Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008
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Secretory Function of the Lachrymal Gland
Because the complex innervation involves multiple transmitters, secretory function of the lachrymal gland is very complicated and the situation currently contains too many unknowns. However, acetylcholine, norepinephrine, and VIP represent major stimuli for lachrymal gland secretion and activate different signaling pathways.30-34 From the perspective of secretion type, the major thrusts of research are divided broadly into 2 categories: protein secretion, and water secretion.35-37
Protein Secretion
Protein secretion basically involves the secretion of granules from acinar cells by exocytosis. Secretion of lachrymal proteins is stimulated by neurotransmitters and neuropeptides released from the neurons innervating the gland. Acinar cells have receptors for acetylcholine (muscarinic M3), norepinephrine, and VIP.30-34
In many cells, membrane receptors are coupled to G proteins that in turn regulate the activity of several second-messenger systems. Muscarinic acetylcholine receptors interact with G proteins, which activate phospholipase C, resulting in increased production of 1,4,5-inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces the release of intracellular stores of Ca2+ from the endoplasmic reticulum and the influx of extracellular Ca2+. This intracellular increase of Ca2+ stimulates secretion by activating Ca2+/calmodulin-dependent protein kinases. In contrast to IP3, DAG activates specific isoforms of protein kinase C (PKC), which stimulate further secretion.
Norepinephrine binds to both α1- and β-adrenergic receptors. In the lachrymal gland, α1-adrenergic agonists are a potent stimulus for secretion and activate a signaling pathway involving Ca2+ and PKC. In contrast, β-adrenergic agonists offer less stimulus of secretion and activate a 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathway.
VIP activates a cAMP-dependent pathway. An increase in the level of cAMP activates protein kinase A, which stimulates lachrymal secretion. VIP also increases intracellular Ca2+ levels. An increase in intracellular Ca2+ levels by all three agonists (acetylcholine, α1-adrenergic, and VIP) is necessary to simulate secretion. Other stimuli for lachrymal gland secretion include the EGF family of growth factors.38 For more information about signal transduction and activation of the lachrymal gland, see review articles.30-32
A recent article reviewed the molecular mechanism of exocytosis, including protein and membrane trafficking and transport factors (microtubules, actin filaments, and motor proteins) in lachrymal acinar cells.39
Water Secretion
Water is moved mainly from the interstitial spaces of the gland into the lumen of the gland. This water movement is attributed to the osmotic gradient, which depends on the movement of ions from the acinar cells and interstitium into the lumen.35-37
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The basolateral membranes contain numerous sodium pumps, with Na+-K+-ATPase to actively transport K+ into the cell and Na+ from the cytosol into the interstitium and maintain low cytosolic Na+ activities. The apical membranes have Cl− and K+ channels. Activation of cells by increased intracellular Ca2+ drives an outward movement of Cl− into the lumen. The resulting lumen-negative transepithelial voltage drives the paracellular flux of Na+ from the interstitium to the lumen. In turn, the osmotic gradient provides the motive force for the movement of water through the intercellular space. Some studies over the last decade have revealed that the apical membranes contain aquaporin 5 water channels, which facilitate the movement of water intracellularly to the lumen.40,41 In addition, basolateral membranes also have Cl−, K+, and Ca2+ channels. One study using connexin 32-deficient mice showed that gap junctions are essential for optimal fluid secretion by the lachrymal gland.42
See the review articles for more information about water and electrolyte secretion.35-37
Age-Related Changes to Tear Fluid
As reported previously, the quality and quantity of tear fluid changes with age.6-13 Reflex secretion of tears as measured by the Schirmer test without anesthesia is known to decrease with age. As for a more detailed picture of tear flow, one study has shown tear volume and flow decline with age, whereas osmolarity and evaporation increase.11
In terms of the quality of tear fluid, both lysozyme and lactoferrin, as major proteins of tear fluid, have been shown to similarly decline with age.9 Interestingly, IgA levels gradually decline with age, but do not significantly correlate with age.9 These results probably correspond to the fact that the cell source and secretory mechanism of IgA differ from those of lysozyme and lactoferrin. Another study has shown that epidermal growth factor (EGF) levels in tear fluid do not correlate with age.12 These studies suggest that not all proteins necessarily decrease with age.
Peroxidase activity in tear fluid decreases with age, but differs between men and women. Peroxidase activity in women decreases during and after menopause, but remains constant in men up to middle age, subsequently declining with advancing age.13 This suggests that gender-related differences are accentuated during aging.
Corneal innervation is important for reflex tearing. Corneal sensitivity and the density of sensory nerves in the cornea decrease with age, resulting in decreased reflex loop activation of autonomic nerves that innervate the lachrymal gland.43,44
Age-Related Changes in the Lachrymal Gland
The mechanisms causing lachrymal gland dysfunction are still poorly understood. Many possible factors have been proposed, including sex hormonal imbalances,45-47 pituitary hormones,48-51 neural dysfunction,52,53 and inflammation.54-64 Inflammation
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includes various factors such as environmental factors, proinflammatory cytokines such as interleukin 1β (IL-1β) and tissue necrosis factor α (TNF-α),56,57,59 autoimmue reaction,60-62 and infection.63,64 Compared to the number of physiological, biochemical, and immunological studies of secretory function and dysfunction in lachrymal glands,65 research into the effects of aging on lachrymal glands has been limited.
Human Studies
Some histopathological studies have examined the human lachrymal gland. In general, age-related pathological changes of lachrymal glands include diffuse fibrosis, diffuse atrophy, and periductal fibrosis. A histopathological study of 80 human lachrymal glands showed significant correlations between age and diffuse fibrosis, diffuse atrophy, and periductal fibrosis in the orbital lobes of females, and periductal fibrosis in the palpebral lobes of males.68 Moreover, diffuse fibrosis and diffuse atrophy in the orbital lobes were more frequently observed in females than in males. This result is of great interest, as it suggests a relationship with the greater frequency of dry eye in elderly women. An example of age-related histopathological change is shown in Fig. 18.1. The acinar area in the lachrymal glands of aged females is clearly much smaller than that of young males. One of the mechanisms behind these age-related changes is speculated to be a loss of nerve branches, causing fibrosis and acinar atrophy in aged glands, as these pathological changes are characteristically observed per unit area of lobule (Fig. 18.2). Another possibility is that these changes might be induced by circulatory disturbance or ischemia. Aging of the vascular system is an important issue, as seen with the most frequent and serious vascular diseases in elderly people, myocardial infarction and brain infarction.
Periductal fibrosis may be an important factor related to the decrease in outflow of tear fluids.68 Atrophic ductal epithelium is often associated with periductal fibrosis. These ductal pathologic changes may interfere with electrolyte and water secretion, as ductal epithelial cells are considered responsible for this function.19,35
Periductal lymphocytic infiltration, which is not an age-related finding, is observed as a pathological change in the human lachrymal gland (Fig. 18.3).68 Focal lymphocytic infiltration of the lachrymal gland suggests subclinical dacryoadenitis, but the question of how lymphocytic infiltration might alter secretory function remains unresolved. In Sjögren’s syndrome, the most severe dry eye syndrome, periductal lymphocytic infiltration is thought to be the earliest histopathological finding. As for the relationship between inflammation and fibrosis, fibrosis may become the most prominent feature of chronic inflammation. Liver fibrosis and cirrhosis often follow chronic hepatitis. In the lachrymal gland, however, whether periductal fibrosis may follow periductal lymphocytic infiltration is unclear.
Interlobular ductal dilatation is not an age-related finding, but is of importance when considering the pathogenesis of dry eye.68 This suggests stenosis or obstruction
Fig. 18.1 Histological findings of age-related changes A) Normal histological finding from a 17-year old male. B) Histological finding of an 87-year old female shows acinar atrophy and periacinar and periductal fibrosis at the same magnification. Reprinted from Obata et al., copyright 1995, with permission from the American Academy of Ophthalmology
Fig. 18.2 Lobular atrophy with fibrosis Acinar atrophy with periacinar fibrosis is present throughout one lobule. Normal acini are present on the right side of the photograph
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Fig. 18.3 Periductal lymphocytic infiltration Periductal lymphocytic infiltration, which is not age-related, suggests subclinical dacryoadenitis, but the question of how lymphocytic infiltration might alter the secretory function, and whether periductal fibrosis might follow periductal lymphocytic infiltration remains unresolved
of the orifices of excretory ducts in the fornix of the conjunctiva. Conjunctivitis might thus play a crucial role in causing obstructive dry eye.
Regarding gross anatomy, magnetic resonance imaging has revealed that the thickness and area of the lachrymal gland decrease with age in women, but not in men.69
Many unknowns remain with regard to the molecular mechanisms of aging in the human lachrymal gland. One reason probably involves the difficulty in obtaining human lachrymal gland tissue for study. The human lachrymal gland is rarely removed at surgery or autopsy, and biopsy is considered unadvisable for such a small organ to prevent iatrogenic dry eye. Implementing a longitudinal study of age-related human lachrymal gland dysfunction is thus quite difficult.
Animal Studies
Animal models of lachrymal gland dysfunction would offer a useful tool for investigating pathological mechanisms.70 Although animal models mimicking human age-related dry eye disease have not yet been reported, comparative studies of young and old animals have been described.
Morphological studies in rats have shown that the type of acini change initially from serous to seromucous acini, followed by gradual transformation of seromucous acini to mucous acini with age.71-73 Another study in mice has shown that periductal fibrosis and acinar atrophy, as in the case of humans, are observed in glands from 24and 32-month-old mice.74 Ultrastructural examination has revealed marked reductions in the Golgi apparatus and dilatation of the rough endoplasmic reticulum in the acinar cells of glands from 24-month-old rats.71,73
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Several studies have revealed that age-related dropout of nerves occurs in the lachrymal gland.74,75 The number and intensity of immunoreactive nerves for substances such as acetylcholinesterase, VIP, neuropeptide Y, CGRP, SP, tyrosine hydroxylase, and dopamine β-hydroxylase are reduced in the glands of aged mice and rats.74,75 One study has shown that decreases in innervation start in 24- month-old mice, coinciding with a decline in acetylcholine release from the gland.74
Protein secretion in response to several neural agonists also decreases with increasing age. Acetylcholine, carbachol, adrenaline, phenylephrine, isoproterenol, SP, VIP, histamine, and 5-hydroxytryptamine were used as stimulants in these studies. However, secretion of peroxidase became highly variable in the aged gland and differed from protein secretion in response to sympathomimetic stimulation,76,77 suggesting a complex etiology of age-related lachrymal gland dysfunction. Stimulated peroxidase secretion decreased in 8-month-old mice and continued for 12–24 months before starting the decrease of innervation in 24-month-old mice.74 This means that impairment of protein secretion in the early stages of aging cannot be explained simply by decreases in innervation.
Inflammatory cells such as lymphocytes and mast cells infiltrate the aged lachrymal gland of mice and rats.71,74,75 As seen with Sjögren’s syndrome, lymphocytic infiltration might play a role in inhibiting lachrymal gland secretion during aging. A study in the NZB/W mouse model of Sjögren’s syndrome found no correlation between the extent of lymphocytic infiltration and the degree of tear flow reduction,78 suggesting lymphocytic infiltration alone is insufficient to explain secretory dysfunction in this model mouse. Conversely, another study in NZB/W mice showed age-related decreases in the density of innervation to the acini.79 Of note is the fact that the decrease in innervation density is observed before any lymphocytic infiltration. Taken together, both inflammation and innervation might play crucial roles in causing lachrymal gland dysfunction.
Carbonic anhydrase is part of a family of metalloenzymes that catalyze the rapid conversion of CO2 to H+ and HCO3−. An age-related increase in carbonic anhydrase activity was present in the gland from aged male rats, but not aged females,80 suggesting gender-related differences in the lachrymal gland.81,82 The physiological significance of this increase is not yet known.
One study showed that aging significantly reduces tyrosine phosphorylation of insulin receptors in the lachrymal gland of rats, suggesting that this reduced phosphorylation may affect later stages of insulin signal transduction.83 Recently, advanced glycation end products (AGEs) have been found to increase with age and contribute to the chronic complications of aging in several tissues. AGE binding to its receptor leads to activation of the transcription factor nuclear factor-κB (NF-κB). AGE, its receptor, and NF-κB are highly expressed in aged lachrymal glands of rats compared to young glands.84 These metabolic events may therefore be related to lachrymal gland dysfunction with aging.
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Conclusion
The mechanisms behind age-related lachrymal gland dysfunction remain unclear due to the multifactorial and complex nature of this system. To take a broad view, both inflammation and neural dysfunction may play crucial roles in age-related lachrymal gland dysfunction. The chance of encountering foreign antigens on the ocular surface increases with age, causing subclinical inflammation of the conjunctiva. Thereafter, the lachrymal gland could also be affected and inflamed because both conjunctiva and lachrymal gland are MALTs, and antigens are shared by both tissues. If this immune defense mechanism is dysregulated, the lachrymal gland might undergo some sort of adverse effect, such as excessive inflammation. Conversely, the density of innervation to the cornea and lachrymal gland reduces with age. Alteration of both sensory nerves innervating the cornea and autonomic nerves innervating the lachrymal gland could cause decreases in tear secretion. Moreover, to account for gender differences, since dry eye is observed more frequently in women than in men, hormonal influences also need to be resolved in the pathogenesis of lachrymal gland dysfunction. For instance, androgen level is considered to decrease with increasing age, affecting immunohomeostasis on the ocular surface. Exploring a neuroendocrine immune network in the lachrymal gland is thus absolutely essential, despite being an old issue.
Senescence can be activated by both telomere-dependent and telomereindependent pathways. Genetic alterations, genome-wide DNA damage, and oxidative stress have recently been identified as inducers of senescence. Development of aging research will elucidate the most pertinent molecular pathways linking lachrymal gland dysfunction and aging.
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