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Published in final edited form as: Exp Eye Res. 2020 Jun 16;197:108115. doi: 10.1016/j.exer.2020.108115

Biological Functions of Tear Film

Stephen C Pflugfelder 1, Michael E Stern 1,2
PMCID: PMC7483968  NIHMSID: NIHMS1608174  PMID: 32561483

Abstract

Tears have a vital function to protect and lubricate the ocular surface. Tear production, distribution and clearance is tightly regulated by the lacrimal functional unit (LFU) to meet ocular surface demands. The tear film consists of an aqueous-mucin layer, containing fluid and soluble factors produced by the lacrimal glands and mucin secreted by the goblet cells, that is covered by a lipid layer. The array of proteins, glycoproteins and lipids in tears function to maintain a stable, well-lubricated and smooth optical surface. Tear factors also promote wound healing, suppress inflammation, scavenge free radicals, and defend against microbial infection. Disease and dysfunction of the LFU leads to tear instability, increased evaporation, inflammation, and blurred and fluctuating vision. The function of tear components and the consequences of tear deficiency on the ocular surface are reviewed.

Keywords: Tears, Tear stability, mucin, lipid, growth factor, innate immunity, dry eye, dry eye disease, visual acuity, pain

1. Introduction

The tear film is the interface between the ocular surface epithelium and the environment. Although the precorneal tear thickness is estimated to be 3 microns (King-Smith et al., 2000), it has a highly complex composition containing water, electrolytes, mucins, and an array of proteins and lipids. Indeed, a study surveying human tear fluid using liquid chromatography-mass spectroscopy (LC-MS) reported detection of over 1500 proteins (Zhou et al., 2012). The structure of the tear film continues to evolve, but evidence suggests it consists of a hydrated mucus layer (secretory mucus layer) covered by lipid that moves over the glycocalyx on the surface epithelium (Figure 1) (Yokoi and Georgiev, 2018). Knowledge regarding the biological function of the tears is based on activity of individual constituents (e.g. growth factors), imaging studies and the consequences of tear deficiency. Findings from these studies show tears function to maintain comfort, prevent infection, suppress inflammation, heal traumatic and surgical injuries, clear debris and maintain high quality vision. Evidence in support of these functions are reviewed herein.

Figure 1.

Figure 1.

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Tear film structure. Evidence suggests the tear film consists of membrane associated mucins (MAM) such as MUC16 that form the glycocalyx on the apical epithelium, a secretory mucus layer containing soluble MUC5AC mucin secreted by the conjunctival goblet cells, aqueous fluid and electrolytes, and proteins secreted by the lacrimal glands. The surface of the tears is covered with a lipid layer with polar lipids adjacent to the aqueous layer and nonpolar lipids interfacing with the air.

2. Methods.

A literature search of clinical and basic studies, and review articles published from 1960 to 2020 was performed in PubMed.gov using major terms tear film, tear function and tear stability and subheadings mucin, lipid, growth factors, cytokines, visual acuity and pain. The bibliographies of references identified by this strategy were also reviewed.

3. Regulation of Tear production

The normal tear film contains a tightly controlled complement of ions, proteins and lipids which allow it to fulfill its basic functions. Perhaps its most important function is the primary optical surface of the eye (Tutt et al., 2000). The tear film assures eye comfort through its lubricative properties which decrease shear forces from the lid margin as it traverses the ocular surface during a blink cycle (Rolando and Zierhut, 2001). Reduced tear volume and altered tear film composition in DED can lead to increased shear force levels capable of causing epitheliopathy of the lid marginal conjunctiva that wipes the ocular surface during blinking (termed lid wiper epitheliopathy), as well as corneal epithelial disease, nociceptor stimulation and pain (Korb et al., 2005). Another function of the normal tear film is protection of the ocular surface epithelium from the environmental insults incurred on a daily basis. These include microbes, pollutants, allergens and adverse environmental conditions, such as low humidity and rapid air movement from wind or inside air handling. This is accomplished through regulated secretion of fluid containing protective factors, including hydrating glycoproteins and antimicrobials (e.g. IgA, lactoferrin, lysozyme and defensins) (Zhou et al., 2007; Zhou et al., 2004). The tear film functions to provide a trophic environment to the ocular surface epithelial tissues. Integrity and secretory function of the epithelium is important to maintain its role as an innate barrier and “seal” over the extensive network of epithelial free nerve endings (Zhou and Beuerman, 2012).

The lacrimal functional unit (LFU) regulates the production, delivery and clearance of tears to maintain a homeostatic environment on the ocular surface (Stern et al., 1998a, b). Anatomically, the LFU includes the tear secreting glands (main and accessory glands lacrimal glands, Meibomian glands, conjunctival goblet cells), the surface epithelium, eye lids, lacrimal drainage system, the glandular and mucosal immune system and the interconnecting innervation. The neural component of the LFU consists of a reflexive loop starting at the highly innervated cornea with afferent traffic to the central nervous system, including the brainstem and cerebral cortex (Figure 2). These afferents along with emotional centers in the brain project to secretory and motor efferent nerves to drive tear production and blinking. The efferent pathways are found to terminate within the main and accessory lacrimal glands, conjunctival goblet cells and the meibomian glands, indicating that secretion of all major components of the tear film are tightly controlled to maintain a normal homeostatic tear composition. Seminal work by Carlos Belmonte and colleagues characterized the types of ocular surface nociceptors and made a critical discovery that the TRPM8 “cold receptor” stimulated by cooling of the corneal surface between blinks, is responsible for driving normal tear flow (Parra et al., 2010).

Figure 2.

Figure 2.

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Lacrimal Functional Unit (LFU). The LFU regulates the production, delivery and clearance of tears to maintain a homeostatic environment on the ocular surface. Anatomically, the LFU includes the main and accessory lacrimal glands, Meibomian glands, conjunctival goblet cells, the surface epithelium, eye lids, lacrimal drainage system, the glandular and mucosal immune system and the interconnecting innervation. The neural component of the LFU consists of a reflexive loop starting at the highly innervated cornea surface with afferent traffic to the central nervous system, including the brainstem and cerebral cortex. These afferents project to secretory and motor efferent nerves to drive tear production and blinking. The efferent pathways are found to terminate within the secretory glands. Innate and adaptive inflammatory/immune pathways maintain immune tone to defend the ocular surface from microbial infection. Dysfunction of the LFU stimulates cytokine, chemokine and protease production by ocular surface epithelial and immune cells (cytokine storm) that results in autoantigen release, antigen presenting cell activation and migration to the lymph nodes and priming of effector CD4+ T cells that can traffic to the ocular surface and can provide the cytokines to stimulate autoantibody production by plasma cells. These immune mediators and cells cause ocular surface epithelial disease and can sensitize pain receptors.

Functional denervation of the ocular surface, either as a result of surgery or chronic disease such as diabetes, results in decreased tear secretion and surface epithelial disease with disrupted barrier function. It is now recognized that the dense innervation of the cornea is susceptible to insults that can cause neuropathic pain, including altered tear composition, inflammation and trauma (Rosenthal and Borsook, 2016).

Dysfunction of the LFU results in dry eye disease (DED), also described as Dysfunctional Tear Syndrome by the Delphi Panel, results in an altered tear composition that can’t maintain stability and protect the ocular surface and activates innate inflammatory and adaptive immunity to yet to be determined ocular surface antigens (Figure 2) (Behrens et al., 2006; Pflugfelder and de Paiva, 2017).

4. Stability.

Maintenance of tear stability is essential for maintaining comfort and quality vision. Tear stability requires dynamic interaction between the major tear constituents described below. An unstable tear film is the hallmark of tear dysfunction/deficiency and maintenance of stability is a major goal of therapy.

4.1. Mucins.

Tear mucus, composed of water and mucin glycoproteins serve to maintain barrier function, hydration and wettability of the hydrophobic surface epithelial cell membranes, provide a matrix for lacrimal secreted factors and minimize friction from blinking. The surface epithelial cells on the cornea and conjunctiva produce membrane associated mucins (MAM), including MUC1, MUC4, MUC16 that are the major constituents of the glycocalyx (Gipson, 2004; Pflugfelder et al., 2000) (Gipson et al., 2014). In addition to being expressed on the apical corneal and conjunctival epithelia, MUC16 has also been found on the surface of mucin granules in human conjunctival goblet cells and may participate in expelling gel forming mucin from these cells (Gipson et al., 2016). The goblet cells express the gel-forming mucin genes MUC5AC, MUC5B (in a subpopulation) and MUC2 (Gipson and Inatomi, 1998; Jumblatt et al., 2003; Marko et al., 2014; McKenzie et al., 2000) (Argueso et al., 2002; Spurr-Michaud et al., 2007) (Alam et al., 2020) Tear mucus is composed primarily of the gel forming mucin MUC5AC with minor contributions from membrane associated mucins shed from the surface epithelium (Spurr-Michaud et al., 2007).

MUC16 has the longest ectodomain of the membrane associated mucins and has an important function in maintaining lubricity and wettability by forming H-bonds with water (Georgiev et al., 2019). While there is no evidence that secreted mucins bind to MUC16, there may be chemical attractions between MUC16 and soluble tear mucins. Treatment of the rabbit cornea with N-acetylcysteine (NAC), an agent that disrupts disulfide linkages between cysteine residues was reported to decrease wettability (Tiffany, 1990), while treatment of the rat ocular surface decreased conjunctival microvilli area, increased tear MUC16 (indicating shedding) and corneal fluorescein staining and decreased tear MUC5AC concentration, surface wettability and tear break up time (Li et al., 2018). The gel formed by goblet cell secretory mucus moves over the ocular surface and contributes to tear stability by binding water (Gipson and Argueso, 2003). Secretory mucin also has been found to clear pathogens and debris (Gipson, 2016). Spdef knockout mice that lack goblet cells have increased debris in the tears and did not clear topically applied Pseudomonas bacteria, although they didn’t show increased susceptibility to corneal infection (Gipson, 2016).

Reduced conjunctival goblet cell density and levels of soluble goblet cell MUC5AC and have been reported in DED (Pflugfelder SC, 2015) (Khimani et al., 2020) (Uchino et al., 2014). Goblet cell loss also occurs in systemic inflammatory diseases, such as Sjögren syndrome, Stevens-Johnson syndrome and graft vs. host disease (GVHD) (Nelson and Wright, 1984; Pflugfelder et al., 1997; Ralph, 1975; Wang et al., 2010) Conjunctival goblet cell loss is correlated with severity of irritation symptoms, clinical ocular surface disease and level of ocular surface inflammation in aqueous tear deficiency (Zuazo et al., 2014). A significant inverse correlation was found between categorical severity of Sjögren syndrome associated DED using the Dry Eye Workshop scale and goblet cell density in the temporal and superior bulbar conjunctiva (Pflugfelder et al., 2018). Goblet cell density in the temporal bulbar conjunctiva was found to inversely correlate with Rose Bengal staining score at that site and with staining of the entire exposure zone (Pflugfelder et al., 1997). Goblet cell density was also noted to be inversely correlated with expression of the cytokine interferon gamma (IFN-γ) in the bulbar conjunctiva (Pflugfelder et al., 2015) and with the percentage of HLA-DR positive cells obtained in impression cytology (Pflugfelder et al., 2018). Eyes with significant goblet cell loss due to Stevens-Johnson syndrome and Sjögren syndrome are at risk for developing sight-threatening corneal ulceration and opacification that can occur bilaterally (Bagga et al., 2018; Ormerod et al., 1988; Pflugfelder et al., 1986).

4.2. Lipids

The surface lipid layer of the tear film, primarily derived from the Meibomian glands, serves as the interface between the aqueous layer and the air. Tear film lipid is composed of a thin layer of polar lipids interfacing with the underlying secretory mucus layer and a thicker layer of non-polar lipids at the air interface (Figure 1). The lipid layer functions as a smooth optical surface, reduces surface tension of the tear film, prevents anterior migration of aqueous tears on to the lid margin and retards evaporation (Georgiev et al., 2017) (Cwiklik, 2016). The lipid layer is compressed towards the lower lid during a blink, then spreads upward as the lid opens. Altered spreading and focal thinning of the lipid layer in Meibomian gland disease contributes to tear instability (Braun et al., 2015). Increased tear evaporation and osmolarity in areas of lipid thinning has been proposed to further destabilize the tears (Braun et al., 2014; Braun et al., 2015)

Modeling of tear osmolarity in areas of tear break up predicts that osmolarity could reach levels as high as 800–900 mOsM, much higher than the range measured in the inferior tear meniscus (290–340 mOsm in normal and 305–360 mOsm in DED) (Braun et al., 2015) (Braun et al., 2014; Peng et al., 2014) (Zubkov et al., 2012) (Lemp et al., 2011). The threshold of tear osmolarity stimulating pain sensation by corneal nociceptors is approximately 450mOsm (Liu et al., 2009), and topical application of hypertonic solutions in the range of 800–900 mOsm produced a similar level of irritation that occurs during tear break up (Liu et al., 2009). These findings indicate the focal rise in tear osmolarity could be responsible for the discomfort associated with tear breakup (Braun et al., 2015).

5. Visual performance

The tear film is a critical component of the optical system of the eye. The tears and the anterior surface of the cornea account for approximately 80% of the refractive power for the eye (Rolando and Zierhut, 2001). Deterioration in cornea surface smoothness, reduced contrast sensitivity and increased optical aberrations that degrade retina image quality in eyes with tear film instability highlight the functional role of the tear film in maintaining high quality vision (Rieger, 1992). Studies using the topographic surface regularity index (SRI) developed by Wilson and Klyce have found that reflections from the central cornea/tear film are more irregular in DED (Liu and Pflugfelder, 1999; Wilson and Klyce, 1991) (de Paiva et al., 2003). Furthermore, the timewise increase in SRI from 0–10 seconds after a blink was reported to be higher in DED (Gumus et al., 2011; Kojima et al., 2004). DED has also been found to increase optical scattering and optical aberrations (Diaz-Valle et al., 2012). Differences in tear film thickness during tear film break up increases higher order optical aberrations (Koh, 2016, 2018). These changes in optical properties may be responsible for the reduced low contrast visual acuity and functional visual acuity in DED. (Chotikavanich et al., 2009; Goto et al., 2002; Kaido et al., 2011; Rolando et al., 1998) (Liu et al., 2010; Szczotka-Flynn et al., 2019). These alterations may cause symptoms of visual fatigue, photophobia and stimulate increased blink rate. (Rahman et al., 2015)

6. Trophic/Wound Healing Factors

The aqueous-mucin tear layer contains numerous proteins, including growth and supportive factors. Some of these have a homeostatic function (e.g. suppress inflammation, maintain innervation or barrier), while others participate primarily in epithelial and/or stromal wound healing (Klenkler et al., 2007). The Table lists the most abundant tear growth factors and their function. Certain factors, such as epidermal growth factor (EGF), are secreted by the lacrimal gland into tears (Jones et al., 1997). Others, such as TGF-β are produced by the ocular surface stratified epithelium (TGF-β1 and β2) and goblet cells (TGF-β2) (Contreras-Ruiz and Masli, 2015; Pflugfelder et al., 2008; Torricelli et al., 2016; Yoshino et al., 1996). Concentrations of certain lacrimal gland secreted growth factors, such as EGF, decrease in aqueous tear deficiency (Lam et al., 2009); however, concentration or activity of others, such as NGF and TGF-β1 have been reported to increase in DED. (Lambiase et al., 2011; Zheng et al., 2010)

7. Innate Defense/antimicrobial factors

Since the initial discovery of lysozyme in the tears by Alexander Fleming in 1922, many anti-infective molecules have been found in the normal tear film (Gallo, 2013). They include lysozyme (present at 2.5mg/ml) (Wiesner and Vilcinckas 2010) and lactoferrin (present at 1.5 mg/ml) (Kijlstra et al., 1983; Wiesner and Vilcinskas, 2010). Lactoferrin’s basic anti-bacterial mechanism is through its ability to bind free iron which is necessary for bacterial growth (Flanagan and Willcox, 2009). This molecule, has both anti-infective (suppressing bacterial growth and preventing viral particles from entering cells) and anti-inflammatory (decreasing complement activation and scavenging free radicals) (Flanagan and Willcox, 2009). Like lactoferrin, lipocalin, which is produced and secreted by lacrimal gland acinar cells also exhibits an anti-bacterial function by interfering with free iron uptake (Dartt, 2011; Fluckinger et al., 2004). Prevention of damaging infection and inflammation in the cornea is essential for maintaining its clarity. Unlike the conjunctiva, the cornea poorly tolerates chronic inflammation. (Pers. Comm – J. Niederkorn). Another method by which the ocular surface is protected from pathogen intrusion is through sIgA (secretory immunoglobulin A). This antibody, secreted by plasma cells (terminally differentiated B cells), is taken up by acinar cells and re-secreted in a more stable form complexed with secretory component that can prevent adherence of pathogens to host epithelial cells. This has been shown by in the case of acanthamoeba and Staphylococcus aureus (Campos-Rodriguez et al., 2004; Lan et al., 1997) Use of mass spectrometry (LC-MS/MS) to evaluate protein profiles has elucidated the presence of β-defensins (hBD-2 and hBD-3) in tears. Concentration of β-defensins in normal tears may be sub-antimicrobial; however, they have been found to be upregulated following corneal surgery and in chronic disease processes (Zhou et al., 2007; Zhou et al., 2004). S100 proteins which inhibit bacterial adherence to mucosal epithelial cells have also been found in tears and also increase in chronic inflammation (Garreis et al., 2010; Raquil et al., 2008; Zhou et al., 2009a; Zhou et al., 2009b). A more extensive list of tear antimicrobial proteins is found by a review by Zhou and Beuerman (Zhou and Beuerman, 2012).

7. Anti-inflammatory/antioxidant factors

The tears contain factors that suppress inflammation, such as interleukin 1 receptor antagonist that binds the IL-1 receptor and inhibits IL-1 activity (Solomon et al., 2001), and TGF-β2 and vitamin A and its metabolites that suppress maturation and cytokine production by antigen presenting cells (Contreras-Ruiz and Masli, 2015; Lam et al., 2009; Pflugfelder et al., 2008; Ubels et al., 1986; Xiao et al., 2018) There are a number of antioxidants, including ascorbic acid, lactoferrin and cysteine, that scavenge and protect the ocular surface against damage from free radicals (Ohashi et al., 2006). Tear protease inhibitors include secretory leukocyte protease inhibitor (SLPI) that inhibits serine proteases (e.g. plasmin, elastase, cathepsin G) and tissue inhibitors of matrix metalloproteinases (MMPs). (Corrales et al., 2006; Sathe et al., 1998; Sobrin et al., 2000)

8. Summary

The tear film has a complex structure and composition that protects the cornea, promotes wound healing after injury and maintains eye comfort and high-quality vision. Altered tear composition and stability in DED causes eye irritation, corneal epithelial and nerve disease and blurred vision. The ease of collecting tear fluid, identification of relevant biomarkers in health and disease and more sensitive immunoassays that can be read by smartphones create technological opportunities for developing point of care tear biomarker testing.

Table.

Trophic and Wound Healing Factors

Factor Source Function/Properties
Transforming growth factor alpha (TGF-α) Lacrimal glands Mitogen (van Setten and Schultz, 1994; van Setten et al., 1996)
Transforming growth factor-β1 (TGF-β1) Lacrimal glands, surface epithelium Inhibits corneal epithelial proliferation, profibrotic (Gupta et al., 1996; Tuominen et al., 2001; Vesaluoma and Tervo, 1998; Yoshino et al., 1996)
Transforming growth factor-β2 (TGF-β2) Conjunctival goblet cells Suppresses antigen presenting cell maturation (Contreras-Ruiz and Masli, 2015; Kokawa et al., 1996; Pflugfelder et al., 1997)
Epidermal growth factor (EGF) Lacrimal glands Stimulates corneal epithelial proliferation and migration (Dartt, 2001; Pflugfelder et al., 1999; van Setten et al., 1989)
Hepatocyte growth factor (HGF) Fibroblasts, Lacrimal glands Stimulates corneal epithelial proliferation and migration, promotes wound healing (Li and Tseng, 1995; Li et al., 1996; Vesaluoma and Tervo, 1998; Wilson et al., 1999a; Wilson et al., 1999b)
Keratinocyte growth factor (KGF) Fibroblasts, Lacrimal glands Stimulates corneal epithelial proliferation (Li and Tseng, 1995; Wilson et al., 1999a; Wilson et al., 1999b)
Basic Fibroblast growth factor (FGF) Corneal epithelium Mitogenic, angiogenic and neurotrophic (Sekiyama et al., 2006; van Setten, 1996)
Platelet derived growth factor (PDGF BB) Fibroblast proliferation and migration (Tuominen et al., 2001; Vesaluoma et al., 1997a; Vesaluoma and Tervo, 1998)
Vascular endothelial growth factor (VEGF) Ocular surface epithelium Angiogenic (Enriquez-de-Salamanca et al., 2010; Vesaluoma et al., 1997b)
Insulin/IGF Lacrimal glands Stimulates corneal epithelial proliferation (Patel et al., 2018; Rocha et al., 2002)
Substance P Nerves Stimulates epithelial growth, wound healing (Fujishima et al., 1997; Varnell et al., 1997; Yamada et al., 2003)
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Highlights.

This review highlights the biological function of the tear film. The tear film has a complex structure and composition that protects the cornea, promotes wound healing after injury and maintains eye comfort and high-quality vision. Altered tear composition and stability in dry eye cause eye inflammation, corneal disease and blurred vision.

Funding:

This work was supported by NIH Grant EY11915 (SCP), NIH Core Grants-EY002520 & EY020799, Pathology Cell Core P30CA125123, Biology of Inflammation Center Baylor College of Medicine, an unrestricted grant from Research to Prevent Blindness, New York, NY (SCP), the Oshman Foundation, Houston, TX (SCP), the William Stamps Farish Fund, Houston, TX (SCP), Hamill Foundation, Houston, TX (SCP), Sid W. Richardson Foundation, Ft Worth, TX (SCP).

Footnotes

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Disclosure statement: None of the authors have any financial or personal relationships to disclose that would cause a conflict of interest regarding this article.

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