Neural regulation of lacrimal gland secretory processes: Relevance in dry eye diseases
Introduction
The lacrimal gland, a tubuloacinar exocrine gland, secretes electrolytes, water, proteins, and mucins known as lacrimal gland fluid, into the tear film. The appropriate amount and composition of lacrimal gland fluid is critical for a healthy, intact ocular surface. As a small change in the concentration of tear electrolytes is correlated with dry eye syndrome, secretion of lacrimal gland electrolytes must be tightly regulated. Furthermore the lacrimal gland synthesizes and secretes a plethora of proteins with a variety of functions that help to nourish and protect the corneal and conjunctival epithelia and to regulate the function of these tissues. Protein secretion, similarly to electrolyte and water secretion, is highly regulated. In the context of the need for control of lacrimal gland fluid secretion, neural regulation plays an integral role regulating lacrimal gland protein, electrolyte, and water secretion and hence tear volume and composition. A rapid neural response is critical to meet the needs of the ocular surface both in protection from the stresses of the environment (temperature, humidity, mechanical, chemical, or pathogenic) and the requirements of the surface epithelia (growth control, wound healing, electrolyte transport, maintenance of the tear/aqueous humor barrier, and shedding of surface proteins).
The neural response that regulates lacrimal gland fluid secretion is an integral part of the lacrimal gland functional unit that consists of sensory afferent nerves of the cornea and conjunctiva, the efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland, the lacrimal gland secretory cells, and the lacrimal gland excretory ducts (Fig. 1). Stimulation of the plentiful afferent, sensory corneal and conjunctival nerves activates the efferent nerves to the lacrimal gland stimulating secretion of lacrimal gland electrolytes, water, and proteins that exit the gland as lacrimal gland fluid via the excretory ducts onto the surface of the eye. This is not a simple reflex, but rather the sensory input is processed in the lacrimal nucleus of the brain, which also processes input from other centers (e.g. emotional input) to generate a graded output. The stimulation is graded so that low levels of sensory nerve stimulation produce enough lacrimal gland fluid to cover the ocular surface as the pre-corneal tear film. More intense stimulation causes increased lacrimal gland fluid secretion to wash away deleterious compounds on the ocular surface and produce overflow tears.
Sensory nerves of the ocular surface also regulate secretion of the conjunctival goblet and stratified squamous cells and the corneal epithelial cells that contribute mucins, proteins, electrolytes, and water to the tear film. In turn these secretions can affect function of the sensory nerves. The neural regulation of corneal and conjunctival secretion has been recently reviewed (Lucarelli et al., 2002, Dartt, 2004a, Dartt, 2004b, Burkett et al., 2006).
This review will focus on neural stimulation of lacrimal gland secretion and will be divided into regulation of: 1) afferent sensory nerve stimulation from the ocular surface, 2) efferent parasympathetic and sympathetic activation of lacrimal gland secretory cells, and 3) the mechanism of protein, electrolyte, and water secretion from the lacrimal gland cells.
Section snippets
Structure of lacrimal gland
The main lacrimal gland is an almond-shaped gland that in many species, including humans and rabbits, is located within the bony orbit of the eye. In rats and mice, the main lacrimal gland is exorbital, lying just below the ear with its long axis perpendicular to the zygomatic arch, and is connected to the ocular surface with a single, long excretory duct (Venable and Grafflin, 1940). The excretory duct of the exorbital lacrimal gland runs forward across the temporal muscle directly to the
Afferent sensory regulation
The first segment of the lacrimal gland functional unit that regulates lacrimal gland secretion is the activation of sensory nerves in the corneal and conjunctival epithelia. The ocular surface epithelia are richly endowed with sensory nerve endings that respond to changes in the environment causing a rapid secretion of lacrimal gland fluid to wash away and chemically neutralize foreign substances that have entered the tear film (Mutch, 1944, Ruskell, 1971, Ruskell, 2004). Stimulation of
Overview of neural stimulation of lacrimal gland secretion
Activation of either parasympathetic or sympathetic nerves releases neurotransmitters that control lacrimal gland secretion of both proteins and electrolytes and water (Fig. 6). The major neurotransmitters that regulate secretion are the parasympathetic neurotransmitters acetylcholine and VIP, as well as the sympathetic neurotransmitter norepinephrine. These agonists are all stimulatory and each activates a different, separate signaling pathway, although these pathways interact. The signaling
Cholinergic agonist effects on secretion
When considering the target tissue of the nerves, the lacrimal gland, the evidence is overwhelming that cholinergic agonists stimulate lacrimal gland protein and fluid (electrolyte and water) secretion. Evidence is based on drug effects in humans, in vivo studies in rabbits and rats using denervation or systemic administration of agonists and antagonists, and in vitro studies in rabbits, rats, and mice using tissue pieces or collagenase-digested acini (groups of acinar cells). In humans,
Neural stimulation of lacrimal gland secretion – VIP, parasympathetic pathway
Parasympathetic nerves release VIP in addition to the cholinergic agonist acetylcholine. VIP is an important regulator of tear production in humans (Gilbard et al., 1988). This was illustrated by a patient who had a VIP secreting tumor, a VIPoma that raised the circulating VIP levels. This individual had an increased tear volume and decreased tear osmolarity compared to aged matched controls indicating that VIP increases tear production in humans and the effect was most likely by stimulating
Stimulatory nitric oxide signaling pathway
Sympathetic nerves release the neurotransmitter norepinephrine that can activate α- and β-adrenergic signaling pathways. In the lacrimal gland, the predominant pathway activated by norepinephrine is the α1-adrenergic pathway (Thorig et al., 1983, Dartt et al., 1994). Cloned α1-adrenergic receptors activate PLC to produce InsP3 and stimulate PLD activity. In contrast, in the lacrimal gland, α1-adrenergic receptors do not activate these pathways (Hodges et al., 1992, Gromada et al., 1995a,
Neural stimulation of secretion–interaction of cholinergic and α1-adrenergic pathways with the VIP pathway
Several laboratories demonstrated that the simultaneous addition of a Ca2+/PKC-dependent agonist such as cholinergic agonists, α1-adrenergic agonists or EGF with a cAMP-dependent agonist such as VIP caused synergism or potentiation of protein secretion (Dartt et al., 1984a, Dartt et al., 1984b, Dartt et al., 1988, Mauduit et al., 1987). Potentiation also occurred when the second messengers such as the intracellluar [Ca2+] or PKC activity were increased at the same time as cellular levels of
Newly identified lacrimal gland secretory proteins
One of the main functions of the lacrimal gland is to synthesize and secrete proteins into the tear fluid. These proteins play critical roles in protecting the cornea and conjunctiva from challenges in the external environment, as well as in regulating the function of these epithelia. Not surprisingly, the lacrimal gland secretes a myriad of proteins many of which are listed in Dartt and Sullivan (2000). Several secretory proteins have been newly identified in the lacrimal gland.
Sanghi et al.
Neural regulation of lacrimal gland electrolyte and water secretion
Although protein secretion is easily studied in a variety of in vitro preparations of lacrimal gland tissue, in vitro study of electrolyte and water secretion has been difficult until recent developments. Selvam et al., 2007a, Selvam et al., 2007b developed a method to culture lacrimal gland acinar cell monolayers on polyester membrane scaffolds. Using rabbit lacrimal gland acinar cells Selvam et al., 2007a, Selvam et al., 2007b confirmed the previous models of electrolyte and water secretion
Overview
Neural regulation of lacrimal gland function is complex with the first step in regulation being activation of sensory nerves in the cornea and conjunctiva, the second being stimulation of the efferent parasympathetic and sympathetic nerves, the third being activation of the cellular signaling pathways in acinar and duct cells, and the final step being the secretion of proteins, electrolytes, and water. An impairment of lacrimal gland function and resultant ocular surface diseases could occur at
Potential directions for future studies
Proper functioning of each component of the lacrimal gland functional unit including the afferent sensory nerves from the ocular surface, the efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland, and the lacrimal gland acinar and ductal cells is essential for secretion of lacrimal gland fluid in appropriate amount and composition thus ensuring a healthy ocular surface. Over the past few years significant progress has been made describing the activation of sensory
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