ReviewTear film lipids
Graphical abstract
Introduction
Meibomian glands (or tarsal glands) are holocrine glands that populate the upper and the lower eyelids of humans and most animals. The glands were discovered and described in 1666 by a German physician/scientist Heinrich Meibom (Meibom, 1666). The glands are situated in the inner part of the tarsal plates of the eyelids. On average, there are about 31 meibomian glands found in the upper eyelids, and 26 in the lower ones (Knop and Knop, 2009). The glands produce an oily, lipid-enriched secretion, often called meibum (Nicolaides et al., 1981), which is excreted onto the ocular surface through orifices located at the eyelid's rim, next to the mucocutaneous junction. They are believed to excrete meibum onto the posterior lid margin either spontaneously, or upon blinking. An average amount of meibum stored in the meibomian glands is in the range of several hundred micrograms per eyelid (Bron et al., 2004). Once excreted, meibum mixes with aqueous tears that are produced by another type of ocular glands – lachrymal glands – to form the tear film. The relatively thin and dynamic tear film [whose depth was estimated to be 3.5 ± 0.8 μm (Kimball et al., 2010)] covers the entire ocular surface, though a large portion of aqueous tears is stored in the tear meniscus.
Aqueous tears, being a relatively hydrophilic environment, tend to separate from generally hydrophobic meibum. Due to their poor miscibility and because of the lower density of the latter, meibum tends to form the upper, outermost part of the tear film, called the tear film lipid layer (TFLL) (Fig. 1), though some lipids may bind with proteins that reside either in the bulk of the aqueous subphase, or are associated with the TFLL (Glasgow et al., 2010, Miano et al., 2005, Saaren-Seppala et al., 2005). A mean thickness of the TFLL was recently reported to be about 42 nm, with a range of 15–157 nm (King-Smith et al., 2010), though in an earlier report an average thickness of TFLL in normal (i.e. non-dry eye) controls was measured to be 90–100 nm (Suzuki et al., 2006). Obviously, the thickness of this layer is orders of magnitude greater than the sizes of most typical lipid molecules, or even proteins, and hints at a complex, multilayered structure of the TFLL. Because of uneven delivery of meibum over time, reflectory blinking, the drainage of the tears through the nasal ducts, and because of the overall thermodynamic instability of the oil/water mixtures, thickness of TFLL may change over time.
The tear film is considered a vital structure whose main roles are to protect the ocular surface from desiccating caused by the tear film evaporation (King-Smith et al., 2009) and bacterial infections (Garreis et al., 2011), among others. The quality of the tear film was shown to be affecting the visual acuity (Kaido et al., 2012, Rolando et al., 1997), while artificial tears were reported to improve vision of dry eye patients (Ridder et al., 2005).
In certain ocular pathologies, such as dry eye syndrome (DES) and Sjogren syndrome, the tear film stability is severely diminished (Hong et al., 2013, Wakamatsu et al., 2013). Not a small part in it may be played by some unwelcome changes in the TFLL (Hong et al., 2013, Rolando et al., 2008). Both thinning (Hosaka et al., 2011) and thickening (Hong et al., 2013) of the TFLL were reported in conjunction with shortening the tear film breakup times (TFBUT). Experiments of Olson et al. (2003) demonstrated that an increase in meibum delivery onto the ocular surface led to a concomitant increase in the TFLL thickness, while Craig and Tomlinson (1997) reported that thicker TFLL retarded evaporation from the tear film surface more effectively than thin or ruptured ones, and were more stable. Interestingly and controversially, Suzuki et al. (2006) came to a conclusion that a thicker TFLL in their cohort of allergic conjunctivitis patients led to a statistically significant decrease in the values of TFBUT. A plausible explanation of this controversy is that the quality of meibum and/or the tear film in those two different cohorts of subjects differed dramatically, which could be reflective of some major differences in their respective chemical compositions of meibum and the tear film. Therefore, a need for comprehensive knowledge of the chemical compositions of meibum and the tear film, and better understanding of what differentiates normal meibum from a pathological one are needed.
In this review, only recent developments in the area of human tear film and TFLL studies will be discussed. Earlier reviews on the topic (Bron et al., 2004, Bron and Tiffany, 1998, Butovich, 2009c, Butovich, 2011a, Ohashi et al., 2006, Tiffany, 2008) and special issues of Ocular Surface and IOVS dedicated to the meibomian glands and the tear film in relation to the dry eye disease (Anon, 2007, Green-Church et al., 2011) have extensively covered most of the preceding reports, and are strongly suggested to be considered alongside with this paper.
However, it is impossible not to mention the major contributions of scientists like Pes (Pes, 1897), Linton (Linton, 1961), Ehlers (Ehlers, 1965), Andrews (Andrews, 1973), Cory (Cory et al., 1973), Nicolaides (Nicolaides et al., 1981, Nicolaides and Santos, 1985), Tiffany (Tiffany, 1987) and many others that laid a solid foundation for future studies in the area, while discussing recent meibomian glands and tear film studies.
Despite those earlier efforts, major advances have been made in the area of qualitative and quantitative analyses of meibum, aqueous tears, and the tear film during the course of a last decade. Making this progress possible, and differentiating it from the past achievements, is, first and foremost, a new technological base that has provided researchers with analytical capabilities unimaginable in the earlier years. New analytical methods, instrumentation, that boosts high sensitivity and selectivity, and a rapid progress in molecular biological techniques have made it possible to look into the details of the biochemistry, biophysics, and physiology of the meibomian and lachrymal glands, in an attempt to draw a comprehensive picture of the normal ocular surface, and visualize its changes upon onset of various ocular pathologies.
Section snippets
Methodological aspects
The chemical analyses of meibum performed over the period of a few decades provided a great deal of information on its chemical composition. It has been recognized that meibum is formed largely from nonpolar lipids, a smaller and, apparently, variable amount of amphiphilic (or polar) lipids, and undefined amounts of other types of molecules typically found in organisms, such as proteins, peptides, inorganic salts, etc.
By and large, technological limitations of the earlier analytical protocols
Acknowledgments
This work has been supported in part by an NIH Grant R01EY019480, an unrestricted grant from the Research to Prevent Blindness Foundation, New York, New York, and the Department of Ophthalmology of the UT Southwestern Medical Center.
The author would like to acknowledge invaluable scientific and technical help of his long-time collaborators and coworkers: Juan C. Arciniega, M.D., J. Corinna Eule, Ph.D, Hua Lu, M.D./Ph.D., James P. McCulley, M.D., Anne McMahon, Ph.D., Thomas J. Millar, Ph.D.,
References (129)
- et al.
Liquid chromatographic analysis of sebum lipids and other lipids of medical interest
Journal of Chromatography
(1978) - et al.
Functional aspects of the tear film lipid layer
Experimental Eye Research
(2004) Cholesteryl esters as a depot for very long chain fatty acids in human meibum
Journal of Lipid Research
(2009)The meibomian puzzle: combining pieces together
Progress in Retinal and Eye Research
(2009)Fatty acid composition of cholesteryl esters of human meibomian gland secretions
Steroids
(2010)Lipidomics of human meibomian gland secretions: chemistry, biophysics, and physiological role of meibomian lipids
Progress in Lipid Research
(2011)- et al.
Lipids of human meibum: mass-spectrometric analysis and structural elucidation
Journal of Lipid Research
(2007) - et al.
Human tear film and meibum. Very long chain wax esters and (O-acyl)-omega-hydroxy fatty acids of meibum
Journal of Lipid Research
(2009) - et al.
The crystal structure of the Escherichia coli lipocalin Blc suggests a possible role in phospholipid binding
FEBS Letters
(2004) - et al.
Wax-tear and meibum protein, wax-beta-carotene interactions in vitro using infrared spectroscopy
Experimental Eye Research
(2012)
Comparison of macro-gravimetric and micro-colorimetric lipid determination methods
Talanta
Effects of oral vitamin E and beta-carotene supplementation on ultraviolet radiation-induced oxidative stress in human skin
The American Journal of Clinical Nutrition
Insertion of tear proteins into a meibomian lipids film
Colloids and Surfaces B: Biointerfaces
Laboratory findings in tear fluid analysis
Clinica Chimica Acta; International Journal of Clinical Chemistry
Analysis of meibum and tear lipids
The Ocular Surface
Quantitative evaluation of sebum lipid components with nuclear magnetic resonance
Journal of Lipid Research
The meibomian secretion
International Ophthalmology Clinics
Disruption and destabilization of meibomian lipid films caused by increasing amounts of ceramides and cholesterol
Investigative Ophthalmology & Visual Science
Guidance for industry. Bioanalytical method validation
Carotenoid pigmentation of salmonid fishes – recent progress
Changes in human meibum lipid composition with age using nuclear magnetic resonance spectroscopy
Investigative Ophthalmology & Visual Science
Differences in human meibum lipid composition with meibomian gland dysfunction using NMR and principal component analysis
Investigative Ophthalmology & Visual Science
The meibomian glands and tear film lipids. Structure, function, and control
Advances in Experimental Medicine and Biology
On the lipid composition of human meibum and tears: comparative analysis of nonpolar lipids
Investigative Ophthalmology & Visual Science
Lipidomic analysis of human meibum using HPLC-MSn
Methods in Molecular Biology
On the presence and role of polar lipids in meibum
Investigative Ophthalmology & Visual Science
On the presence of (O-acyl)-omega-hydroxy fatty acids and of their esters in human meibomian gland secretions
Investigative Ophthalmology & Visual Science
Evaluation and quantitation of intact wax esters of human meibum by gas-liquid chromatography-ion trap mass spectrometry
Investigative Ophthalmology & Visual Science
Comparative HPLC–MS analysis of canine and human meibomian lipidomes: many similarities, a few differences
Scientific Reports
Toward an animal model of the human tear film: biochemical comparison of the mouse, canine, rabbit, and human meibomian lipidomes
Investigative Ophthalmology & Visual Science
Understanding and analyzing meibomian lipids–a review
Current Eye Research
Liquid chromatography-mass spectrometric analysis of lipids present in human meibomian gland secretions
Lipids
On the presence of oleamide in human meibum: quantitation by LC/MS
Investigative Ophthalmology & Visual Science
Tear analysis and lens-tear interactions: part II. Ocular lipids-nature and fate of meibomian gland phospholipids
Cornea
Identification and analysis of polymer additives using packed-column supercritical fluid chromatography with APCI mass spectrometric detection
Analyst
Une nouvele reaction pour l'etudes des lipides: L'oleidemie
La Presse Medicale
Hypercarotenaemia or hypercarotenoidaemia
Annals of Clinical Biochemistry
Shotgun lipidomic analysis of human meibomian gland secretions with electrospray ionization tandem mass spectrometry
Investigative Ophthalmology & Visual Science
Author response: on the presence of (O-acyl)-omega-hydroxy fatty acids and their esters in human meibomian gland secretions
Investigative Ophthalmology & Visual Science
Rapid quantitative analysis of lipids using a colorimetric method in a microplate format
Lipids
Guideline on bioanalytical method validation
SR-BI and HDL cholesteryl ester metabolism
Endocrine Research
Migration studies on fatty acid amide slip additives from plastics into food simulants
Food Additives and Contaminants
Meibomian gland secretion in the red eyes of rosacea
The British Journal of Dermatology
Importance of the lipid layer in human tear film stability and evaporation
Optometry and Vision Science
Chemical characterization of a family of brain lipids that induce sleep
Science
Mass spectrometric identification of phospholipids in human tears and tear lipocalin
Investigative Ophthalmology & Visual Science
Analysis of the free fatty acid component of meibomian secretions in chronic blepharitis
Investigative Ophthalmology & Visual Science
The precorneal tear film. Biomicroscopical, histological and chemical investigations
Acta Ophthalmologica
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