Lacrimal Functional Unit

Tear flow is reflexively regulated by the lacrimal functional unit (Fig. 2.1). The lacrimal functional unit comprises the ocular surface, including the cornea, conjunctiva, and meibomian glands, the main and accessory lacrimal glands, and the neural network that connects them [33, 41]. Its overall purpose is to maintain corneal clarity and the quality of the image projected onto the retina. Corneal clarity depends, in turn, on the integrity of the tear film and the health of the ocular surface.

The lacrimal functional unit operates by a homeostatic mechanism. The status of the ocu

2.1 Introduction 13

lar surface is monitored by sensory nerves carrying information to the lacrimal centre in the brain stem. Autonomic secretomotor nerves direct secretory tissues and glands, including the main and accessory lacrimal glands, the meibomian glands, and the conjunctival goblet cells. The major variables which can be adjusted to influence the system's status (and thereby maintain or return to stasis) are the volume and composition of the tear film [33,41].

The tear film serves four important functions: it provides a smooth optical surface for normal vision, it maintains ocular surface comfort, it protects ocular surface tissues from environmental and infectious insults, and it contain factors important for maintenance of epithelial cell health. The tear film and the anterior surface of the cornea combine to provide approximately 80 % of the refractive power for the eye's focusing mechanism. Small changes in tear film stability and volume can result in tear film break-up, causing optical aberrations that can significantly degrade the quality of vision, primarily by decrease in contrast sensitivity. Tear film break-up likely contributes to the visual fatigue and photophobia experienced by many LKC patients [4]. Ocular surface comfort depends on the tear film's lubricating properties, which decrease the shear forces exerted by the superior lid margin during a normal blink cycle [6]. The mucin layer of the tear film is critical for this lubrication. The tear film protects the ocular surface, the most environmentally exposed mucosal surface of the body, from extremes of temperature and humidity, allergens, irritants and infectious agents. The surface lipid layer, secreted by the meibomian glands, prevents evaporation of the aqueous component and consequent increases in osmolarity of the tear film in adverse environments. Some of the proteins present in the tear film, such as immunoglobulin A, lactoferrin, lysozyme, and peroxidase, help resist bacterial or viral infections. Because the corneal epithelium lacks vasculature, it is dependent on tear film electrolytes and oxygen for tissue health, and on tear film growth factors to stimulate the constant regeneration of the corneal epithelium and for wound healing. An-tioxidants in the tear film help maintain a reducing environment and scavenge free radicals.

Traditionally the tear film was envisioned as three distinct components: a mucin layer coating the surface epithelium, an aqueous layer making up the majority of the tear film, and a thin lipid layer sitting on top to slow evaporation. That view has evolved to the currently proposed structure of a mucin/aqueous gel containing electrolytes, proteins, and regulatory factors that decreases in density toward the lipid layer (Table 2.1) [6,33]. The mucin component functions as a surfactant for the ocular surface, allowing the tear film to spread evenly over the hydrophobic epithelium. It includes the gly-cocalyx, composed of transmembrane mucins anchored to the epithelial cell surface [11], and soluble mucins, shed by epithelial cells and secreted by conjunctival goblet cells and the lacrimal glands [16]. Soluble mucins interact with the glycocalyx and the aqueous component to form a water-trapping gel.The mucin component may also help prevent adherence of inflammatory cells, bacteria, and debris to the ocular surface [11]. The aqueous component solubilizes oxygen, electrolytes, and numerous proteins and regulatory factors. Normal tear osmolarity, about 300 mOsm/l, is important to maintain normal epithelial cell volume, for maintenance of correct nerve membrane potential, and for cellular homeostasis and secretory function. The main and accessory lacrimal glands secrete the aqueous component of tears, although their relative contributions to tear volume are unresolved. The main lacrimal gland is responsible for reflex tearing,which can flush infective or irritating particles from the ocular surface. The composition of the lipid layer is complex, with polar lipids found mostly at the lipid-aqueous interface, and non-polar lipids found at the lipid-air interface. The very diverse array of lipids found in the tear film are secreted by the meibomian glands, whose ducts exit just anterior to the mucocutaneous junction of the lids. Blinking helps to spread the lipid layer uniformly over the tear film surface, a process assisted by the low surface tension of the lipid-air interface.

The lacrimal functional unit is provided information about the status of the ocular surface by afferent innervation via the first (ophthalmic) division of the trigeminal ganglion (or the second division for the lower lid). The

Table 2.1. Components of the tear film

Component

Secreted by:

Functions

Lipid Aqueous

Main and accessory lacrimal glands

Goblet cells, epithelia, lacrimal glands

Minimize evaporation Solubilize mucins, electrolytes, proteins Flush irritants (reflex tears) Lubrication; surfactant between hydrophobic epithelium and aqueous component

cornea, the most densely innervated epithelial surface in the body, and the rest of the ocular surface epithelia are populated by sensory neural receptors of a morphologically unspecified type, called free nerve endings. Sensations evoked are painful in nature, but aside from relatively infrequent traumatic events such as debris on the corneal surface, they are usually subconscious, and an individual is unaware of sensory input from the ocular surface. Reflex tearing and eyelid closure are the obvious responses to stimulation of corneal nerves.

Nerves from the parasympathetic spheno-palatine (pterygopalatine) ganglion are associated with the secretory glands of the lacrimal functional unit. Parasympathetic cholinergic nerves are primarily responsible for signalling reflex tear secretion, and acetylcholine (M3) receptors are present on secretory epithelia of lacrimal glands and on mucin-producing goblet cells in the conjunctiva [5]. Other parasympa-thetic neurotransmitters have also been detected near the lacrimal epithelium and meibomian glands [13]. Evidence for nerves of sympathetic origin has been found for the main and accessory lacrimal glands, the meibomian glands, and conjunctival goblet cells. Maintenance of the lacrimal gland secretory environment is also regulated by serum-derived factors, including androgen, oestrogen, progesterone, cortisol, insulin, thyroxin, and growth factors [43].

Lacrimal glands are composed of numerous lobules with secretory acini and ducts that converge into excretory ducts. The acini appear as rosettes of polarized columnar secretory epithelial cells in cross section whose apical surfaces terminate in the central lumen. The mid and apical regions of acinar cells contain numerous se cretory granules of protein products to be released, whereas the basal regions contain the nucleus surrounded by a prominent endoplasmic reticulum and Golgi apparatus. When a neuro-transmitter molecule binds a cognate receptor on the exterior of the acinar cell's basolateral membrane, it activates heterotrimeric G proteins on the cytoplasmic side [13, 25]. Their Ga subunits dissociate, exchange GDP for GTP, and initiate a cascade of intracellular regulatory events leading to Ca2+ influx and elevated cAMP. These mediators cause preformed transport vesicles (derived from the Golgi apparatus), containing proteins destined for secretion, to fuse with the apical cell membrane of the acinar cell, releasing the vesicle contents [44]. Secretion of water by lacrimal epithelial cells depends mostly on osmotic pressure generated by secretion of electrolytes, although secretion of proteins and mucins may contribute. The same receptor binding event that triggers protein secretion activates at least seven ion transporters that function together to secrete Na+, K+, and Cl- ions, resulting in secretion of water into the lacrimal ducts [45].

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