The Lacrimal Gland and Its Veil of Tears

Benjamin Walcott

The secretory cells of the lacrimal gland produce a highly complex product of
water, ions and proteins. At least five neurotransmitter receptors and three
different second message systems are involved in controlling the different
secretory processes of this highly sophisticated secretory epithelium.

T he tear film that covers the anterior surface of

the mammalian eye has a variety of con-
stituents that are essential for the maintenance of
the avascular transparent corneal epithelium.
This film keeps the cornea wet, thus allowing gas
B. Walcott is an Associate Professor in the Dept. of Neuro-
biology and Behavior at the State University of New York,
Stony Brook, NY 11794–5230, USA.
0886-1714/98 5.00 @ 1998 Int. Union Physiol. Sci./Am.Physiol. Soc.
exchange between the air and the epithelium. It
cleans debris from the transparent surface, pro-
viding a clear optical path to the retina, and pro-
“The tear film also
provides essential
tects the ocular surface from invasion by bacteria metabolites such as
and viruses. The tear film also provides essential retinol. . . .”
metabolites such as retinol, which serves to pre-
serve the transparent nature of the epithelium.
The tear film is structurally complex with three
distinct layers: a surface lipid layer (0.1–0.2 µm
thick), a middle aqueous layer (7–8 µm thick),
News Physiol. Sci. • Volume 13 • April 1998 97
 and an inner mucus layer (30 µm thick). The
mucus layer is associated with the microvilli of
the corneal epithelial cells and becomes less
dense toward the aqueous layer where the
boundary is indistinct. In mammals, the mucus
layer is produced by goblet cells in the cornea
and conjunctiva, the aqueous layer by the
lacrimal glands and other accessory glands, and
the surface lipid layer by the meibomian glands
and, in the case of many nonprimates, by the
harderian glands as well.
The most studied of these sources of the tear
“The growth factors. . . film are the lacrimal glands, which are the largest
are thought to be of these organs in mammals and are easily acces-
involved in the sible. In rodents, for example, the extraorbital
wound healing lacrimal gland is found under the skin on the lat-
process. . . .” eral side of the face near the ear. In the rabbit, the
gland is located within the orbit but is relatively
easy to remove and is larger in size. Most physi-
ological studies have used glands from either the
mouse, rat, or rabbit to examine the control and
mechanisms of secretion by this epithelium. This
work is important in part because dysfunction of
the lacrimal gland can lead to dry eye, which is
a painful and potentially blinding condition. The
lacrimal gland epithelium also is an elegant
secretory tissue of multiple functions with com-
plex control systems that can serve as a model
for other secretory epithelia.
The nature of tear fluid
The fluid secreted by the lacrimal glands is a
complex solution of ions and proteins produced
by two resident secretory cell populations: the
plasma cells of the immune system and the aci-
nar and duct cells of the secretory epithelium of
the gland. The plasma cells are found in the inter-
stitial spaces of the gland and migrate into it from
lymphoid organs such as the gut-associated lym-
phoid tissue (GALT). These plasma cells secrete
immunoglobin A (IgA) which is important in pro-
tecting the ocular surface from infection. The aci-
nar cells of the secretory epithelium have three
main functions: to synthesize and secrete a num-
ber of tear-specific proteins, to secrete water, and
to transport the IgA secreted by the plasma cells
from the interstitial compartment into the lumen
of the gland.
The lacrimal gland-specific proteins found at
highest concentrations in the tears are lactoferrin,
tear-specific prealbumin (TSP or lipocalin), and
lysozyme (7). Other proteins occurring at lower
concentrations are amylase, peroxidase, plas-
minogen activator, prolactin, epidermal growth
factor (EGF), transforming growth factor-β (TGF-
β), endothelin-1, and retinol. Lactoferrin, TSP,
peroxidase, and lysozyme as well as IgA function
98 News Physiol. Sci. • Volume 13 • April 1998
to protect the cornea from viral and bacterial
infections. This is important because the cornea
is a wet, warm surface and thus is an ideal path-
way for pathogens to invade the body and to
affect the cornea. Retinol, which is derived from
vitamin A, is necessary for the health of the
cornea. The growth factors, TGF, EGF, and
endothelin-1, are thought to be involved in the
wound healing process in response to corneal
abrasion or ulceration. The osmolarity of the
lacrimal fluid is about 300 mosM and contains
Na+ (128.7 mM), K+ (17 mM), Cl– (141.3 mM),
and bicarbonate (HCO3–; 12.4 mM) (12). This
fluid has about the same osmolarity as plasma
but has lower Na+ (140 mM plasma) and higher
K+ (4 mM plasma) and much higher Cl– (100 mM
plasma). As is discussed later, the higher K+ and
Cl– are a reflection of the way in which water is
moved across the epithelium and into the gland
lumen.
Anatomy
The lacrimal glands consist of a tubular secre-
tory epithelium organized into lobes that drain
into ducts; these ducts anastomose into larger
ducts that finally drain onto the ocular surface.
Associated with the secretory tubules are myoep-
ithelial cells (which are thought to “squeeze” the
secretory products down the tubules), fibroblasts
(which produce the collagen and matrix that fill
the interstitial regions), and occasional mast cells
(which secrete histamine and heparin). In addi-
tion, there are B cells and T cells of the immune
system as well as plasma cells normally scattered
throughout the interstitium of the gland. As with
most secretory epithelia, the cells of the secreto-
ry tubules (the acinar cells) are columnar with
basally located nuclei and a large perinuclear
Golgi apparatus. The duct cells are similarly
organized, although they are more cuboidal in
shape. The apical portion of the acinar and duct
cells is filled with vesicles, which, in most cells,
are not dense and therefore give the cell a
“frothy” appearance in the light microscope. The
base of the cells has an associated basement
membrane, which is important in the polariza-
tion and function of the cell. The cells have a
large junctional complex near the luminal pole
that serves to mechanically attach the cells to
each other and to couple them electrically and
chemically. There are extensive gap junctions in
this region, which consist of the connexins 26
and 32. Gap junctions can also be found outside
of the junctional complex in some species such
as the mouse. The high density of junctions in
this gland suggests that acinar cells could be cou-
pled both within and between secretory tubules.
FIGURE 1. A flow diagram showing the various receptors found on the acinar cell surface, their relation to second messenger
systems, and their ultimate effect on protein and water secretion. Many gaps in this scheme remain to be filled, for example,
how the activity of protein kinase C (PKC) and protein kinase A (PKA) actually increases vesicle fusion. Note that ion channels
(and thus water movement) are largely regulated by intracellular Ca2+ (Cai), which is increased by the action of both inositol
trisphosphate (IP3) (in the ACh pathway) and cAMP [in the vasoactive intestinal peptide (VIP) pathway]. Enk, enkephalin; a-
ADR, a-adrenoreceptor; ACTH, adrenocorticotropic hormone; AC, adenylate cyclase; DAG, diacylglycerol.

The glands are innervated by both the sympa-

thetic and parasympathetic divisions of the auto-
nomic nervous system (8). The detailed pattern
and nature of the innervation vary considerably
among different species, but all have extensive
numbers of cholinergic fibers, many of which
also contain the neuropeptide vasoactive intesti-
nal polypeptide (VIP), and fewer adrenergic
fibers. The rat extraorbital lacrimal gland, for
example, has a moderate density of large non-
varicose fibers, whereas the same gland in the
mouse has a very dense pattern of small, highly
varicose fibers. Birds have large numbers of
adrenergic neurons and also substance P-con-
taining neurons (14). In the rabbit and rat, fibers
that are positive for the enkephalins, specifically
Leu and Met enkephalin, also exist. Other neu-
ropeptides have been reported in various
lacrimal glands as well; for example, in the mon-
key, neuropeptide Y and calcitonin gene-related
peptide are present. The innervation therefore is
highly complex and is species specific in detail.
The nerves that innervate the lacrimal glands
come from autonomic ganglia. The parasympa-
thetic postganglionic neural cell bodies are
found in the pterygopalatine (sphenopalatine)
ganglion as well as the ciliary ganglion. Sympa-
thetic fibers originate in the superior cervical
ganglion, and there is some innervation, proba-
bly sensory, from the trigeminal ganglion (13).
The pathways from these ganglia to the gland
vary significantly from species to species.
Protein secretion
As described earlier, a number of proteins are
synthesized and secreted by the lacrimal gland “. . .a number of
acinar cells. The secretion of these proteins is proteins are
stimulated by the neurotransmitters and neu- synthesized and
ropeptides found in the neurons that innervate secreted by the
the gland. The acinar cells, therefore, have recep- lacrimal gland acinar
tors for acetylcholine (muscarinic M3) (9), VIP cells.”
(types I and II), and norepinephrine (α1 and β)
and presumably, in some cases, have receptors
for peptides of the proenkephalin family as well
as other peptides such as neuropeptide Y,
adrenocorticotropic hormone (ACTH), and α-
melanocyte-stimulating hormone (α-MSH).
Immunocytochemical localization of M3 mus-
carinic acetylcholine receptors and of both VIP
receptors shows that not all acinar cells possess
these receptors. However, because the acinar
cells are extensively coupled by gap junctions,
second messengers produced by activation of
those receptors, such as Ca2+ and inositol
trisphosphate (IP3), could easily diffuse from
stimulated cells to adjacent nonstimulated ones,
causing them to become activated. As far as is
known, all the membrane receptors are coupled
to G proteins that in turn regulate the activity of
the several second messenger systems found in
many cells (Fig.1).
The muscarinic acetylcholine receptors are
linked to G proteins (Gs and Gq/11), which are
coupled to phospholipase C, resulting, on activa-
News Physiol. Sci. • Volume 13 • April 1998 99
 tion, in increased production of IP3 and diacyl-
glycerol (DAG) (4). IP3 induces the release of
intracellular stores of Ca2+ and also is believed to
open membrane Ca2+ channels. These ion chan-
nels are few in number and are small so that their
detection by patch-clamp methods is difficult.
The effect of these actions is to increase the intra-
cellular Ca2+ levels transiently as shown by exper-
iments using the Ca2+-sensitive dye fura 2. DAG
activates several protein kinase C (PKC) isozymes,
specifically α, ε, and δ, which will further stimu-
late secretion. VIP receptors are coupled to G pro-
teins that activate adenylate cyclase. The activa-
tion of the adenylate cyclase increases adenosine
39,59-cyclic monophosphate (cAMP) levels,
which in turn activates protein kinase A, which
causes the phosphorylation of proteins that stim-
ulate protein secretion (5). In addition, VIP causes
an increase in intracellular Ca2+, presumably by
means of second message systems that open Ca2+
channels in the plasma membrane. The increase
in intracellular Ca2+ from both acetylcholine and
VIP stimulation will increase the open time and
thus the total conductance of the Ca2+-dependent
K+ and Cl– channels, which are important in the
secretion of water.
α-Adrenergic agonists stimulate protein secre-
tion by activating PKC but not through the inter-
mediary action of IP3, Ca2+, or cAMP. The
enkephalins have an inhibitory effect on protein
secretion induced by either VIP or acetylcholine.
These receptors are coupled to Gi proteins that
inhibit the stimulatory activity of other G pro-
teins on the adenylate cyclase and phospholi-
pase C systems.
Most of the preceding data are from studies that
determined the secretion of either total protein or
“. . .to move dimeric a specific protein such as peroxidase from gland
IgA from the interstitial fragments from a variety of different animals.
fluid. . . onto the Given the species variation in the nature of the
ocular surface.” innervation, perhaps not all of the mechanisms
described occur in all animals. However, it is
clear that all species seem to have both acetyl-
choline and VIP present and have receptors for
both. An additional generalization is that in the
lacrimal glands, for example, in rabbits, where
there are adrenergic nerve fibers, activation of
both sympathetic and parasympathetic neurons
induces an increase in protein secretion. An issue
then is the reason for such a complex innervation
pattern with so many neurotransmitters and
receptors if their sole function is to increase total
protein secretion. A possible clue is seen in the rat
secretion data, in which the ratio of a specific pro-
tein (peroxidase) to the total protein is different if
stimulation is with carbachol (a muscarinic
cholinergic agonist) or propranolol (a β-adrener-
gic agonist) (3). The possibility exists, then, that
100 News Physiol. Sci. • Volume 13 • April 1998
acinar cells have segregated secretory pathways
for certain secreted proteins and neurotransmit-
ters have different stimulatory effects on these
secretory pathways. It is also possible that differ-
ent populations of cells in the same gland have
different secretory products whose secretion can
be differentially controlled, resulting in a different
secretory product. This latter possibility is less
likely because of the high degree of coupling of
acinar cells by gap junctions and the ease with
which second messenger molecules could diffuse
from one cell to another.
The secretion of proteins by the acinar cells
involves vesicle fusion with the apical membrane
and depends on membrane movement from
intracellular structures such as the Golgi appara-
tus. To conserve membrane, there is an endocy-
totic process of internalization and intracellular
processing of apical membrane, as seen in most
secretory cells. In addition in the lacrimal gland
acinar cells, there is endocytotic movement of
membrane from the basolateral surface into the
cell where it is processed. Whereas some of this
basolateral membrane is used for apical secre-
tion, particularly of the sIgA complex, a signifi-
cant amount is cycled back to the basolateral sur-
face after intracellular processing. This basolater-
al membrane traffic may have several important
functions. It can be an important route by which
certain molecules such as prolactin enter the aci-
nar cells and exert their regulatory effect. In addi-
tion, stimulated acinar cells can express major
histocompatability complex II molecules, a char-
acteristic of antigen-presenting cells of the
immune system. The basolateral membrane recy-
cling, therefore, could be involved in antigen
presentation as well as secretion of autoantigens
(11). Understanding this process is important for
Sjögren’s syndrome, for example, a dry eye dis-
ease in which an autoimmune response occurs
involving lymphocytic infiltration of the lacrimal
gland that results in destruction of some acinar
tissue with loss of function.
Transport of IgA
Another major function of the lacrimal gland
acinar cells is to move dimeric IgA from the inter-
stitial fluid into the tear ducts and thus onto the
ocular surface. IgA is produced by plasma cells
resident in the lacrimal gland. There is a constant
traffic of these plasma cells into the gland, as
antibodies can be evoked by antigens either
placed on the ocular surface or introduced into
the animal through other means such as the gut.
It is thought that most plasma cells arise in the
GALT and then migrate to peripheral lymphoid
organs such as the lacrimal glands. Most circu-

FIGURE 2. Secretion of water by the acinar cells is by osmo-
sis and is driven by the outward movement of ions, particu-
larly Cl–. Neurotransmitter receptors are linked via second
messenger systems to ion channels and regulate their perme-
ability and thus the movement of water.
lating B cells that are destined to become plasma
cells are specific for IgG with a minority being
IgA. Therefore, there must be selective retention
of the IgA cells within the lacrimal gland,
although the precise mechanism is not known.
The IgA produced by the resident plasma cells
is secreted as a dimer, with the pair of antibody
molecules linked by a protein called “J chain”
that is also synthesized by the plasma cell. The
complex is referred to as sIgA. For the sIgA to
reach the glandular lumen, it must be transported
through the acinar cells. To do this, the acinar
cells produce a glycoprotein known as secretory
component (SC) that functions as a “sacrificial
receptor.” SC is found on the basolateral mem-
branes of the acinar cells as well as in the mem-
branes of the Golgi apparatus, secretory vesicles,
and the rough endoplasmic reticulum. The sIgA
complex has a high affinity for the SC and binds
to it on the basolateral surface of the acinar cells.
By the process of endocytosis, the SC-sIgA com-
plex is internalized in vesicles and transported
across the acinar cell to the apical surface. There,
the vesicles fuse with the apical membranes of
the acinar cells and the SC is cleaved into two
parts, one of which is retained in the membrane
and the other that remains attached to the now
free sIgA complex.
The majority of the IgA found in tears, therefore,
consists of a dimer linked by J chain that has
attached to it the soluble portion of the SC. This
transport of sIgA is regulated by a variety of factors
that affect the levels of SC synthesis in the acinar
cells. Androgens, such as testosterone, increase
the levels of the SC and thus the rate of transport
(6). Understanding the role that androgens have in
the normal functioning of the secretory acinar
cells is important because over 90% of patients
with Sjögren’s syndrome, a dry eye disease, are
female. In addition to androgens, VIP induces a
dose-dependent increase in SC production as do
various lymphokines such as interleukin-1α and
tumor necrosis factor-α. Isoproterenol (a β-adren-
ergic agonist) stimulates SC production but only in
the presence of the hormone dihydrotestosterone.
However, carbachol, an acetylcholine agonist,
actually decreases SC synthesis, possibly by inter- “Androgens, such as
fering with the production of cAMP. This reduction testosterone, increase
in SC due to carbachol is odd because acetyl- the levels of the SC
choline is known to stimulate both protein and and thus the rate of
water secretion by these cells. Such an observa- transport. . . .”
tion, however, does raise the interesting issue of
different secretory pathways and their control and
suggests that the complex innervation and second
messenger pathways that exist in this gland could
differentially regulate protein synthesis/secretion,
water transport, and sIgA transport.
Whereas sIgA is the dominant immunoglobu-
lin in mammalian tears, smaller amounts of IgG
and IgM are also produced by plasma cells in the
gland. In birds, the major lacrimal gland, the
harderian gland, has a very large population of
plasma cells that secrete IgG and few that secrete
IgA. IgG is not actively transported across the
epithelium as is sIgA in mammals but rather dif-
fuses between the epithelial cells. It seems likely
that, in birds, large numbers of plasma cells are
required to produce a significant concentration
gradient across the epithelium so that diffusion of
significant amounts of IgG can occur. In this
gland, the plasma cells have cholinergic neurons
among them and have muscarinic acetylcholine
receptors on their surface (2). Activation of these
receptors with carbachol increases intracellular
Ca2+, which increases the rate of secretion of IgG
above the basal level. Thus, in birds, there is
neural modulation of the production of
immunoglobulins, whereas, in mammals, there
is modulation of the transport across the epithe-
lium, but both systems serve to regulate the con-
centration of immunoglobulins in the tear fluid.
Secretion of water
One of the major secretory “products” of the
lacrimal gland is water. This water is moved from
the interstitial spaces of the gland into the lumen
of the gland where it is mixed with the other
secretory products. This water movement is
accomplished by osmosis, which depends on the
movement of particles (ions) from the acinar cells
into the lumen (Fig. 2). Therefore, most studies
News Physiol. Sci. • Volume 13 • April 1998 101
 FIGURE 3. Diagram showing the major ion channels, coupled transporters (CT), and active transport systems (AT) responsible
for the aqueous and ionic nature of the secretory product. Note that large numbers of Na+-K+ pumps (AT) in the basolateral
membrane exist that create the ion gradients that allow the coupled transport systems to work. There are many types of K+ and
Cl– channels, distinguished by their conductance, but most are regulated by Ca2+, and it is this process that regulates the move-
ment of water across the epithelium.

have examined the process of water movement
indirectly by characterizing the membrane chan-
nels through which ions move in and out of the
acinar cells. Similar to the salivary gland, the
lacrimal gland has a distinction between the aci-
nar cells that produce the bulk of the fluid and
protein and the duct cells that modify the ionic
composition of the fluid by retaining Na+. How-
ever, most physiological studies are not able to
differentiate between these two cell types and
most consider that these mechanisms take place
in all the cells (Fig. 2).
The acinar cell surface membrane is differenti-
ated into basolateral and apical domain, which
are separated by the junctional complex (Fig. 3).
The apical domain is thought to contain water
channels (aquaporin 5), which facilitate the
movement of water across the epithelium. In
addition, Cl– and K+ channels are present to
“The apical domain allow the movement of solute across the epithe-
is thought to contain lium. The basolateral membranes contain large
water channels numbers of Na+ pumps, the Na+-K+-ATPase,
(aquaporin 5). . . .” which actively move K+ into the cell and Na+ out
of the cell, maintaining the usual gradients that
are seen in all cells. It is this gradient (more Na+
outside and K+ inside) that provides the motive
force for the movement of ions and water across
the epithelium. In addition, there are several
coupled transport systems (porters) driven by the
concentration gradients created by the Na+
pump and by the activity of carbonic anhydrase.
One cotransport system mediates the inward
102 News Physiol. Sci. • Volume 13 • April 1998
movement of Na+ coupled to the outward flux of
H+, and a second system affects the outward
movement of bicarbonate ion (HCO 3–) as Cl–
moves in (10). HCO 3– are produced by carbonic
anhydrase in the cells and serve to buffer the
lacrimal gland cells and fluid.
The basolateral membranes also have ion
channels, specifically for K+, Cl–, and Ca2+ as
well as more general cation and anion channels.
The Ca2+ channels are involved generally in the
process of excitation/secretion coupling and, by
affecting the permeability of other ion channels,
indirectly regulate the movement of water.
Because the number of Ca2+ ions that move is
small and there are few channels, they have little
direct effect on water movement themselves. The
apical membrane of the cell, however, is
believed to be rich in Cl– channels, which are
Ca2+ sensitive. On activation of the cell, the
raised intracellular Ca2+ will open the Cl– chan-
nels and that will allow an outward movement of
Cl– into the lumen. Na+ will follow across the
epithelium through the junctional complexes as
well as through the cation channels in the acinar
cells. This movement of ions into the lumen will
osmotically drive the movement of water through
the aquaporin channels into the lumen to main-
tain the osmotic balance.
The movement of Cl– out of the apical mem-
brane is dependent on the ion gradient of the Cl–
across the cell membrane and on the relation of
the membrane potential of the cell to the Cl– equi-
librium potential. As long as the membrane poten-
tial is below the Cl– equilibrium potential, Cl– will
move out of the cell into the lumen and so will
water. As the cell becomes depolarized, less Cl–
will move and thus less water. If the membrane
potential becomes equal to or depolarized above
the Cl– equilibrium potential, then there will be no
net outward Cl– or water movement. Because the
movement of Cl– out of the cell will depolarize the
membrane potential, the outward movement of K+
in the basolateral surface and apical domains is
necessary to effectively provide a hyperpolarizing
force and thus to maintain the membrane poten-
tial below the Cl– equilibrium potential. The per-
meability of both Cl– and K+ channels therefore
regulates, and solute concentration gradient is the
motive force for the movement of water across the
epithelium. Because this movement results in both
an efflux of K+ and an influx of Na+, the Na+-K+
pump must be present in high concentrations and
must be active to counteract these fluxes and
maintain a relatively constant gradient. Consistent
with this is the observation that the stimulation of
acinar cells with carbachol (an acetylcholine ago-
nist) will move the Na+-K+ pumps from the Golgi
membranes to the basolateral membranes of the
cell, thereby increasing the effective movement of
K+ in and Na+ out of the cells (15).
This link between ion channels and their per-
meability and the movement of water may form
the underlying cause of certain disease states in
which lacrimal gland secretion of fluid is greatly
reduced, resulting in dry eyes. Patients with Sjö-
gren’s syndrome have dry eyes and mouth, and
their lacrimal and salivary glands are heavily
infiltrated with lymphocytes that have destroyed
significant areas of secretory tissue. However,
there are still areas of intact secretory acini that
appear to be unable to secrete fluid. A possible
explanation for this failure to transport water is
suggested by measurements of membrane chan-
nels and the membrane potential in a mouse
model of this disease, the NZB/NZW F1 female
mouse. Cells from young, nondiseased animals
have large numbers of active maxi-K+ channels
and have membrane potentials on the order of
–40 mV. Recordings from the acinar cells of older
diseased animals, however, do not show active
maxi-K+ channels and the membrane potential is
only –5 to –10 mV, above the normal Cl– equi-
librium potential. Thus these cells do not have a
significant outward movement of Cl– on activa-
tion and therefore secrete little water, resulting in
the dry eye condition (1).
In summary, the lacrimal gland secretory
epithelium synthesizes and secretes a number of
specific proteins essential for the health of the
cornea. In addition, it transports immunoglobu-
lins and water, which also are essential elements
of the tear film. There are at least four neuro-
transmitter/neuropeptide receptors associated
with the acinar cells that affect a number of dif-
ferent second message systems that, in turn, reg-
ulate the various secretory/transport processes.
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