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Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

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The Normal Tear Film and Ocular Surface

Michael E. Stern

Allergan, Inc., Irvine, California, U.S.A.

Roger W. Beuerman

Louisiana State University Eye Center, New Orleans, Louisiana, U.S.A., and Singapore Eye Research Institute, Singapore

Stephen C. Pflugfelder

Baylor College of Medicine, Houston, Texas, U.S.A.

A normal tear film is required to maintain the health and function of the ocular surface. The pathological changes seen in dry eye disease affect all components of the tear film, changing the ocular surface environment from “ocular surface supportive” to “pro-inflammatory”. In this chapter we will discuss the makeup of the normal tear film and how it provides a supportive and protective environment for the mucosal surfaces of the eye—the cornea and conjunctiva.

I.FUNCTIONS OF THE TEAR FILM

The tear film serves four important functions: a smooth optical surface for normal vision, maintenance of ocular surface comfort, protection from environmental and infectious insults, and maintenance of epithelial cell health.

First, the tear film is a critical component of the eye’s optical system. It and the anterior surface of the cornea combine to provide approximately 80% of the refractive power for the eye’s focusing mechanism (1). Even a small change in tear film stability and volume will significantly change the quality of vision (primarily contrast sensitivity) (2,3). The lens and its controlling anatomy “fine-tune” this refractive power. Tear film breakup causes optical aberrations that can degrade the

42	Stern et al.

quality of images focused on the retina (4). Accordingly, the irregular preocular tear film of patients with lacrimal keratoconjunctivitis may be responsible for symptoms of visual fatigue and photophobia (5–7).

Second, the tear film helps maintain ocular surface comfort by continuously lubricating the ocular surface. The normal tear film is subjected to a shear force of about 150 dynes/cm2 by the superior lid margin traversing the ocular surface during a normal blink cycle (1,8). Non-Newtonian properties of the tear film’s mucin layer decrease this shear force, which would otherwise be exerted on the ocular surface epithelium, to a negligible level (9). In lacrimal keratoconjunctivitis, alterations of the mucin layer render the ocular surface epithelial cell membranes more susceptible to this shear force, resulting in increased epithelial desquamation and induction of pathological apoptosis (10).

Third, the tear film protects the ocular surface from environmental and infective intrusions. The ocular surface is the most environmentally exposed mucosal surface of the body. It continually encounters temperature extremes, humidity, wind, UV irradiation, allergens, and irritants, such as pollutants and particulate matter. The tear film must have sufficient stability to buffer the ocular surface microenvironment against these challenges. Protective components of the tear film, such as immunoglobulin A, lactoferrin, lysozyme, and peroxidase, resist bacterial or viral infections. The surface lipid layer minimizes evaporation of the aqueous component of the tear film in adverse environments. Additionally, tear production may be stimulated to help wash out particulates, irritants, and allergens.

Fourth, the tear film provides a trophic environment for the corneal epithelium. Because it lacks vasculature, the corneal epithelium depends on the tear film for growth factors and for certain nutritional support. The electrolyte and oxygen supply of the corneal epithelium is provided by the tear film (see Table 1). While most of the glucose utilized by the corneal epithelium is supplied by diffusion from the aqueous humor, tears contain about 25 g/mL glucose, roughly 4% of the glucose concentration in blood (13), a sufficient concentration to support nonmuscular tissue (Table 2). Tear film antioxidants help maintain a reducing environment and scavenge free radicals. The tear film also contains a plethora of growth factors, important for the constant regeneration of the corneal epithelium, and for wound healing (Table 3).

II.ALTERATIONS OF THE TEAR FILM LEADING TO LKC

Alterations of these tear film functions can result in visual disturbance and irritation, inflammation, and infection. As discussed at length in Chapter 2, the cornea is the most densely innervated surface of the body. Disruption of the corneal epithelium causes acute, severe pain. When the ocular surface is subjected to constant irritation, constant stimulation of ocular surface sensory nerve endings leads

The Normal Tear Film and Ocular Surface		43
Table 1 Electrolyte Concentrations in the Tear Film of Healthy Subjects

Sodium	133 mM
Potassium	24 mM
Calcium	0.80 mM
Magnesium	0.61 mM
Chloride	128 mM
Bicarbonate	33 mM
Nitrate	0.14 mM
Phosphate	0.22 mM
Sulfate	0.39 mM

Data sources: Refs. 11 and 12.

Table 2 Small-Molecule Concentrations in the Tear Film

Molecule	Concentration	Function	Reference

Retinol	16 ng/mL	Epithelial maintenance	14
	117 g/mL	and differentiation
Vitamin C	117 g/mL	Antioxidant	12
Tyrosine	45 M	Antioxidant	12
Glutathione	107 M	Antioxidant	12
Glucose	26 g/mL	Cellular metabolism	12
Prostaglandin E2	82 pg/mL		15

to release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), which are capable of inducing neurogenic inflammation. This is believed to be an important initiating factor in the pathogenesis of many cases of lacrimal keratoconjunctivitis. If left unchecked, constant environmental stimulation and increased surface shear forces will cause further irritation, abnormal sloughing of the ocular surface epithelium, and hyperemia of conjunctival vessels. Inflammation is initiated by blood proteins and immune cells leaking from the vessels into the substantia propria of the conjunctiva. Chronic inflammation of the ocular surface activates genes responsible for differentiation, such as keratins. Hyperkeratinization of the corneal and conjunctival epithelium results in a poorly lubricated and nonwettable surface (82,83), perpetuating a cycle of increasing inflammation and decreasing tear production.

III.TEAR FILM STRUCTURE AND STABILITY

The tear film is structured to maintain a stable supportive environment for the ocular surface in the face of challenging environments. The traditional structure of the

Table 3 Tear Proteins and Small Molecules

	M.W.	Concentration
Protein	(kDa)a	in tearsb	Source	Function/properties	References

Protective/anti-infective
Lactoferrin	76	1.35–6.3 mg/mL	Lacrimal gland	Iron binding, antibacterial, antioxidant;	16–23
				decreased in Sjögren’s syndrome
Lysozyme/muramidase	14.7	0.5–4.5 mg/mL	Lacrimal gland	Lyses bacteria by degrading	22,24,25
		30–55 µg/mL		peptidoglycan; buffers tear film
Phospholipase A2	16.1	30–55 µg/mL	Lacrimal gland	Antibacterial vs Gram positives,	26–28
				degrades phospholipids
Ceruloplasmin	120	103 ng/mL		Copper binding oxidase, superoxide	22
				dismutase activity
CuZn superoxide dismutase	16.1	0.76 mg/mL		Oxygen radical scavenger, produces	29
(SOD)				peroxide
Lysosomal enzymes				Phosphatase, sugar hydrolases	30
Immune system/inflammatory		186 µg/mL–
sIgA	385	186 µg/mL–	Lacrimal gland	Antibody, secretory form, includes	25,31,32
		2.42 mg/mL		secretory component
Secretory component	61	5.6 µg/mL	Lacrimal gland	Free form	33
sIgM	970	5.6 µg/mL	Lacrimal gland	Antibody, secretory form	31
IgG	146	6.7 µg/mL	plasma	Antibody	31
Complement components				Bacterial and cell lysis	34–36
IL-1α	18.0	43 pg/mL	Lacrimal	Pro-inflammatory cytokine, elevated in	23
			gland, ocular	dry eye
			surface cells

.al et Stern

IL-1β	17.4	30 pg/mL	Lacrimal	Pro-inflammatory cytokine, elevated in	23
			gland, ocular	dry eye
			surface cells	Cytokine; inhibits IL-1α and -β
IL-1 Ra (IL-1 receptor	17.1	295 ng/mL	Lacrimal	Cytokine; inhibits IL-1α and -β	23
antagonist)			gland, ocular	activities by competitively binding
			surface cells	to soluble IL-1
IL-2	15.4	38 pg/mL	Ocular surface	T-cell homing and activation	37
			T cells
IL-5	13.1	40 pg/mL	Ocular surface	TH2 cytokine; stimulates eosinophils,	37
			T cells	increased in allergy
IL-6	20.8	42 pg/mL; 4.5	Lacrimal	Pro-inflammatory cytokine; increased	38,39
		pg/mg protein	gland, ocular	in Sjögren’s syndrome
			surface cells
FasL	31.5	0.30 ng/mL		Regulator of apoptosis	40
Tumor necrosis factor-α	25.6	0.36–1.97 ng/mL	Lacrimal	Pro-inflammatory cytokine, regulator	41–43
(TNF-α)			gland, ocular	of apoptosis
Interferon-γ			surface cells
Interferon-γ	19.3	91 pg/mL	Ocular surface	Pro-inflammatory cytokine	37
			T cells
Tear film maintenance
Lipocalin [tear-specific pre-	17.4	0.5–1.5 mg/mL	Lacrimal	Lipid scavenging and transport to	44
albumin (TSPA)]			glands	outer tear layer
Albumin	66		Plasma	Bulk lubricant
MUC1	120++		Ocular surface	Transmembrane component of tear	45
			epithelia	mucin gel, lubrication/protection

Surface Ocular and Film Tear Normal The

(continues)

Table 3 Continued

	M.W.	Concentration
Protein	(kDa)a	in tearsb	Source	Function/properties	References

MUC4 (Sialomucin)	125++		Lacrimal	Both soluble and membrane-bound	46–48
		variable, 0–200	glands,	forms exist; tear mucin gel,
		µg/mL	Ocular	lubrication/protection
			surface
			epithelia
MUC5AC	113++		Conjunctival	Glycoproteins, MW > 1000 kDa with	47,49,50
			goblet cells	carbohydrate moieties, tear mucin
				gel, lubrication/protection; tear
				concentration decreased in
				Sjögren’s syndrome
MUC7	37+		Lacrimal	“Salivary mucin”; soluble component	51
			glands,	of tear mucin gel,
			Ocular	lubrication/protection
		19–280 ng/mL	surface
			epithelia
Corneal health & wound
healing
Fibronectin	240	0.10–0.25 ng/mL		Increased concentration after PRK	52–55
Gm-CSF protein	14.5			Granulocyte macrophage colony	56
		63 pg/mL–8		stimulating factor; pro-inflammatory
		ng/ml		cytokine
Transforming growth factor-	5.6	2.98 ng/ml; 55	Lacrimal	Mitogen	57,58
α (TGF-α)		pg/mL	glands
Transforming growth factor-	12.8	(mature form)	Lacrimal	Inhibits corneal epithelial cell prolife-	41,43,
β1 (TGF-β1)		0.5 ng/mL	glands	ration, anti-inflammatory, profibrotic	59,60

.al et Stern

Transforming growth factor-	12.7		Epithelial cells	Inhibits corneal epithelial cell	61
β2 (TGF-β2)				proliferation, anti-inflammatory,
				profibrotic
Tear hepatocyte growth	25.9		Fibroblasts	Hepatopoetin A; stimulates corneal	43,62–
factor (HGF)			Lacrimal	epithelial cells, promotes wound	64,
			gland	healing	129,
					130
Keratocyte growth factor	18.9		Fibroblasts	Stimulates corneal epithelial cells,	62–64,
		0.71–1.7 ng/mL	Lacrimal	promotes wound healing	130
			gland
Basic fibroblast growth	17.2,	0.1–1.7 ng/mL		Mitogenic, angiogenic, and	65
factor (FGFβ; FGF2)	22.6	(variable)		neurotrophic growth factor
Epidermal growth factor	6.2	19 ng/mL	Lacrimal	Mitogen; decreased in Sjögren’s	38,66
(EGF)			glands	syndrome
Platelet-derived growth	12.3	0.40 ng/mL		Induced after PRK	41,43,67
factor BB		0.83 µg/mL
Vascular endothelial growth	25.2			Angiogenic mitogen for vascular	43
factor (VEGF)				endothelial cells
Insulin		0.13–0.31 ng/mL		Effect on surface tissue unknown	68
Tenascin	239			Extracellular matrix protein; wound	43
				healing
Neuropeptides		198 ng/min
Substance P	1.35		Nerve endings	Stimulates epithelial growth, wound	69–71
				healing; elevated in allergic
				conjunctivitis
Calcitonin gene-related	3.79	0.03–0.06 IU/mL	Nerve endings		72
peptide (CGRP)
Proteases/protease		0.0073 IU/mL
inhibitors
					(continues)

Surface Ocular and Film Tear Normal The

Table 3 Continued

	M.W.	Concentration
Protein	(kDa)a	in tearsb	Source	Function/properties	References

Plasminogen activator	31,46			Protease, activates plasminogen,	73
(urokinase type)		1–14 µg/mL		matrix degradation/wound healing
Plasminogen/plasmin	88	1–14 µg/mL		Protease (active form: plasmin)	74
		106 µg/mg tear		cleaves fibronectin, matrix
		protein		degradation/wound healing;
α1-Antichymotrypsin		14 µg/mg tear		elevated in dry eye
α1-Antichymotrypsin	46	protein		Protease inhibitor	75
α1-Protease inhibitor	44			Antitrypsin; protease inhibitor	76
α2-Macroglobulin		5–10 µg/mL		(elastase, plasmin, thrombin)
α2-Macroglobulin	161	5–10 µg/mL	Plasma	Inhibitor of all types of proteases	76
Cystatins	13.8–	0.84 ng/mg tear	Lacrimal gland	Protease inhibitors (thiol proteases)	77
	14.3	protein
Secretory leukocyte protease	11.8			Protease inhibitor (elastase, trypsin,	75
inhibitor (SLPI)				chymotrypsin)

.al et Stern

Matrix metalloproteinase 2	62		Lacrimal	Gelatinase A; matrix	78
(MMP-2)			gland/ocular	degradation/wound healing
			surface
Matrix metalloproteinase 3	43			Stromelysin; activator of MMP-9;	79
(MMP-3)				matrix degradation/wound healing
		7.3 ng/mg or
Collagenase-2 (MMP-8)	42	7.2 U/mg tear	PMNs and	Matrix degradation/wound healing;	80
		protein	epithelial	activated by MMP-14
		3.3 ng/mL	cells
Matrix metalloproteinase 9	66, 87		PMNs and	Matrix degradation/wound healing;	23,78
(MMP-9)			epithelial	66to 90-fold elevated in dry eye,
			cells	activated by MMP-3
Tryptase	27		Mast cells	Protease, elevated in allergic	81
				inflammation

aMolecular weight of mature protein, from the National Center for Biotechnology Information (NCBI) database. Carbohydrate moieties can add to the molecular weight, most substantially for mucins.

bConcentrations given are from tears of normal subjects. A few values are expressed as amount released into tears per unit time.

Surface Ocular and Film Tear Normal The

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