzymes and respective alterations of the lipid composition as well as the downstream effects of toxic mediators and negative influences on the tissue and conceivably on the tear film. 398 We can therefore link seborrhea with increased bacterial growth and subclinical inflammation in the pathogenesis of blepharitis. ...
National Natural Science Foundation of China (NSFC) [30872806, 30872809]; Ministry of Public Health of China; Ministry of Science and Technology of China [2006AA02A131]; Natural Science Foundation of Fujian Province [2009J06023]
... Decreased viscosity would ease the flow through the meibomian gland orifices and create a more uniform, thicker, and stable lipid layer. 38 In our study, normal and DE groups experienced similar diminishing evaporation rates during the first measurement (12 minutes) using RHs of 25% to 35% and 35% to 45%. However, the DE group had higher evaporative values. ...
... Chemical analysis of meibum from patients with MGD suggests an increase in the proportion of saturated versus unsaturated nonpolar fatty acids. 38 This may play an important role in determining the more paste-like consistency of the lipids and an increase in their melting points. The amount of meibomian lipids and their physical properties are fundamental to preventing AT evaporation and consequent DE disease. ...
To evaluate the effect of excess meibum on tear evaporation rate in patients with and without dry eye.
Eleven healthy subjects and 16 patients with dry eye were tested. The dry eye group was divided into 2 subgroups: classic keratoconjunctivitis sicca (KCS) with clear and easily expressed meibum and KCS with meibomian gland dysfunction (MGD) with turbid secretions and difficult-to-express meibum. Evaporative measurements were performed at baseline and after digital expression of meibomian glands at 12, 24, 36, and 48 minutes. Two ranges of relative humidity were used, 25% to 35% and 35% to 45%. The data were expressed as microliters per square centimeter per minute.
An increase in the evaporation rate of the tear film was noted for all measurements at both relative humidities in the classic KCS and KCS with MGD groups compared with healthy subjects (P < 0.05). The average evaporation rates at relative humidities of 25% to 35% and 35% to 45% were 0.056 ± 0.016 and 0.040 ± 0.008 for the classic KCS group; 0.055 ± 0.026 and 0.037 ± 0.019 for the KCS with MGD group and 0.033 ± 0.012 and 0.023 ± 0.008 for the healthy group. Also, a decrease in the evaporation rate was observed in the healthy and KCS with MGD groups between baseline and the first measurement after digital expression for both relative humidities (P < 0.05). The classic KCS group did not show any changes after expression.
Classic KCS and KCS with MGD groups showed an increase in tear evaporation rates compared with the healthy group. Aqueous tear evaporation diminished in the healthy and KCS with MGD groups after expression of meibomian glands. However, this effect was transient and negligible after the second measurement.
... Patients with chronic blepharitis without obvious obstructive dysfunction of the meibomian gland demonstrate significant changes in lipid fractions, including a decrease in the levels of polar lipids, in particular phosphatidyl ethanolamine and sphingomyelin, in TF [55]. In patients with chronic blepharitis and viscous meibum, a decrease in the content of TF monounsaturated fatty acids, in particular oleic acid, was revealed, which explains the obstructive nature of the disease [56]. ...
The simplicity of collecting and evaluating tear fluid (TF) can potentially provide a convenient non-invasive diagnostic tool that easily fits into a personalized approach to medicine based on risk assessment. Though, to date, most tear biomarkers are not yet ready for routine use due to problems with their clinical validation, given the huge clinical advantage of TF and the emerging advanced technical approaches developed for proteomic, lipidomic and metabolomic analysis of tears, TF studies will doubtless become a routine test for health monitoring in the near future. A number of associations between the levels of different substances in TF and the brain makes TF an invaluable source of brain disease biomarkers helpful in early diagnostics and personalized treatment. TF is a promising biological material, an invaluable source for pre-dictive, diagnostic, prognostic, and mechanistic biomarkers.
... However, it is important to emphasize that, while the overall TAG content in normal meibum and TPs is, generally, rather low, compared with the more prominent components such as WEs and CEs, it may reach high levels in certain pathological conditions (16). As (1) melting characteristics of meibum heavily depend on its chemical composition (18)(19)(20)(21)(22) and (2) melting characteristics of TAGs change dramatically depending on the FA content (23), testing the ability of dietary lipids to be directly incorporated into, or have an effect onto, Meibomian lipidome is an important scenario to explore. ...
Exocrine Meibomian glands (MGs) play a central role in the ocular physiology and biochemistry by producing in situ and, mostly, de novo, a secretion (meibum), which is composed of a complex mixture of homologous lipids of various classes, in a metabolic pathway termed meibogenesis. Recent in vivo experiments with a number of mouse models demonstrated that inactivation of any of the major genes of meibogenesis led to alterations in the lipid composition of meibum and severe ocular and MG abnormalities that replicated various human ocular pathologies. However, the role of dietary lipids in meibogenesis, and in the onset and/or alleviation of these diseases, remains controversial. To uncover the role of dietary lipids, the metabolic transformations of a dietary lipid tracer - stable isotope-labeled glyceryl tri(oleate-1,2,3,7,8-13C5) (13C15-TO) - were investigated using LC-high-resolution TOF-MS/MS. We demonstrated that major metabolic transformations of the tracer occurred in the stomach and small intestines where 13C15-TO underwent immediate and extensive transesterification into 13C5- and 13C10-substituted triacylglycerols of various lengths, giving a mixture of 13C-labeled compounds that remain virtually unchanged in the mouse plasma, liver, and white adipose tissue, but were almost undetectable in the feces. Importantly, the tracer and its metabolites were virtually undetectable in MGs, even after 4 weeks of daily supplementation. Notably, unbiased Principal Component Analysis of the data revealed no measurable changes in the overall chemical composition of meibum after the treatment, which implies no direct effect of dietary triacylglycerols on meibogenesis, and left their systemic effects as the most likely mechanism.
... Согласно исследованиям американских ученых, у пациентов с мейбомиевым кератоконъюнктивитом уровень олеиновой кислоты, являющейся основным продуктом SCD, снижен, а у пациентов с мейбомиевой себореей -повышен [49,65]. ...
Lens opacity, which leads to cataract, is one of the most complicated issues in ophthalmology. Pathophysiology of cataract progression is far from being clearly established. Despite low lipid content in the lens of the eye, there is an assumption that they and their predecessors may be involved in the development of this disease. Given the many roles of monounsaturated fatty acids, it can be expected that variations in stearoyl-Coa desaturase activity will affect a number of key physiological processes.
... The genes involved in the synthesis of long-and very-longchain fatty acids, such as fatty acid transport protein 4, was up-regulated in the androgen group. This was consistent with the findings of Shine and McCulley [52] that the length of hydrocarbon chains of WE and CE was significantly shorter in MGD patients with androgen deficiency. Genes associated with intracellular and extracellular transport of phospholipid and cholesterol, such as Abca1, Abcd3, sterol carrier protein 2 and phosphatidylcholine transfer protein were also found to be regulated by androgen. ...
Meibomian gland, the largest sebaceous gland of the body, is responsible for the biosynthesis of lipid layer of the tear film to prevent excessive evaporation. The loss of normal functions of meibomian gland, known as meibomian gland dysfunction (MGD), is a chronic disease and is the leading cause of dry eye symptoms in the clinics. Studies have found sex hormones, especially androgen, play vital roles in the regulation of the functions of meibomian gland. Recently, androgen has also been preliminarily applied in clinics for the treatment of MGD and showed promising results, especially in people with endogenous androgen deficiency. This review summarized the mechanisms of the function of androgen on meibomian gland based on molecular, animal, and clinical studies, and proposed evidence-based views about its potential applications for the treatment of MGD. © 2021 International Journal of Ophthalmology (c/o Editorial Office). All rights reserved.
... [77][78][79] In addition, a decrease in oleic acid, palmitic acid and stearic acid was also observed. 80,81 Furthermore, meibum of patients with blepharitis and dry eye symptoms have generally low levels of phosphatidyl ethanol-amine and sphingomyelin. 82 Overall, research on the underlying mechanisms of meibomian gland pathology must be intensified, since in most cases only a few scientific groups conduct experiments on the respective topics. ...
Purpose: The meibomian glands are located in the tarsal plate of the upper and lower eyelid and are responsible for the production of a lipid-rich secretion, the meibum, which forms the outer component of the tear film. Meibomian gland dysfunction results in excessive evaporation of the tear film and is the leading cause of dry eye disease (DED). Despite the high prevalence of DED, the etiology of meibomian gland dysfunction is only basically understood. In addition, the molecular mechanisms of meibomian gland maturation and physiological function are currently the focus of research.
Methods: A systematic literature search was performed using the main scientific databases, including all relevant published articles up to September 2020.
Results: This article provides an overview of the current state of knowledge about meibomian gland stem cells, cell surface marker expression and PPARγ signaling, as well as the pathological causes of meibomian gland dysfunction.
Conclusion: Androgen deficiency, hyperkeratinization, PPARγ signaling and inflammatory reactions including neutrophil extracellular traps (NETs) seem to be key factors within the pathological processes of the meibomian gland.
... In a pilot study it was reported that, order of the neutral and polar lipid molecules gets altered in the disease state compared to normal state and treatment with azithromycin (antibacterial agent) can improve that abnormal condition towards normal by reducing the bacterial load in the eye lid [11,14]. Changes in the concentration of oleic acid in the meibum results in the increase in percentage of unsaturation of fatty acid associated with phospholipids in case of meibomitis was also reported in some studies [15,16]. In another pilot study over blepharitis, it was reported that, azithromycin provided significant improvement in signs and symptoms of blepharitis infections of the eyes [13,17]. ...
... This subtype of MGD has been linked to acne rosacea, where skin sebocytes produce excess sebum. Since the MG is a modified sebaceous gland, the proposed explanation is that the seborrhea may be due to an end-organ hyper-response of the MG to androgens [1,14]. On one hand, reduction in levels of some androgens like testosterone, dehydroepiandrosterone and its conjugated dehydroepiandrosterone sulfate are considered as potential risk factors for developing MGD [15]. ...
Meibomian gland dysfunction (MGD) is the leading cause of dry eye disease and loss of ocular surface homeostasis. Increasingly, several observational clinical studies suggest that dyslipidemia (elevated blood cholesterol, triglyceride or lipoprotein levels) can initiate the development of MGD. However, conclusive evidence is lacking, and an experimental approach using a suitable model is necessary to interrogate the relationship between dyslipidemia and MGD. This systematic review discusses current knowledge on the associations between dyslipidemia and MGD. We briefly introduce a diet-induced obesity model where mice develop dyslipidemia, which can serve as a potential tool for investigating the effects of dyslipidemia on the meibomian gland. Finally, the utility of lipidomics to examine the link between dyslipidemia and MGD is considered.
... Klinisch erkennt man bei der Untersuchung von Patienten mit einer Funktionsstörung der Meibom-Drüsen eine veränderte Konsistenz des Sekrets, dies soll durch Veränderungen der Ölsäurekonzentration in Wachs-und Sterolestern sowie in Hydroxyfettsäuren -also in nichtpolaren wie auch in polaren Fetten -bedingt sein [35]. Außerdem wurde im Meibom-Drüsen-Sekret von Patienten mit chronischer Blepharitis im Vergleich zu dem von Normalpersonen eine Zunahme der Konzentration ungesättigter Fettsäuren festgestellt [15], was möglicherweise auf die Lipaseaktivität der Lidkantenflora (insbesondere Staphylococcus aureus, koagulasenegative Staphylokokken [enzymatische Aktivität stammabhängig], Propionibacterium) zurückzuführen ist [14]. ...
In dieser Übersicht werden weiterhin relevante ältere sowie neuere Informationen zur chronischen Blepharitis mit Epidemiologie, Symptomen, Befunden und Pathophysiologie insbesondere im Kontext des trockenen Auges dargestellt. Die chronische Blepharitis ist häufig die eigentliche Ursache des trockenen Auges, die nicht selten übersehen wird und unbehandelt bleibt. Sie kann jedoch auch Folge des (hypovolämischen) trockenen Auges sein und teils schweren Komplikationen der Hornhaut zugrunde liegen, die mit Material aus eigenem Patientenarchiv illustriert werden. Neue Erkenntnisse bezüglich der Zusammensetzung der Lipide im Tränenfilm in Korrelation mit denen des Meibom-Drüsen-Sekrets, Hypothese eines Biofilms als Grundlage der chronischen Blepharitis als theoretische, noch nicht bewiesene Ergänzung der bislang bekannten pathophysiologischen Faktoren werden erörtert.
... 206 Loss of the mono-unsaturated OFAs, like oleic acid, in LL has been associated with chronic blepharitis and viscous meibum in patients with DED. 207 The PTF structure could also be altered by isomerization of the C=C bonds in the OFAs, like in oleic acid, by the action of nitrogen dioxide. 208 Such isomerization 54 may alter the structure of the LL aggravating the PTF stability. ...
... 206 Loss of the mono-unsaturated OFAs, like oleic acid, in LL has been associated with chronic blepharitis and viscous meibum in patients with DED. 207 The PTF structure could also be altered by isomerization of the C=C bonds in the OFAs, like in oleic acid, by the action of nitrogen dioxide. 208 Such isomerization 54 may alter the structure of the LL aggravating the PTF stability. ...
Eye irritation, e.g. dry or irritated eyes, is generally among top-3 reported symptoms in office-like environments; in particular, among workplaces with cognitive demanding visual display unit (VDU) work. The symptoms are especially among middle and advanced ages and particularly among women more than men. The symptoms are also among the most commonly reported complaints in the eye clinic. To be in a position to interpret the high prevalence of eye symptoms, a multidisciplinary and integrated approach is necessary that involves the external eye physiology (separate from internal eye effects), eye diseases (evaporative dry eye, aqueous-deficient dry eye, and gland dysfunctions), and risk factors that aggravate the stability of precorneal tear film resulting in hyperosmolarity and initiation of inflammatory reactions. Indoor environmental, occupational and personal risk factors may aggravate the precorneal tear film stability, factors such as age, contact lenses, cosmetics, diet, draft, gender, low humidity and high temperature, medication, outdoor and combustion pollutants, and VDU work. Psychological stressors may further influence the reporting behavior of eye symptoms. The impact of the risk factors may occur in a combined and exacerbating manner.
... [51][52][53] As concerns the increased polyunsaturation, it is of interest that a decreased unsaturation of nonpolar fatty acids has been associated with MGD. [54][55][56] The human meibomian gland epithelial cell lipids detected in our study do not reflect the levels of neutral and polar lipids typically found in human meibum. 2,[57][58][59][60] The reason is that we analyzed cellular extracts, not meibum, and the lipid components of these products are not necessarily the same. ...
Purpose:
We hypothesize that culturing immortalized human meibomian gland epithelial cells in serum-containing medium will induce their differentiation. The purpose of this investigation was to begin to test our hypothesis, and explore the impact of serum on gene expression and lipid accumulation in human meibomian gland epithelial cells.
Methods:
Immortalized and primary human meibomian gland epithelial cells were cultured in the presence or absence of serum. Cells were evaluated for lysosome and lipid accumulation, polar and neutral lipid profiles, and gene expression.
Results:
Our results support our hypothesis that serum stimulates the differentiation of human meibomian gland epithelial cells. This serum-induced effect is associated with a significant increase in the expression of genes linked to cell differentiation, epithelium development, the endoplasmic reticulum, Golgi apparatus, vesicles, and lysosomes, and a significant decrease in gene activity related to the cell cycle, mitochondria, ribosomes, and translation. These cellular responses are accompanied by an accumulation of lipids within lysosomes, as well as alterations in the fatty acid content of polar and nonpolar lipids. Of particular importance, our results show that the molecular and biochemical changes of immortalized human meibomian gland epithelial cells during differentiation are analogous to those of primary cells.
Conclusions:
Overall, our findings indicate that immortalized human meibomian gland epithelial cells may serve as an ideal preclinical model to identify factors that control cellular differentiation in the meibomian gland.
... The rigid evaporation barrier forms the central thickness of the nonpolar lamellae, while the surfaces of these lamellae allow easy slippage and provide the fluidity needed for respreading the TFLL. It would have an important clinical implication if the lamellae were disrupted by factors such as biosynthetic anomalies in meibomian glands, 64 inclusion of keratin proteins, 65 structural disorder associated with TFLL deposition on contact lenses, 66 or the ocular surface, bacterial lipases 67 and oxidative stress. 68 Such lamellar disruption could lead to increased evaporation, hyperosmolarity and dry eye. ...
It is proposed that a normal, effective tear film lipid layer (TFLL) should have the following four characteristics: 1) high evaporation resistance to prevent water loss and consequent hyperosmolarity; 2) respreadability, so it will return to its original state after the compression-expansion cycle of the blink; 3) fluidity sufficient to avoid blocking secretion from meibomian glands; 4) gel-like and incompressible structure that can resist forces that may tend to disrupt it. These characteristics tend to be incompatible; for example, lipids that form good evaporation barriers tend to be disrupted by compression-expansion cycles. It is noted that clues about the function and organization of the TFLL can be obtained by comparison with other biological lipid layers, such as lung surfactant and the lipid evaporation barrier of the skin. In an attempt to satisfy the conflicting characteristics, a "multilamellar sandwich model" of the TFLL is proposed, having features in common with the skin evaporation barrier.
... [2][3][4] This outer layer is believed to prevent the evaporation of the TF, lubricate the ocular surface, and avert the invasion of pathogenic microorganisms. 5 Reportedly, adverse changes in the lipid composition of meibum [6][7][8][9][10][11][12] could impact negatively the integrity and stability of the TF, compromising the health of the ocular surface, and predisposing it to the development of various ocular pathologies. One of the latter, the dry eye disease (DED), is one of the most prevalent ocular diseases. ...
Purpose:
We evaluated quantitatively direct effects of ceramide (Cer) and free cholesterol (FC) on meibomian lipid films (MLF) using a Langmuir trough (LT) and a Brewster angle microscope (BAM).
Methods:
Meibum was obtained from healthy volunteers. A series of mixtures of meibum with Cer or FC (mixed MLF) taken in different ratios were tested. Standard rheologic parameters, such as elasticity and hysteresis of MLF, were computed. BAM was used to study the morphology of MLF.
Results:
Pure MLF were capable of withstanding multiple compression/expansion cycles with little hysteresis observed (1.9 J/G meibum). The films made of either pure CER or pure FC were clearly collapsible, and had much higher rigidity and hysteresis than pure meibum. Adding progressively higher amounts of CER or FC to meibum had a strong impact on the rigidity, stability, and morphology of the mixed MLF: their hysteresis increased many fold compared to pure meibum. A concomitant increase in the rigidity and collapsibility of the mixed MLF was observed.
Conclusions:
Cer and FC changed the surface properties of mixed MLF in a way that implied their destabilization and/or disruption. One of the mechanisms that might lead to these effects is strong aggregation of meibum lipids with FC or Cer that leads to the formation of smaller particles of meibum surrounded by a thinner layer of FC or Cer. As Cer and FC can be elevated in meibum and the tear film because of certain pathologic processes, or can be of exogenous nature, our results can explain (partially) a less stable tear film in those subjects.
... Factors which affect the functional integrity of the lipid layer such as meibomian gland hypo-secretion or alterations in lipid composition result in a lipid deficiency dry eye syndrome [9] that is associated with an enhanced risk of infection. Hyper-secretion and͞or alteration of meibomian lipid composition provides fodder for the proliferation of the normal flora as well as pathogens (e.g., S. aureus and Pityrosporum oûale) of the lid and lid margins [10][11][12]. This can result in chronic infection with secondary inflammatory and immune reactions extending to the cornea. ...
The defense of the ocular surfaces presents an unique challenge in that not only must integrity be maintained against microbial, inflammatory and physical assault, but it must be done while minimizing the risk of loss of corneal transparency. This puts severe limitations on the degree to which scarring or neovascularization can occur in the cornea secondary to any infectious, inflammatory, immunological or wound healing process. Moreover, this defense system must be equally effective under two extremes of conditions: those found in the open eye and the closed eye environments. It is our contention that these constraints have resulted in the evolution of a highly complex fail-safe defense system that utilizes distinctly different strategies in open and closed eye conditions. The extraordinary effectiveness of this system is evidenced by the fact that despite continued exposure to a microbe rich environment, the external ocular surfaces maintain a very low microbial titer and are highly resistant to breaching by all but a few pathogens. It is the intent of this review to provide a working model of this defense system as it operates under both open and closed eye conditions, to provide evidence in support of this model as well as highlight some of the many areas of uncertainty.
... Meibomian gland dysfunction (MGD) is a common clinical problem responsible for symptoms and signs of eyelid irritation and is frequently a cause of evaporative dry eye. 1,2 Spectroscopic 3-14 and other approachs [15][16][17][18][19][20] have been used to characterize alterations of the lipids of the meibomian glands with advancing age and disease. 2,21 The identified changes in the lipids help to explain some of the abnormalities of tear film function in evaporative dry eye. ...
Purpose:
Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment.
Methods:
Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer.
Results:
Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal. Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment.
Conclusions:
The mechanism of action of doxycycline may be different from that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eyes. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eyes.
... 26 Triglycerides in Md were more saturated compared to those in Mn, 27 and Md had a lower percentage of monounsaturated (oleic acid). 28 Another group has shown that Md contains a lower percentage of saturation and a higher percentage of branched acyl chains. 29 Md also contains higher levels of phosphatidylcholine 30 and phospholipid unsaturation 31 and lower levels of phosphatidylethanolamine and sphingomyelin 32 compared with Mn. ...
Nuclear magnetic resonance (NMR) spectroscopy has been used to quantify lipid wax, cholesterol ester terpenoid and glyceride composition, saturation, oxidation, and CH₂ and CH₃ moiety distribution. This tool was used to measure changes in human meibum composition with meibomian gland dysfunction (MGD).
(1)H-NMR spectra of meibum from 39 donors with meibomian gland dysfunction (Md) were compared to meibum from 33 normal donors (Mn).
Principal component analysis (PCA) was applied to the CH₂/CH₃ regions of a set of training NMR spectra of human meibum. PCA discriminated between Mn and Md with an accuracy of 86%. There was a bias toward more accurately predicting normal samples (92%) compared with predicting MGD samples (78%). When the NMR spectra of Md were compared with those of Mn, three statistically significant decreases were observed in the relative amounts of CH₃ moieties at 1.26 ppm, the products of lipid oxidation above 7 ppm, and the =CH moieties at 5.2 ppm associated with terpenoids.
Loss of the terpenoids could be deleterious to meibum since they exhibit a plethora of mostly positive biological functions and could account for the lower level of cholesterol esters observed in Md compared with Mn. All three changes could account for the higher degree of lipid order of Md compared with age-matched Mn. In addition to the power of NMR spectroscopy to detect differences in the composition of meibum, it is promising that NMR can be used as a diagnostic tool.
... These are important for the PTF stability by interconnecting the aqueous mucin layer with the OLL (Butovich et al., 2009) and the polar lipids in building up the PTF after a blink (Aydemir et al., in press). For instance, loss of the mono-unsaturated EFAs, like oleic acid, has been associated with chronic blepharitis and viscous meibum in patients (Shine and McCulley, 2000). Another possible mechanism is isomerization of the carbon-carbon double bonds in the EFAs, like in oleic acid, by nitrogen dioxide . ...
Ocular discomfort (e.g. burning, dry and itching eyes) is among top 2 symptoms in office environments. The ophthalmological explanation is aqueous-deficient dry eye and evaporative dry eye and exposure to allergens, while indoor air pollutants causing chemesthesis generally is the rationale of the indoor environmental community. Review of salient environmental, occupational, and personal risk factors, that alter the precorneal tear film (PTF), reveals at least three mechanisms resulting in ocular discomfort. First, the PTF structure is altered by a physical process that increases the emission rate of aqua loss resulting in hyperosmolarity, gland dysfunctions, and associated discomfort. Second, the structural composition of the outermost lipid layer of the PTF is altered by aggressive aerosols and combustion products, both indoors and outdoors, that facilitate loss of aqua, and possibly chemesthesis. Third, strong sensory irritating pollutants cause chemesthesis by trigeminal stimulation. In general, organic and inorganic indoor air pollutant concentrations are too low causing chemesthesis, but the odor may cause reported discomfort. The total risk of ocular discomfort is exacerbated by physical alteration of the PTF by visual tasking and climate conditions (low humidity, high temperature, and draft); further, personal factors like age, gender and use of certain medication also influence the overall stability of the PTF.
... 3,44 Numerous changes in meibum composition have been documented that may contribute to and be diagnostic of dry eye symptoms. Shine and McCulley 10 have shown that meibum from donors with meibomian keratoconjunctivitis contains waxes and cholesterol esters and triglycerides 45 that are more saturated and contain less monounsaturated hydrocarbons 46 and branched hydrocarbon chains compared with meibum from normal donors. In contrast, Joffre et al. 47 have shown that meibum from donors with MGD contains less saturation and more branching. ...
To recount the historic evaluation of meibomian gland dysfunction (MGD) and describe new techniques to monitor disease and therapy.
A review of the literature regarding the description of MGD and the role of abnormalities of meibomian gland secretion in health and disease.
Meibomian gland dysfunction is a common clinical condition and is a major cause of evaporative dry eye with associated discomfort, visual disturbance, and contact lens intolerance. Despite the early description of the anatomy and physiology of the meibomian gland, recognition of the importance of the MGD and particularly therapeutic options to treat it has been limited.
Improved methods of spectroscopic and chemical analysis of the meibomian gland secretion in health and disease are providing a better understanding of the physical and chemical abnormalities of the meibomian gland secretions and are allowing better evaluation of medical therapies.
Innate and adaptive immunity is the first line of defence on the ocular surface against ocular diseases. The cellular and molecular basis of several ocular diseases is discussed with respect to the role of accumulation of various cell types and various proteins and lipids that are either up- or downregulated in the diseased state of the eye. Nevertheless, the cellular and molecular sequence of events that trigger the pathogenesis and sustain the diseased state is yet to be clearly established. Such data would eventually help in targeted therapy of an ocular disease.KeywordsOcular diseaseCellularMolecularPathogenesisTherapy
Conrad Röentgen; 1895 yılında X-ray cihazını tanımlayarak tıp ala�nına yenilik katmıştır. Yüz yıldan fazla süredir, Ortopedide iki boyutlu röntgenografiler kullanılmaktaydı.(1,2) Görüntüleme teknolojisinin son yüzyılda hızlıca gelişmesiyle Bilgisayarlı Tomografi (BT) ve Manyetik Rezonans Görüntüleme (MRG) iki boyutlu anatomik detayları göstermede etkili olmaktadır.(2,3) Teşhis, tanı ve tedavi takibinde kullanılan bu moda�liteler bir bilgisayar yazılımı ile insan anatomisini üç boyutlu olarak gös�terebilmektedir.
Üç boyutlu (Three-Dimensional, 3D) görüntülemenin ilerlemesinin yanında 3D yazıcı teknolojisi de son yıllarda hızla ilerlemektedir. (4) Bu yazıcılar, bilgisayar görüntülerini somut ve fonksiyonel objelere çevirir. 3D yazıcıların uygun fiyatlı ve ulaşılabilir olması, bu teknolojinin ortopedi alanında kullanılmasına olanak sağlamıştır. Benzer şekilde; baskı türleri ve maliyetlerinin azalması bu teknolojinin yaygın olarak kullanılmasına ve
ortopedistler tarafından kabul edilmesini kolaylaştırmıştır. (2,5) Başlangıçta, 3D baskı ürünleri karmaşık durumlar için kullanılırken, şimdi rutin kullanılır hale gelmiştir ve avantajları da göz önüne alındığın�da, önümüzdeki yıllarda tüm uygulamalarımız üzerinde etkilerinin artması muhtemeldir. Örneğin, pelvis-asetabulum travmaları gibi komplike cerra�hilerde deneyimsiz cerrahlara yardımcı olabilirler. Modeller sterilize edile�bilir ve gerekirse intraoperatif olarak gözden geçirme amaçlı kullanılabilir. (2,4,6,7) 3D modelin preoperatif gözden geçirilmesi, cerrahın intraoperatif zorlukları tahmin etmesine, optimal cerrahi yaklaşımı seçmesine, implant yerleştirmeyi planlamasına, vida yörüngesini görselleştirmesine olanak ta�nır. Son olarak, ameliyattan sonra bireysel anatominin değerlendirilmesin�de de yardımcı olabilir. Başka tekniklerle anatomik olarak net görüleme�yen tanılarda ve sonraki planlamalarda yardımcı olabilir. Bunların yanında
yapay kıkırdak çatı ve 3D biyoyazdırma ilginin yöneldiği yeni alanlar ola�rak ortaya çıkmaktadır. (2,4,6–10)
Yüksek kaliteli literatürlerin çoğunda, 3D baskı kullanımı operasyon süresini, tahmini kan kaybını ve floroskopi çekimlerinin sayısını önem�li ölçüde azalttığından bahsedilmektedir. Farklı çalışmalar arasında kli�nik açıdan önemli heterojenlik göz önüne alındığında, bu bulguların kli�nik önemini değerlendirmek zordur. Bununla birlikte, ameliyat süresinin
azaltılması maliyet açısından kesinlikle faydalıdır ve daha uzun ameliyat süreleri ile komplikasyon riskinin arttığı göz önüne alındığında, (11,12) bunun hasta için de faydalı olduğunu varsaymak mantıklıdır. Benzer şekil�de tahmini kan kaybındaki bir azalmanın hastaya teorik bir faydası vardır. Bunların yanında az floroskopi çekiminin hasta üzerinde doğrudan bir et�kisi olmayabilir, ancak özellikle uzun vadede ameliyathane personelinin güvenliği için önemlidir. (12,13)
Bu bölümün amacı, ortopedi ve Travmatoloji alanında kullanılan 3D yazıcı tiplerini, bu yazıcıların fonksiyonları, yazıcılardan çıkan ortopedi ile ilgili ürünlerin düzenlenmesi ve ortopedideki şimdi ve gelecekteki kulla�nımlarını gözden geçirmektir. Bu yazı ile ortopedistlerin son zamanlarda geliştirilen teknolojiyi nasıl kullanacağını görmesi ve klinik uygulamala�rı hakkında bilgi sahibi olması amaçlanmaktadır. 3D yazıcı teknolojisi ve
konseptlerinin öğrenilmesi ortopedistler için önemlidir; çünkü ortopedide 3D yazıcılar hasta yönetiminde geniş ve etkili bir role sahiptir ve bu rol yakın gelecekte de devam edecektir. (2,4,9)
The structure and function of meibomian gland lipids in the tear film are highly complex. Evidence shows that the precorneal tear film consists of discrete layers: the inner mucin layer, the middle aqueous layer and the outer lipid layer. In this review we focus on the outer, biphasic lipid layer of the tear film which consists of a ‘thick’ outer, non-polar layer and a ‘thin’ inner, polar layer. We discuss the main composition of the polar and non-polar lipids within meibum (wax esters, cholesteryl esters, mono-, di- and tri-acylglycerols, ceramides, phospholipids et cetera). We address the composition of meibomian lipids in subjects suffering from various ocular diseases in comparison with the composition in healthy individuals. Further analysis is needed to determine whether a correlation exists between the etiology of various ocular diseases and the fluctuation on the lipids as well as to establish whether or not tear lipid analysis can be used as a
diagnostic tool.
Purpose:
To evaluate the meibomian gland function, morphology and the related medical history of patients with blepharokeratoconjunctivitis (BKC) in comparison with healthy population and meibomian gland dysfunction (MGD)-induced evaporative dry eye (EDE) patients.
Methods:
Twenty-two eyes of 22 Asian adult patients with BKC were enrolled as the BKC group. Healthy volunteers and MGD-induced EDE patients were recruited in a 1:1 ratio and were matched in age, and the gender compositions of the three groups were also comparable. Examinations included meibum quality, meibomian gland expressibility, meibomian gland dropout and relevant ocular surface tests. Related medical history was recorded.
Results:
The BKC group had higher incidences of chalazion (OR 4.59, 95% CI 1.29-16.33) and eyelid surgery (OR 4.91, 95% CI 1.33-18.21) than the control group (chalazion, p = 0.007; eyelid surgery, p < 0.001) and EDE group (chalazion, p = 0.031; eyelid surgery, p = 0.005) had. All clinical indexes were worse in the BKC group than in the control group (all p < 0.05). The EDE group had better meibum quality (p = 0.049) and less meibomian gland dropouts (all p < 0.05) than the BKC group. The dropouts of the BKC group were the highest among the three groups, and the distribution over the tarsal plate was even in the BKC group (all p > 0.05).
Conclusions:
Patients with BKC had worse meibomian gland function, poorer morphology and a higher rate of medical histories related to the meibomian gland than the healthy population. The BKC clinical features of meibum quality and meibomian gland dropout were different from other MGD diseases.
Meibomian glands secrete remarkably diverse components comprising the lipid layer of the tear film. Proper functioning of the glands minimizes evaporation from the tear film. A number of factors may contribute to dysfunction of meibomian glands, often leading to dry eye disease and its characteristic ocular surface inflammation. This chapter reviews the normal anatomy and function of meibomian glands, then considers causes of their dysfunction, the impact of dysfunction on the tear film and ocular surfaces, and treatments for meibomian gland dysfunction.
Meibomian gland dysfunction (MGD) is a chronic disffuse abnormality of the meibomian glands, commonly characterized by terminnal duct obstruction and/or qualitative/quatitative changes in the glandular secretion. The evaporative dry eye disease is mainly caused by MGD. In recent years, the morbidity of the evaporative dry eye disease which caused by MGD is raising, researchers both at home and abroad pay more attention on that. There is no uniform standard on MGD' treatment internationally. It is mainly centered on removing the cause and applicating the local and systemic therapy, including physicotherapeutics, drug therapy, artificial tears replacement therapy, nutrition support therapy, hormonotherapy, Chinese medicine treatment etc. The literature review is mainly talking about the treatment of dry eye which caused by MGD on both at home and abroad.
Dry eye disease affects 15% of the population over the age of 65 years. It is characterized mainly by inflammation of the ocular surface (tear film, conjunctiva and cornea), which represents a relevant target for therapeutic strategies. The side effects and long-term intolerance of anti-inflammatory drugs give rise to an increasing interest in dietary components exhibiting anti-inflammatory properties, such as polyunsaturated fatty acids. In this chapter, we have exposed the dry eye pathology in terms of prevalence and symptoms. Then we have described the anti-inflammatory role of n-3 polyunsaturated fatty acids and some of their mechanisms of actions. Finally, we have shown the influence of n-3 polyunsaturated fatty acid deficiency and supplementation in dry eye. Our conclusions are on the importance of combining dietary polyunsaturated fatty acids to classical therapies.
Meibomian gland dysfunction (MGD) is a common ocular surface disease, characterized by terminal duct obstruction and (or) qualitative and quantitative changes in the glandular secretion. Meibomian lipids are a mixture consisting of various lipids, and they form the lipid layer of tear film and play important roles in preventing the evaporation and maintaining the stability of tear film. Patients with MGD may have different compositions of meibomian lipids, which could be an important indicator for diagnosis of MGD. The methods to analyze the composition of meibomian lipids mainly include chromatography and spectrum analysis. Because the pathogenic factors of MGD are still unclear, the main treatment is to relieve the symptoms. It can contribute to diagnose and treat MGD if we can find some convenient and effective methods to analyze the quality and quantity of meibomian lipids. (Chin J Ophthalmol, 2015, 51: 225-228).
Purpose: To determine abnormal meibomian gland secretion polar lipids from meibomianitis patients and to determine the significance of these lipid differences. Methods: Meibomian gland secretions were collected from controls and patients with chronic blepharitis. These meibomian gland lipids (meibum) were first separated by thin-layer chromatography. Polar lipids were then separated utilizing high-pressure liquid chromatography with ultraviolet detection. Individual peaks were identified by comparison to standards and retention time. Results: A polar lipid with an HPLC retention time longer than either phosphatidylcholine or sphingomyelin and shorter than phosphatidylethanolamine was significantly greater in the meibomianitis group (P < 0.05) compared with other chronic blepharitis groups and normals. This polar lipid’s retention time was similar to that of dimethylphosphatidylcholine or possibly lysophosphatidylcholine. Additionally, meibomianitis polar lipids’ normal fatty acids were highly unsaturated and differed from those of other groups, none of which were unsaturated. Conclusion: Many of the most significant differences in meibomianitis meibum composition occur in the polar lipids rather than the nonpolar lipids. Further investigations will determine the true significance of these findings.
purpose. To determine whether various novel amphipathic polymers could be used to stabilize the tear film of the rat. The rheologic properties of these polymers were examined to investigate whether particular structural or physical characteristics improve the stability of the tear film.
methods. Amphipathic polymers or particular phospholipids were mixed with a test solution of tears and saline and applied to the clean, dry corneal surface of a rat. The specular reflection of the tear film was observed at high magnification and recorded. For each of the polymers or lipids, the effects on surface regularity and tear break-up time were compared. After the experiments, histologic sections of the tested eyes were prepared and examined for acute cytotoxic effects on the cornea and ocular conjunctiva.
results. Tear film break-up time was markedly affected by differences in polymer structure. Copolymers consisting of separate hydrophobic and hydrophilic regions appeared to be the best stabilizers. No acute cytotoxic effects were observed in histologic sections of corneas to which the polymers had been applied.
conclusions. Amphipathic polymers can be designed to increase tear film stability. Increased tear film stability occurred more readily with copolymers, possibly through their interaction with both lipid and aqueous tear components.
■ Chronic blepharitis can cause severe corneal changes, but is surprisingly often not diagnosed
■ Pathogenesis often includes skin diseases, but also bacterial involvement, meibomian gland dysfunction with altered meibomian
gland lipids, hormonal imbalance
■ Important sequelae of chronic blepharitis are dry eye syndrome, corneal involvement like keratitis, phlyctenules, pannus,
vascularization, corneal ulcers, and lid changes like trichiasis and madarosis
■ The treatment includes mechanical measures, preservative-free artificial tears, steroids, antibiotics, immunomodulatory
eye drops (e.g., steroids, cyclosporin) or ointment (e.g., FK506, Pimecrolimus), and occasionally surgical treatment
Sjogren syndrome (SS), the second most common autoimmune rheumatic disease, refers to keratoconjunctivitis sicca and xerostomia resulting from immune lymphocytes that infiltrate the lacrimal and salivary glands. However, differential diagnosis remains confusing due to the high prevalence of vague symptoms of dryness, fatigue, and myalgias in the general population, The problems of diagnosis are further compounded by the finding of "positive" antinuclear antibodies in a high percent of the general population. Unless minor salivary gland biopsies are read by experienced observers, nonspecific changes of sialadenitis are frequently confused with the focal lymphocytic infiltrates that are characteristic of SS. The distinction between fibromyalgia patients with low titer antinuclear antibodies and primary SS remains difficult, Even in patients fulfilling strict criteria for SS, the genomic search for critical genes has proven difficult due to the multigenic pattern of inheritance and strong role of currently undefined environmental factors, No single environmental factor has been detected in the majority of SS patients. SS-like syndrome has been detected in certain patients with HTLV-1 and hepatitis C infection, providing clues to pathogenesis. Even in SS patients with marked sicca symptoms, minor salivary gland biopsy shows that almost 50% of glandular cells are still detected on biopsy, These results imply the importance of immune factors such as cytokines and autoantibodies in decreasing neuro-secretory circuits and induction of glandular dysfunction, Of potential importance, an antibody against muscarinic M3 receptor that can decrease secretory function when injected into rodents is frequently found in the sera of SS patients. Newly developed topical and oral therapies can ease the oral and ocular dryness, Orally administered agonists of the muscarinic M3 receptor (pilocarpine and cevimeline) have recently been approved by the US Food and Drug Administration to increase salivary secretion, Topical ocular use of low-dose corticosteroids or cyclosporin may decrease conjunctival surface inflammation. In a Phase II double-blind study, orally administered interferon alpha (150 U) led to improved saliva flow and symptoms, In pregnant patients with evidence of fetal distress, oral dexamethasone is preferred because this agent crosses the placenta effectively. in animal models, antagonists of tumor necrosis factor and inhibitors of de novo pyrimidine synthesis appear promising. (C) 2000 Lippincott Williams & Wilkins, Inc.
Meibomian lipids are believed to compose the lipid layer of tear film and play important roles in maitaining the stability of tear film. Changes in composition of meibomian lipids contribute to the ocular surface disease, such as dry eye. The understanding of composion and role of meibolian lipids can help us understand the cause of these disease. This review is intended to summarize the current state of knowledge about meibomian lipids, lipidomic analysis of meibomian lipids and changes of meibum regarding to diseases.
Protein-meibum and terpenoids-meibum lipid interactions could be important in the etiology of meibomian gland dysfunction (MGD) and dry eye symptoms. In the current model studies, attenuated total reflectance (ATR) infrared (IR) spectroscopy was used to determine if the terpenoid β-carotene and the major proteins in tears and meibum affect the hydrocarbon chain conformation and carbonyl environment of wax, an abundant component of meibum. The main finding of these studies is that mucin binding to wax disordered slightly the conformation of the hydrocarbon chains of wax and caused the wax carbonyls to become hydrogen bonded or experience a more hydrophilic environment. Lysozyme and lactoglobulin, two proteins shown to bind to monolayers of meibum, did not have such an effect. Keratin and β-carotene did not affect the fluidity (viscosity) or environment of the carbonyl moieties of wax. Based on these results, tetraterpenoids are not likely to influence the structure of meibum in the meibomian glands. In addition, these findings suggest that it is unlikely that keratin blocks meibomian glands by causing the meibum to become more viscous. Among the tear fluid proteins studied, mucin is the most likely to influence the conformation and carbonyl environment of meibum at the tear film surface.
To determine whether Nile Red and Oil Red O stains are able to detect tear film lipids deposited on silicone hydrogel contact lenses.
Eight unworn lotrafilcon A lenses were individually soaked in successively decreasing amounts of cholesterol oleate solution (5.6 to 0.00 mg/ml) for 1 day in triplicate for each staining procedure (etafilcon A lenses were also soaked as a control). The sets of lenses were then stained with Nile Red or Oil Red O. The lenses were then individually visualized with a Nikon Eclipse 80i florescent microscope at 100× magnification, and two representative photos were taken of each lens. Both staining procedures were repeated with human worn lotrafilcon A lenses.
The Nile Red stain detected variable yet decreasing amounts of lipids when lenses were incubated in lipid concentrations ≥0.09 mg/ml. Oil Red O detected decreasing amounts of lipids when lenses were soaked in lipid concentrations ≥0.35 mg/ml. The Nile Red stain produced considerably more background staining than Oil Red O, and approximately half of the negative control lenses stained with Nile Red while there was minimal staining of lenses stained with Oil Red O. Etafilcon A lenses yielded decreasing amounts of lipid when soaked in successively lower concentrations of lipid when stained with Nile Red. Human-worn lotrafilcon A lenses yielded similar lipid characteristics when compared with in vitro lenses, with variable amounts of lipid detection when comparing individual subjects.
Nile Red and Oil Red O are both able to detect lipids on soft lenses in both in vitro and ex vivo conditions. Oil Red O appears to be a better stain for silicone hydrogel lenses as it offers a higher signal to noise ratio.
Understanding the molecular composition (e.g., proteins and lipids) of the tear film (TF) and the contribution of the meibomian gland to the TF is critical in gaining knowledge about TF instabilities, dry eye syndromes, contact lens (CL) incompatibilities, and other eye diseases. Among its functions, the lipid layer of the TF slows evaporation of the aqueous component, preserves a clear optical surface, and forms a barrier to protect the eye from microbial agents and organic matter, such as dust and pollen.1 The TF contains a complex mixture of proteins, enzymes, lipids, mucins, and salts that allows the TF to perform its functions (Fig. 1). Researchers believe the outer lipid layer is 5 to 10 molecules thick and is composed primarily of wax and sterol esters, possibly intercalated with each other and with proteins rather than forming distinct repeating layers of molecules.2,3 Evidence from interferometric studies indicate that the TF lipid layer thickness ranges from 20 to 160 nm.4 If the size of a lipid molecule is approximately 2.2 nm (22 Å), then the calculated thickness for one layer would be 11 to 44 nm. The addition of polar and nonpolar layers would add to the lipid thickness, which indicates that the lipid component of the TF may be multiple layers thick or have other contributing sources to correspond with reported thickness measurements.5
Figure 1.
A proposed model of the precorneal tear film showing the relationship and interaction of lipid-binding proteins and the outer lipid layer.
While the signs and symptoms of TF instability are reasonably well characterized, we are only beginning to understand the specific molecular components of the TF and their relationship with disease and TF stability. The purpose of this review is to examine the meibomian gland's contribution to TF lipids and lipid–protein interactions in health and disease.
Instability of the tear film with rapid tear break-up time is a common feature of aqueous-deficient and evaporative dry eye diseases, suggesting that there may be a shared structural abnormality of the tear film that is responsible for the instability. It may be that a change in the normal meibum lipid composition and conformation causes this abnormality. Principle component analyses of infrared spectra of human meibum indicate that human meibum collected from normal donors (Mn) is less ordered than meibum from donors with meibomian gland dysfunction (Md). In this study the conformation of Md was quantified to test this finding.
Changes in lipid conformation with temperature were measured by infrared spectroscopy. There were two phases to our study. In phase 1, the phase transitions of human samples, Mn and Md, were measured. In phase 2, the phase transitions of model lipid standards composed of different waxes and cholesterol esters were measured.
The phase-transition temperature was significantly higher (4°C) for the Md compared with the Mn of age-matched donors with no history of dry-eye symptoms. Most (82%) of the phase-transition temperatures measured for Md were above the values for Mn. The small change in the transition temperature was amplified in the average lipid order (stiffness) at 33.4°C. The average lipid order at 33.4°C for Md was significantly higher (30%, P = 0.004) than for Mn. The strength of lipid-lipid interactions was 72% higher for Md than for Mn. The ability of one lipid to influence the melting of adjacent lipids is termed cooperativity. There were no significant differences between Mn and Md in phase-transition cooperativity, nor was there a difference between Mn and Md in the minimum order or maximum order that Mn and Md achieved at very low and very high temperatures, respectively. The model wax studies showed that the phase transition of complex mixtures of natural lipids was set by the level of unsaturation. A double bond decreased the phase-transition temperature by approximately 40°C. The addition of a second CH CH moiety decreased the phase-transition temperature by approximately 19°C. Unsaturated waxes were miscible with saturated waxes. When a saturated wax was mixed with an unsaturated one, the saturated wax disproportionately increased the phase transition of the mixture by approximately 30°C compared with the saturated wax alone. Cholesterol ester had little effect on the phase-transition temperature of the waxes. Model studies indicated that changes in the amount of lipid saturation, rather than the amount of cholesterol esters, could be a factor in the observed conformational changes.
Meibum lipid compositional changes with meibomian gland dysfunction reflect changes in hydrocarbon chain conformation and lipid-lipid interaction strength. Spectroscopic techniques are useful in studying the lipid-lipid interactions and conformation of lipid from individual patients. (ClinicalTrials.gov number, NCT00803452.).
Meibomian gland dysfunction (MGD) may be the leading cause of dry eye syndrome throughout the world. However, the precise mechanism(s) underlying the pathogenesis of this disease is unclear. This study was conducted to identify meibomian gland genes that may promote the development and/or progression of human MGD.
Lid tissues were obtained from male and female MGD patients and age-matched controls after eyelid surgeries (e.g., to correct entropion or ectropion). Meibomian glands were isolated and processed for RNA extraction and the analysis of gene expression.
The results show that MGD is associated with significant alterations in the expression of almost 400 genes in the human meibomian gland. The levels of 197 transcripts, including those encoding various small proline-rich proteins and S100 calcium-binding proteins, are significantly increased, whereas the expression of 194 genes, such as claudin 3 and cell adhesion molecule 1, is significantly decreased. These changes, which cannot be accounted for by sex differences, are accompanied by alterations in many gene ontologies (e.g., keratinization, cell cycle, and DNA repair). The findings also show that the human meibomian gland contains several highly expressed genes that are distinct from those in an adjacent tissue (i.e., conjunctival epithelium).
The results demonstrate that MGD is accompanied by multiple changes in gene expression in the meibomian gland. The nature of these alterations, including the upregulation of genes encoding small proline-rich proteins and S100 calcium-binding proteins, suggest that keratinization plays an important role in the pathogenesis of MGD.
We evaluated, dermatologically and ophthalmologically, 26 patients who had chronic blepharitis (meibomitis); we also investigated 26 age- and sex-matched controls. All of the blepharitic patients had an abnormality of sebaceous gland function ranging from seborrhea sicca to seborrheic dermatitis or acne rosacea, suggesting a generalized sebaceous gland dysfunction that included the meibomian glands. Sebaceous gland abnormalities most frequently involved the cool areas of the face or scalp. Stagnation of the meibomian glands presumably caused a defect in the tear lipid layer; this resulted in an unstable tear film that produced superficial punctate keratopathy. The break-up time was much lower in these patients than in controls. The break-up time returned to normal or super-normal levels when fresh meibomian secretions were expressed into the tear film. The superficial punctate keratopathy had the characteristics of those seen in conditions with a known unstable tear film and not of those experimentally produced by staphylococcus toxin.
The authors analyzed the long-chain fatty acids derived from the wax and sterol ester fractions of meibomian secretions from patients with chronic blepharitis and normal individuals. Meibomian secretions were partitioned into separate lipid classes by thin-layer chromatography (TLC). Wax and sterol esters were eluted and transesterified. The liberated fatty acid methyl esters (FAME) were analyzed by gas liquid chromatography. Equivalent chain lengths (ECL) were determined for the 58 peaks found. Thirty-three peaks were positively identified by standards. Peaks were quantified by area normalization. Percentage compositions were computed for each individual and tabulated by group; each fatty acid was analyzed by analysis of variance, and each clinical group was compared with normal subjects. The authors found increases in the series of monounsaturated fatty acids from patient wax/sterol esters compared with normal subjects (P less than 0.05). The authors also found differences in some members of the series of normal, straight, and branched saturated moieties. These differences between normal groups and the blepharitic groups represent a biologically significant pattern that may relate to the disease process. Discriminant analysis provided a 73% probability of correct classification into clinical groups based strictly on FAME analysis (P less than 0.05).
Meibomian secretions were collected from 43 patients with chronic blepharitis and 8 normal controls. Patients were divided into six clinically distinct groups of chronic blepharitis. Individual secretions were weighed and separated into specific lipid classes by thin-layer chromatography. The free fatty acid (FFA) fraction was recovered, methylated, and analyzed by gas-liquid chromatography. Quantitation was achieved through the use of an internal standard, and qualitative analyses were aided by the use of commercial external standards. Carbon numbers were expressed in terms of their equivalent chain lengths (E.C.L.). For statistical comparisons, specific acid weights were expressed as nanograms per milligram of secretion. Data from individual subjects were tabulated by group and analyzed by a nonparametric analysis of variance. The FFA portion made up from 0.21% to 1.3% of the total meibomian secretion. Acids ranged in length from 12 to 29 carbon atoms. Iso-branched and anteisobranched carbon chains made up approximately 33% of the FFA fraction. E.C.L.'s corresponding to C16:0, C18:0, and C18:1 together made up a major portion of the total FFA fraction (mean = 49%). When compared to normals, a significantly decreased amount of C12:0 was seen in the mixed seborrheic/staphylococcal group and the meibomian seborrhea group. A significantly decreased amount of anteiso-branched C15:0 was seen in the mixed seborrheic/staphylococcal group. Significantly decreased amounts of anteiso-branched C23:0 were seen in all of the seborrheic blepharitides. A significantly increased amount of isobranched C22:0 was seen in the meibomian keratoconjunctivitis group. No significant differences were seen in the staphylococcal group.
Since last thoroughly evaluated over three decades ago, the clinical spectrum of chronic blepharitis has changed. The relative prevalence of Staphylococcus aureus alone or in combination with seborrheic blepharitis has decreased. The relative prevalence has increased of seborrheic blepharitis with or without associated excess meibomian secretions (meibomian seborrhea) or inflammation (meibomitis). Primary meibomitis appears not to be a primarily infectious entity but to represent a facet of generalized sebaceous gland dysfunction and to be found in association with seborrheic dermatitis or acne rosacea. The keratoconjunctivitis found in association with primary meibomitis may be contributed to by the production of bacterial lypolytic exoenzymes that split neutral lipids, resulting in an increased level of free fatty acids in the tears. A frequent finding of keratoconjunctivitis sicca in this patient population, especially the S. aureus group (50%), is of note. Of particular importance is that these entities be recognized as chronic diseases requiring control and ones for which there is no "cure."
In this study, we analyzed the triglyceride fraction of human meibomian gland secretions to determine whether specific fatty acids were significantly associated with specific chronic blepharitis disease groups. Triglycerides, isolated from the lipid component of human meibomian secretions by thin-layer chromatography, were transmethylated with sodium methoxide/methanol. Samples from individuals were then analyzed by gas chromatography-mass spectroscopy (GC-MS). Significant fatty acid differences were determined by nonparametric analyses, utilizing Kruskal-Wallis analysis of between group differences and Student-Newman-Keuls multiple comparisons. The analyses showed that the triglyceride samples contained the expected normal, iso, and anteiso fatty acids; disease group differences (from normals) in some of these fatty acid types were significant only with a Bonferroni adjustment. The triglycerides also contained previously unreported polyunsaturated fatty acids as well as two four-member families of fatty acids that had mass spectra and retention times consistent with dimethylated carbon chains. Additionally, some members of the meibomian keratoconjunctivitis (MKC) group contained an unusual pattern of normal 20-carbon fatty acids, including a higher level of saturated and lower levels of unsaturated fatty acids. An important exception was the presence of a monosaturated fatty acid whose GC retention time and mass spectrum were consistent with the uncommon cis-10-20:1 isomer. This pattern was associated with the presence of patient posterior hordeola. Thus, the association of triglyceride fatty acid composition with chronic blepharitis disease signs could be much more important than previously thought. Furthermore, this is the first example of the association of specific fatty acids with a specific chronic blepharitis disease sign.