**2. Tear film structure and function**

The traditional description of the tear film is three-layered structure: superficial-oily, middle - aqueous and mucous layer at the base [1–3]. A more recently proposed model consists of two layers: superficial – lipids and mucin/aqueous glycocalyx gel with decreasing mucin concentration from epithelium to lipid layer [1, 3, 7, 8]. Some authors says, that the tear film is a single unit that acts like a fluid shell [9] (**Table 1** and **Figure 1**).


**Table 1.** *The function of tear film layers.*

### **2.1 Lipids**

The lipid layer is secreted by Meibomian glands, located within tarsal plates of upper and lower eyelids with some small contribution by Moll (modified apocrinic, sudoriferous) and Zeiss (modified subeceous) glands, located within superior and lower eyelids (connected with hair follicles) and possibly epithelial cells. The posterior, aqueous interface consists of polar lipids: ceramides, cerebrosides and phospholipids. The lipid-air interface is formed with nonpolar lipids: cholesterol esters, triglycerides and free fatty acids [1, 3, 7, 8, 10].

The main function of the lipid layer is to reduce evaporation of tears and improve the stability of them. Moreover, the lipid layer provides smooth refracting surface, limits contamination of ocular surface from particles (dust) and microorganisms, prevents tear contamination by skin lipids, limits aqueous layer surface tension and counteracts tears overflowing onto the skin. [1, 3, 7–14].

Regulation of lipid secretion supervenes through modulation of lipid synthesis or cell maturation. The Meibomian gland secretion is a subject of neuronal, hormonal

**3**

**2.2 Aqueous component**

**Figure 1.**

*Tear Film – Physiology and Disturbances in Various Diseases and Disorders*

and vascular influences. Androgen, estrogen and progesterone receptors have been identified in adult male and female rats, rabbits and humans. It is suggested that androgens stimulate and estrogens reduce Meibomian secretion [14–17]. Moreover, Meibomian gland function may be under direct neuronal (predominant parasympathetic, also sympathetic and sensory sources) or indirect vascular (vasoactive intestinal polypeptide VIP) influence to control lipid synthesis and/or excretion [2, 14, 15].

*Structure of the tear film: 1. Three layer conception. 2. Two layer conception.*

The main non-reflex production of aqueous part of mucin/aqueous gel is from the Krauze and Wolfring glands (accessory lacrimal glands) located in the conjunctiva of superior eye lid and superior conjunctival fornix. The main lacrimal gland is responsible for aqueous tears production secondary to deleterious stimulation and plays important, though not entirely clear role in non-reflecting tearing (dry eye syndrome is noted in patients with damaged main lacrimal gland) [1, 7, 8, 11, 18]. The aqueous layer consists of water, electrolytes, proteins, cytokines, vitamins, immunoglobulins and peptide growth factors. Moreover, amino acids, bicarbonate,

The aqueous portion of the tear film is responsible for ocular surface lubrication, washing away foreign bodies or contaminations and nourishing avascular cornea (oxygen, inorganic salts, proteins, glucose) [3, 16, 20]. The soluble mucins decrease the surface tension, impact coherence of the aqueous layer, contribute to tear film

calcium, urea and magnesium were detected in tear film [15, 19].

*DOI: http://dx.doi.org/10.5772/intechopen.94142*

*Tear Film – Physiology and Disturbances in Various Diseases and Disorders DOI: http://dx.doi.org/10.5772/intechopen.94142*

#### **Figure 1.**

*Ocular Surface Diseases - Some Current Date on Tear Film Problem and Keratoconic Diagnosis*

The traditional description of the tear film is three-layered structure: superficial-oily, middle - aqueous and mucous layer at the base [1–3]. A more recently proposed model consists of two layers: superficial – lipids and mucin/aqueous glycocalyx gel with decreasing mucin concentration from epithelium to lipid layer [1, 3, 7, 8]. Some authors says, that the tear film is a single unit that acts like a fluid

• Minimize the evaporation of water from the eye surface

• Limit contamination of ocular surface from particles(dust) and microorganisms

• Include proteins (lysozyme, lactoferrin, lipocain), immunoglobulins, defensins and

• Include growth factors, vitamins and electrolytes necessary for ocular surface health

• Form the outer layer of the tear film.

• Improve the stability of tear film • Provide smooth refracting surface

Aqueous phase • Constitutes roughly 90% of the tear film volume • Lubricate the ocular surface

and epithelial integrity

• Reduce friction during blinking • Clear the surface of pathogens and debris

• Take part in regulation of epithelial growth • Might be involved in cellular signaling

• Contribute to tear stability

• Isolate ocular surface from the environment

• Prevent tear contamination by skin lipids • Limit aqueous layer surface tension • Counteract tears overflowing onto the skin

• Wash away foreign bodies and contaminations

• Nourish the avascular cornea (oxygen, proteins, inorganic salts)

glycoproteins responsible for anti-microbial activity

• Realign corneal microirregularities (refractive properties) Mucous layer • Form a glycocalyx over the ocular epithelium that prevents pathogen adhesion • Bind water to hydrate and lubricate the ocular surface.

The lipid layer is secreted by Meibomian glands, located within tarsal plates of upper and lower eyelids with some small contribution by Moll (modified apocrinic, sudoriferous) and Zeiss (modified subeceous) glands, located within superior and lower eyelids (connected with hair follicles) and possibly epithelial cells. The posterior, aqueous interface consists of polar lipids: ceramides, cerebrosides and phospholipids. The lipid-air interface is formed with nonpolar lipids: cholesterol

The main function of the lipid layer is to reduce evaporation of tears and improve the stability of them. Moreover, the lipid layer provides smooth refracting surface, limits contamination of ocular surface from particles (dust) and microorganisms, prevents tear contamination by skin lipids, limits aqueous layer surface

Regulation of lipid secretion supervenes through modulation of lipid synthesis or cell maturation. The Meibomian gland secretion is a subject of neuronal, hormonal

tension and counteracts tears overflowing onto the skin. [1, 3, 7–14].

esters, triglycerides and free fatty acids [1, 3, 7, 8, 10].

**2. Tear film structure and function**

shell [9] (**Table 1** and **Figure 1**).

**Tear film layer Function**

Lipid layer (meibum)

**2**

**2.1 Lipids**

*The function of tear film layers.*

**Table 1.**

*Structure of the tear film: 1. Three layer conception. 2. Two layer conception.*

and vascular influences. Androgen, estrogen and progesterone receptors have been identified in adult male and female rats, rabbits and humans. It is suggested that androgens stimulate and estrogens reduce Meibomian secretion [14–17]. Moreover, Meibomian gland function may be under direct neuronal (predominant parasympathetic, also sympathetic and sensory sources) or indirect vascular (vasoactive intestinal polypeptide VIP) influence to control lipid synthesis and/or excretion [2, 14, 15].

#### **2.2 Aqueous component**

The main non-reflex production of aqueous part of mucin/aqueous gel is from the Krauze and Wolfring glands (accessory lacrimal glands) located in the conjunctiva of superior eye lid and superior conjunctival fornix. The main lacrimal gland is responsible for aqueous tears production secondary to deleterious stimulation and plays important, though not entirely clear role in non-reflecting tearing (dry eye syndrome is noted in patients with damaged main lacrimal gland) [1, 7, 8, 11, 18]. The aqueous layer consists of water, electrolytes, proteins, cytokines, vitamins, immunoglobulins and peptide growth factors. Moreover, amino acids, bicarbonate, calcium, urea and magnesium were detected in tear film [15, 19].

The aqueous portion of the tear film is responsible for ocular surface lubrication, washing away foreign bodies or contaminations and nourishing avascular cornea (oxygen, inorganic salts, proteins, glucose) [3, 16, 20]. The soluble mucins decrease the surface tension, impact coherence of the aqueous layer, contribute to tear film

viscosity [14, 19]. Almost 500 different proteins have been extracted from the tear film [3, 21]. Lactoferrin, lysozyme, lipocalin, secretory immunoglobulin A(sIgA), immunoglobulin G(IgG), immunoglobulin M (IgM), albumin, transferrin, ceruloplasmin, defensins, tear specific prealbumin and glycoproteins participate in the ocular surface antimicrobial activity and defense [3, 15, 22]. Growth factors, vitamins, electrolytes, neuropeptides and protease inhibitors are necessary for retaining ocular surface health and epithelial integrity [1, 3, 23]. Retinol, secreted by the lacrimal gland, is necessary for maintenance of goblet cells and regulates corneal epithelium desquamation, keratinization and metaplasia [15, 24–26].

The lacrimal gland is affected by both nervous system and various hormones [1, 2, 7, 11, 15, 18, 23, 27]. The gland innervation comes from the first brunch of trigeminal nerve, the facial nerve and sympathetic fibers from the superior cervical ganglion [1, 11, 15, 28]. Stimulation of the ocular surface is the beginning of the main lacrimal gland production (reflexing tearing). The emotional tearing is also connected with this reflex loop (**Figure 2**). The meaning of the sympathetic part of innervation is thought to stimulate basal tearing but is still not completely understood. The accessory lacrimal glands are heavily innervated, but there is lack of parasympathetic part and most of the innervation is undefined [8, 15, 29].

Androgens and estrogens influence lacrimal gland production. Androgens lack is responsible for reversible degenerative changes of lacrimal gland, decreased volume of the tears, decreased level of proteins in tears. Estrogens remain controversial: some studies described estrogen deficiency linked to keratoconjunctivitis sicca (KCS) and lacrimal gland degeneration, other works have shown no changes in the lacrimal gland and tear film with decreased level of estrogens [15, 17, 30, 31]. Thyroid stimulating hormone (TSH) receptors (present in lacrimal gland) as well as thyroid

#### **Figure 2.**

*Reflex loop of tearing: 1. Stimulants: - ocular surface and nasal mucosa - afferent arm of the loop (first branch of the fifth cranial nerve)- emotions, 2. brain - efferent arm of the loop (parasympathetic part of the seventh nerve), 3. lacrimal glands.*

**5**

*Tear Film – Physiology and Disturbances in Various Diseases and Disorders*

glucose, leukocytes, cellular debris and enzymes [1, 3, 15, 33–35].

the mucins: cell surface-associated and secreted [36].

osmosensors in eukaryotic cells [36, 39, 40].

reason of evaporation (about 1,4–39,3 x 10−7 g/cm2

**2.4 Tear film dynamics**

hormone and tissue interaction are necessary for lacrimal gland secretion. Adequate insulin level is important for lacrimal gland and ocular surface stability and function, because it is necessary for acinar cell and cornea epithelial cell proliferation [32].

The mucous layer of the tear film is produced by both corneal and conjunctival epithelium and the lacrimal gland and conjunctival goblet cells [1, 3, 7, 11, 15, 33]. It is composed of secreted and transmembrane mucins, immunoglobulins, salts, urea,

Traditional description of the mucins role limits to secreted gel-forming mucins working as lubricating agents and clearing molecules. Current date indicate its role also as a barrier for corneal and conjunctival epithelium. We can find two kinds of

**Cell surface-associated mucins** form a thick cell surface glycocalyx, providing through their O-glucans a disadhesive character to the apical surface of the corneal epithelium. That is why they assure boundary lubrication and prevent adhesion of corneal epithelium and tarsal conjunctiva during blinking and sleeping [36, 37]. Moreover, membrane-bound mucins take part in the maintenance of the mucosal barrier integrity to prevent the penetrance molecules onto ocular surface epithelia [36, 38]. Some recent studies have weighed up membrane-bound mucins as

**Secreted mucins** have a capability to trap contaminations (e.g. allergens, debris, pathogens) in order to clearance them from mucosal surface. Gel-forming mucins retaining water, form highly hydrated gel to lubricate ocular surface and reduce shear stress during blinking or rubbing. Moreover, MUC 7 (detected in lacrimal gland), has potent antifungal and antimicrobial activity [34, 35, 37, 41–43].

Goblet cells may be stimulated for mucin secretion by histamine, antigen, immune complex, mechanical action (i.e. blinking), direct (muscarinic and α-adrenergic receptors on immature goblet cells) and indirect (sensory, sympathetic and parasympathetic innervation of conjunctiva surrounding goblet cells) neural control [15, 16, 44–46].

Balanced tear film production and elimination is crucial for its integrity, stability and right osmolality [3]. Tear film production is a complex process, controlled by the various factors: main and accessory lacrimal glands, ocular surface structures (cornea, conjunctiva, eyelids with Meibomian gland) and interconnecting nerves (both sensory and motor) [3, 47, 48]. Ryc.1. Tears elimination proceeds as evaporation, drainage and absorption. Tear film interfaces with the environment; that is the

factors like humidity, temperature and air movements impact the rate of tear evaporation from the ocular surface [50]. Higher evaporation is the reason of tear film thinning and, because of that, instability and hyperosmolality [51]. Regardless of the recent date on evaporation, tears outflow through the lacrimal drainage system remains the main way of its elimination. With each blink, tears with contaminations (like cellular debris, toxins, inflammatory cells and other waste products) are moved towards the lacrimal puncta and next - due to the negative pressure created in lacrimal drainage system - to the lacrimal drainage tract [3, 52]. Some studies noted reduction of tears production in patients with impaired drainage that highlights the importance of this process in the model of tear dynamics [53–55]. At least absorption: process necessary for proper tear film dynamics, connected with cornea, conjunctiva and - mainly - nasolacrimal duct epithelium [56]. The equilibrium in

/s) [5, 49]. Some environmental

*DOI: http://dx.doi.org/10.5772/intechopen.94142*

**2.3 Mucins**

hormone and tissue interaction are necessary for lacrimal gland secretion. Adequate insulin level is important for lacrimal gland and ocular surface stability and function, because it is necessary for acinar cell and cornea epithelial cell proliferation [32].

## **2.3 Mucins**

*Ocular Surface Diseases - Some Current Date on Tear Film Problem and Keratoconic Diagnosis*

viscosity [14, 19]. Almost 500 different proteins have been extracted from the tear film [3, 21]. Lactoferrin, lysozyme, lipocalin, secretory immunoglobulin A(sIgA), immunoglobulin G(IgG), immunoglobulin M (IgM), albumin, transferrin, ceruloplasmin, defensins, tear specific prealbumin and glycoproteins participate in the ocular surface antimicrobial activity and defense [3, 15, 22]. Growth factors, vitamins, electrolytes, neuropeptides and protease inhibitors are necessary for retaining ocular surface health and epithelial integrity [1, 3, 23]. Retinol, secreted by the lacrimal gland, is necessary for maintenance of goblet cells and regulates corneal epithelium desquamation, keratinization and metaplasia [15, 24–26]. The lacrimal gland is affected by both nervous system and various hormones [1, 2, 7, 11, 15, 18, 23, 27]. The gland innervation comes from the first brunch of trigeminal nerve, the facial nerve and sympathetic fibers from the superior cervical ganglion [1, 11, 15, 28]. Stimulation of the ocular surface is the beginning of the main lacrimal gland production (reflexing tearing). The emotional tearing is also connected with this reflex loop (**Figure 2**). The meaning of the sympathetic part of innervation is thought to stimulate basal tearing but is still not completely understood. The accessory lacrimal glands are heavily innervated, but there is lack of parasympathetic part and most of the innervation is undefined [8, 15, 29].

Androgens and estrogens influence lacrimal gland production. Androgens lack is responsible for reversible degenerative changes of lacrimal gland, decreased volume of the tears, decreased level of proteins in tears. Estrogens remain controversial: some studies described estrogen deficiency linked to keratoconjunctivitis sicca (KCS) and lacrimal gland degeneration, other works have shown no changes in the lacrimal gland and tear film with decreased level of estrogens [15, 17, 30, 31]. Thyroid stimulating hormone (TSH) receptors (present in lacrimal gland) as well as thyroid

*Reflex loop of tearing: 1. Stimulants: - ocular surface and nasal mucosa - afferent arm of the loop (first branch of the fifth cranial nerve)- emotions, 2. brain - efferent arm of the loop (parasympathetic part of the seventh* 

**4**

**Figure 2.**

*nerve), 3. lacrimal glands.*

The mucous layer of the tear film is produced by both corneal and conjunctival epithelium and the lacrimal gland and conjunctival goblet cells [1, 3, 7, 11, 15, 33]. It is composed of secreted and transmembrane mucins, immunoglobulins, salts, urea, glucose, leukocytes, cellular debris and enzymes [1, 3, 15, 33–35].

Traditional description of the mucins role limits to secreted gel-forming mucins working as lubricating agents and clearing molecules. Current date indicate its role also as a barrier for corneal and conjunctival epithelium. We can find two kinds of the mucins: cell surface-associated and secreted [36].

**Cell surface-associated mucins** form a thick cell surface glycocalyx, providing through their O-glucans a disadhesive character to the apical surface of the corneal epithelium. That is why they assure boundary lubrication and prevent adhesion of corneal epithelium and tarsal conjunctiva during blinking and sleeping [36, 37]. Moreover, membrane-bound mucins take part in the maintenance of the mucosal barrier integrity to prevent the penetrance molecules onto ocular surface epithelia [36, 38]. Some recent studies have weighed up membrane-bound mucins as osmosensors in eukaryotic cells [36, 39, 40].

**Secreted mucins** have a capability to trap contaminations (e.g. allergens, debris, pathogens) in order to clearance them from mucosal surface. Gel-forming mucins retaining water, form highly hydrated gel to lubricate ocular surface and reduce shear stress during blinking or rubbing. Moreover, MUC 7 (detected in lacrimal gland), has potent antifungal and antimicrobial activity [34, 35, 37, 41–43].

Goblet cells may be stimulated for mucin secretion by histamine, antigen, immune complex, mechanical action (i.e. blinking), direct (muscarinic and α-adrenergic receptors on immature goblet cells) and indirect (sensory, sympathetic and parasympathetic innervation of conjunctiva surrounding goblet cells) neural control [15, 16, 44–46].

#### **2.4 Tear film dynamics**

Balanced tear film production and elimination is crucial for its integrity, stability and right osmolality [3]. Tear film production is a complex process, controlled by the various factors: main and accessory lacrimal glands, ocular surface structures (cornea, conjunctiva, eyelids with Meibomian gland) and interconnecting nerves (both sensory and motor) [3, 47, 48]. Ryc.1. Tears elimination proceeds as evaporation, drainage and absorption. Tear film interfaces with the environment; that is the reason of evaporation (about 1,4–39,3 x 10−7 g/cm2 /s) [5, 49]. Some environmental factors like humidity, temperature and air movements impact the rate of tear evaporation from the ocular surface [50]. Higher evaporation is the reason of tear film thinning and, because of that, instability and hyperosmolality [51]. Regardless of the recent date on evaporation, tears outflow through the lacrimal drainage system remains the main way of its elimination. With each blink, tears with contaminations (like cellular debris, toxins, inflammatory cells and other waste products) are moved towards the lacrimal puncta and next - due to the negative pressure created in lacrimal drainage system - to the lacrimal drainage tract [3, 52]. Some studies noted reduction of tears production in patients with impaired drainage that highlights the importance of this process in the model of tear dynamics [53–55]. At least absorption: process necessary for proper tear film dynamics, connected with cornea, conjunctiva and - mainly - nasolacrimal duct epithelium [56]. The equilibrium in

the tear film production, retention and elimination acts the crucial role in its proper functioning, thereby ocular surface health [3].
