Neural regulation of lacrimal gland secretory processes: Relevance in dry eye diseases

doi:10.1016/j.preteyeres.2009.04.003

Progress in Retinal and Eye Research

Volume 28, Issue 3, May 2009, Pages 155-177

https://doi.org/10.1016/j.preteyeres.2009.04.003 Get rights and content

Abstract

The lacrimal gland is the major contributor to the aqueous layer of the tear film which consists of water, electrolytes and proteins. The amount and composition of this layer is critical for the health, maintenance, and protection of the cells of the cornea and conjunctiva (the ocular surface). Small changes in the concentration of tear electrolytes have been correlated with dry eye syndrome. While the mechanisms of secretion of water, electrolytes and proteins from the lacrimal gland differ, all three are under tight neural control. This allows for a rapid response to meet the needs of the cells of the ocular surface in response to environmental conditions. The neural response consists of the activation of the afferent sensory nerves in the cornea and conjunctiva to stimulate efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland. Neurotransmitters are released from the stimulated parasympathetic and sympathetic nerves that cause secretion of water, electrolytes, and proteins from the lacrimal gland and onto the ocular surface. This review focuses on the neural regulation of lacrimal gland secretion under normal and dry eye conditions.

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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Neural regulation of lacrimal gland secretory processes: Relevance in dry eye diseases

Abstract

Introduction

Section snippets

Structure of lacrimal gland

Afferent sensory regulation

Overview of neural stimulation of lacrimal gland secretion

Cholinergic agonist effects on secretion

Neural stimulation of lacrimal gland secretion – VIP, parasympathetic pathway

Stimulatory nitric oxide signaling pathway

Neural stimulation of secretion–interaction of cholinergic and α1-adrenergic pathways with the VIP pathway

Newly identified lacrimal gland secretory proteins

Neural regulation of lacrimal gland electrolyte and water secretion

Overview

Potential directions for future studies

Am. J. Ophthalmol.

Exp. Eye Res.

Neurosci. Lett.

Curr. Opin. Cell Biol.

Exp. Eye Res.

Trends Biochem. Sci.

Exp. Eye Res.

Exp. Eye Res.

J. Biol. Chem.

J. Diabetes Complications

Exp. Eye Res.

Ocul. Surf.

Exp. Eye Res.

Exp. Eye Res.

J. Steroid. Biochem. Mol. Biol.

Am. J. Med.

Brain Res.

Cell. Calcium

Microbes Infect.

Mol. Immunol.

Neuron

Int. Rev. Cytol.

J. Biol. Chem.

FEBS Lett.

FEBS Lett.

Neuron

Curr. Biol.

FEBS Lett.

Peptides

Exp. Eye Res.

Tear secretion induced by selective stimulation of corneal and conjunctival sensory nerve fibers

Invest. Ophthalmol. Vis. Sci.

Sensations evoked by selective mechanical, chemical, and thermal stimulation of the conjunctiva and cornea

Invest. Ophthalmol. Vis. Sci.

Muscarinic acetylcholine receptor antibodies as a new marker of dry eye Sjogren syndrome

Invest. Ophthalmol. Vis. Sci.

Involvement of the peripheral nervous system in primary Sjogren's syndrome

Ann. Rheum. Dis.

Eye dryness sensations after refractive surgery: impaired tear secretion or “phantom” cornea?

J. Refract. Surg.

Activation of protein kinase C does not cause desensitization in rat and rabbit mandibular acinar cells

Pflugers Arch.

Activation of Ca2+ entry into acinar cells by a non-phosphorylatable inositol trisphosphate

Nature

LBP and CD14 secreted in tears by the lacrimal glands modulate the LPS response of corneal epithelial cells

Invest. Ophthalmol. Vis. Sci.

Modification of stimulated lacrimal gland flow by sympathetic nerve impulses in rabbit

Am. J. Physiol.

Detection and localization of the hydrophobic surfactant proteins B and C in human tear fluid and the human lacrimal system

Curr. Eye Res.

Detection of surfactant proteins A and D in human tear fluid and the human lacrimal system

Invest. Ophthalmol. Vis. Sci.

Sympathomimetic protein secretion by young and aged lacrimal gland

Curr. Eye Res.

cAMP antagonizes p21ras-directed activation of extracellular signal-regulated kinase 2 and phosphorylation of mSos nucleotide exchange factor

EMBO J.

Physiology of the lacrimal system

Suppression of Ras-induced transformation of NIH 3T3 cells by activated G alpha s

Science

Effects of alpha1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells

Am. J. Physiol. Cell Physiol.

Inhibition by cAMP of Ras-dependent activation of Raf

Science

Vasoactive intestinal polypeptide stimulation of protein secretion from rat lacrimal gland acini

Am. J. Physiol.

Neural stimulation of secretion–interaction of cholinergic and α₁-adrenergic pathways with the VIP pathway

Activation of Ca²⁺ entry into acinar cells by a non-phosphorylatable inositol trisphosphate