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PloS One 2017The study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry... (Clinical Trial)
Clinical Trial
BACKGROUND
The study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for lacrimal gland diseases requires a better understanding of the gene expression and signaling pathways in lacrimal gland. Differential gene expression analysis between lacrimal gland and other embryologically similar tissues may be helpful in furthering our understanding of lacrimal gland development.
METHODS
We performed global gene expression analysis of human lacrimal gland tissue using Affymetrix ® gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary gland, skin, conjunctiva and corneal epithelium.
RESULTS
The analysis revealed statistically significant difference in the gene expression of lacrimal gland tissue compared to other ectodermal tissues. The lacrimal gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish lacrimal gland from other ectodermal tissues are described.
CONCLUSIONS
Differential gene expression in human lacrimal gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas.
Topics: Databases, Genetic; Dry Eye Syndromes; Eye Proteins; Female; Gene Expression Regulation; Humans; Lacrimal Apparatus; Male
PubMed: 28081151
DOI: 10.1371/journal.pone.0169346 -
Investigative Ophthalmology & Visual... Mar 2023Dry eye disease (DED) is a multifactorial disease that is associated with inflammation. Excessive DNA is present in the tear fluid of patients with DED. Absent in...
PURPOSE
Dry eye disease (DED) is a multifactorial disease that is associated with inflammation. Excessive DNA is present in the tear fluid of patients with DED. Absent in melanoma 2 (AIM2) is a key DNA sensor. This study aimed to investigate the role of AIM2 in the pathogenesis of DED.
METHODS
DED was induced by injection of scopolamine (SCOP). Aberrant DNA was detected by cell-free DNA (cfDNA) ELISA and immunostaining. Corneal epithelial defects were assessed by corneal fluorescein staining, zonula occludens-1 immunostaining and TUNEL. Tear production was analyzed by phenol red thread test. Lacrimal gland (LG) histology was evaluated by hematoxylin and eosin staining, and transmission electron microscopy examination. Macrophage infiltration in LG was detected by immunohistochemistry for the macrophage marker F4/80. Gene expression was analyzed by RT-qPCR. Protein production was examined by immunoblot analysis or ELISA.
RESULTS
Aim2-/- mice displayed a normal structure and function of LG and cornea under normal conditions. In SCOP-induced DED, wild type (WT) mice showed increased cfDNA in tear fluid, and aberrant accumulations of dsDNA accompanied by increased AIM2 expression in the LG. In SCOP-induced DED, WT mice displayed damaged structures of LG, reduced tear production, and severe corneal epithelium defects, whereas Aim2-/- mice had a better preserved LG structure, less decreased tear production, and improved clinical signs of dry eye. Furthermore, genetic deletion of Aim2 suppressed the increased infiltration of macrophages and inhibited N-GSDMD and IL18 production in the LG of SCOP-induced DED.
CONCLUSIONS
Aim2 deficiency alleviates ocular surface damage and LG inflammation in SCOP-induced DED.
Topics: Mice; Animals; Lacrimal Apparatus; Epithelium, Corneal; Dry Eye Syndromes; Tears; Inflammation; Disease Models, Animal; DNA-Binding Proteins
PubMed: 36920364
DOI: 10.1167/iovs.64.3.26 -
The American Journal of Pathology Feb 2021Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice...
Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice were used at 2 to 3, 12, and 24 months of age. Nuclear factor erythroid derived-2-related factor 2 (Nrf2) and corresponding wild-type mice were used at 2 to 3 and 12 to 13 months of age. A separate group of 15.5 to 17 months of age C57BL/6 mice received a diet containing an Nrf2 inducer (Oltipraz) for 8 weeks. Aged C57BL/6 lacrimal glands showed significantly greater lymphocytic infiltration, higher levels of MHC II, IFN-γ, IL-1β, TNF-α, and cathepsin S (Ctss) mRNA transcripts, and greater nitrotyrosine and 4-hydroxynonenal protein. Young Nrf2 mice showed an increase in IL-1β, IFN-γ, MHC II, and Ctss mRNA transcripts compared with young wild-type mice and greater age-related changes at 12 to 13 months of age. Oltipraz diet significantly decreased nitrotyrosine and 4-hydroxynonenal and decreased the expression of IL-1β and TNF-α mRNA transcripts, while decreasing the frequency of CD45CD4 cells in lacrimal glands and significantly increasing conjunctival goblet cell density compared with a standard diet. The findings provide novel insight into the development of chronic, low-grade inflammation and oxidative stress in age-related dry eye. New therapies targeting oxidative stress pathways will be valuable in treating age-related dry eye.
Topics: Aging; Animals; Dry Eye Syndromes; Female; Inflammation; Lacrimal Apparatus; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Pyrazines; Thiones; Thiophenes
PubMed: 33159886
DOI: 10.1016/j.ajpath.2020.10.013 -
The Ocular Surface Oct 2008The afferent nerves of the cornea and conjunctiva, efferent nerves of the lacrimal gland, and the lacrimal gland are a functional unit that works cooperatively to... (Review)
Review
The afferent nerves of the cornea and conjunctiva, efferent nerves of the lacrimal gland, and the lacrimal gland are a functional unit that works cooperatively to produce the aqueous component of tears. A decrease in the lacrimal gland secretory function can lead to dry eye disease. Because aging is a risk factor for dry eye disease, study of the changes in the function of the lacrimal gland functional unit with age is important for developing treatments to prevent dry eye disease. No one mechanism is known to induce the changes that occur with aging, although multiple different mechanisms have been associated with aging. These fall into two theoretical categories: programmed theories of aging (immunological, genetic, apoptotic, and neuroendocrine) and error theories of aging (protein alteration, somatic mutation, etc). Lacrimal glands undergo structural and functional alteration with increasing age. In mouse models of aging, it has been shown that neural stimulation of protein secretion is an early target of aging, accompanied by an increase in mast cells and lipofuscin accumulation. Hyperglycemia and increased lymphocytic infiltration can contribute to this loss of function at older ages. These findings suggest that an increase in oxidative stress may play a role in the loss of lacrimal gland function with age. For the afferent and efferent neural components of the lacrimal gland functional unit, immune or inflammatory mediated decrease in nerve function could contribute to loss of lacrimal gland secretion with age. More research in this area is critically needed.
Topics: Aging; Dry Eye Syndromes; Efferent Pathways; Humans; Lacrimal Apparatus; Tears
PubMed: 18827949
DOI: 10.1016/s1542-0124(12)70177-5 -
The American Journal of Pathology Dec 2020The lacrimal gland is critical for maintaining the homeostasis of the ocular surface microenvironment through secreting aqueous tears in mammals. Many systemic diseases...
The lacrimal gland is critical for maintaining the homeostasis of the ocular surface microenvironment through secreting aqueous tears in mammals. Many systemic diseases such as Sjögren syndrome, rheumatoid arthritis, and diabetes can alter the lacrimal gland function, eventually resulting in aqueous tear-deficient dry eye. Here, a high-fat diet (HFD) experimental mouse model was used to clarify how hyperlipidemia affects lacrimal gland function. Aqueous tear secretion fell about 50% after 1 month on a HFD. Lipid droplets accumulated in the matrix and acinar cells of the lacrimal gland after this period, along with changes in the lipid metabolism, changes in gene expression levels, and disruption of fatty acid oxidative activity. Immune cell infiltration and rises in the gene expression levels of the inflammation-related cytokines Il1β, Tnfα, Tsg6, Il10, Mmp2, and Mmp9 were found. HFD also induced mitochondrial hypermegasoma, increased apoptosis, and decreased lacrimal gland acinar cell proliferation. Replacement of the HFD with the standard diet partially reversed pathologic changes in the lacrimal gland. Similarly, supplementing the HFD with fenofibrate also partially reversed the inhibited tear secretion and reduced lipid accumulation, inflammation, and oxidative stress levels. The authors conclude that a HFD induces pathophysiological changes and functional decompensation of the lacrimal gland. Therefore, ingestion of a HFD may be a causative factor of dry eye disease.
Topics: Animals; Cytokines; Diet, High-Fat; Disease Models, Animal; Dry Eye Syndromes; Lacrimal Apparatus; Male; Mice, Inbred C57BL; Mitochondria; Sjogren's Syndrome; Tears
PubMed: 32919976
DOI: 10.1016/j.ajpath.2020.09.002 -
International Journal of Molecular... Sep 2023Adenoid cystic carcinoma (ACC) has a worldwide incidence of three to four cases per million population. Although more cases occur in the minor and major salivary glands,... (Review)
Review
Adenoid cystic carcinoma (ACC) has a worldwide incidence of three to four cases per million population. Although more cases occur in the minor and major salivary glands, it is the most common lacrimal gland malignancy. ACC has a low-grade, indolent histological appearance, but is relentlessly progressive over time and has a strong proclivity to recur and/or metastasise. Current treatment options are limited to complete surgical excision and adjuvant radiotherapy. Intra-arterial systemic therapy is a recent innovation. Recurrent/metastatic disease is common due to perineural invasion, and it is largely untreatable as it is refractory to conventional chemotherapeutic agents. Given the rarity of this tumour, the molecular mechanisms that govern disease pathogenesis are poorly understood. There is an unmet, critical need to develop effective, personalised targeted therapies for the treatment of ACC in order to reduce morbidity and mortality associated with the disease. This review details the evidence relating to the molecular underpinnings of ACC of the lacrimal gland, including the chromosomal translocations, -signalling pathway aberrations, DNA damage repair gene mutations and epigenetic modifications.
Topics: Humans; Carcinoma, Adenoid Cystic; Lacrimal Apparatus; Salivary Gland Neoplasms; Neoplasm Recurrence, Local; Salivary Glands
PubMed: 37762061
DOI: 10.3390/ijms241813755 -
Journal Francais D'ophtalmologie Oct 2022In parallel to ocular surface disease in dry eye there is often a dysfunctionality of the lacrimal gland apparatus. The functionality of the lacrimal gland is of major...
INTRODUCTION
In parallel to ocular surface disease in dry eye there is often a dysfunctionality of the lacrimal gland apparatus. The functionality of the lacrimal gland is of major importance for maintenance of ocular surface integrity and health, even in conditions of enhanced stimulation and secretion requirements. Such enhanced secretion demands can push the lacrimal gland to its limits, with maximized tear fluid secretion and increased flow through the lacrimal ducts. The goal of this study was to investigate whether G protein-coupled receptor GPR-68 is present in the lacrimal gland, as this protein has recently been shown to be sensitive to flow rate and osmolarity.
METHODS
For this purpose, de-identified sections of human lacrimal gland tissue were stained for the presence of G protein-coupled receptor 68 with specific antibodies using immunohistochemistry.
RESULTS
Specific staining was detected in the acini and ducts of human lacrimal gland. In the ducts, the specific staining was found around the lumen of the ducts. In the acini, the specific staining was observed more towards the lumen but also intercellularly between the acinar cells.
DISCUSSION
The detection of G protein-coupled receptor GPR-68 in the lacrimal gland, especially around the lumen of the ducts, raises the question about its function and purpose. Activation of GPR68 leads to modification of various cell functions and is associated with regulation of inflammation. Accordingly, enhanced, secretion-induced, augmentation of flow might exert fluid flow stress on the ducts and acini. This might lead to transient, localized activation of GPR-68 and secondary inflammation within the gland. Depending on the intensity, continuity or repetitive nature of the stimuli, exhaustion of the lacrimal gland secretion capacity might follow, and chronicity of the inflammation in the parenchyma as well as around the ducts might be a consequence.
CONCLUSION
G protein-coupled receptor GPR-68, sensitive to flow, is present in the human lacrimal gland. Increased flow, triggered by sensations such as are typical for dry eye, might lead to local inflammation. It is possible that these sensations might serve as a better indicator for the need and success of therapy than the clinical signs of dry eye disease, at least in the early stages of the disease.
Topics: Dry Eye Syndromes; Humans; Immunohistochemistry; Inflammation; Lacrimal Apparatus; Receptors, G-Protein-Coupled; Tears
PubMed: 35623913
DOI: 10.1016/j.jfo.2022.02.009 -
BioMed Research International 2021Aquaporins (AQPs) are proteins that selectively transport water across the cell membrane. Although AQPs play important roles in secretion in the lacrimal gland, the...
Aquaporins (AQPs) are proteins that selectively transport water across the cell membrane. Although AQPs play important roles in secretion in the lacrimal gland, the expression and localization of AQPs have not been clarified yet. In the current study, we investigated the expression pattern of AQP family members in the murine lacrimal gland during development. Lacrimal gland tissues were harvested from E13.5 and E17.5 murine embryos and from mice 8 weeks of age (adults). Corneal and conjunctival tissues from the latter served as controls. Total RNA was isolated and analyzed for the expression of AQP family members using qPCR. The localization of AQPs in the adult lacrimal gland in adult murine lacrimal glands was also analyzed. Expression of 8 and 9 mRNAs was detected in the adult lacrimal gland but not in the cornea, conjunctiva, or fetal lacrimal gland. AQP8 and AQP9 and -SMA partially colocalized around the basal regions of the acinar unit. The levels of 3 mRNAs and protein were much lower in the adult lacrimal gland but were readily detected in the adult cornea and conjunctiva. Our study suggests that AQP8 and AQP9 may serve as markers for adult murine lacrimal gland, ductal, and myoepithelial cells.
Topics: Age Factors; Animals; Aquaporins; Cell Membrane; Conjunctiva; Cornea; Epithelial Cells; Female; Gene Expression; Lacrimal Apparatus; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Transcriptome
PubMed: 34540996
DOI: 10.1155/2021/6888494 -
Cell Calcium Jun 2014Lacrimal glands provide the important function of lubricating and protecting the ocular surface. Failure of proper lacrimal gland function results in a number of... (Review)
Review
Lacrimal glands provide the important function of lubricating and protecting the ocular surface. Failure of proper lacrimal gland function results in a number of debilitating dry eye diseases. Lacrimal glands secrete lipids, mucins, proteins, salts and water and these secretions are at least partially regulated by neurotransmitter-mediated cell signaling. The predominant signaling mechanism for lacrimal secretion involves activation of phospholipase C, generation of the Ca(2+)-mobilizing messenger, IP3, and release of Ca(2+) stored in the endoplasmic reticulum. The loss of Ca(2+) from the endoplasmic reticulum then triggers a process known as store-operated Ca(2+) entry, involving a Ca(2+) sensor in the endoplasmic reticulum, STIM1, which activates plasma membrane store-operated channels comprised of Orai subunits. Recent studies with deletions of the channel subunit, Orai1, confirm the important role of SOCE in both fluid and protein secretion in lacrimal glands, both in vivo and in vitro.
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Endoplasmic Reticulum; Humans; Inositol 1,4,5-Trisphosphate; Lacrimal Apparatus; Membrane Proteins; Neoplasm Proteins; Stromal Interaction Molecule 1
PubMed: 24507443
DOI: 10.1016/j.ceca.2014.01.001 -
Korean Journal of Radiology Oct 2022To compare the clinical and radiological features of various etiologies of chronic diffuse lacrimal gland enlargement.
OBJECTIVE
To compare the clinical and radiological features of various etiologies of chronic diffuse lacrimal gland enlargement.
MATERIALS AND METHODS
We retrospectively reviewed 91 consecutive patients who underwent surgical biopsy for chronic diffuse lacrimal gland enlargement and were diagnosed with non-specific dacryoadenitis (DA) (n = 42), immunoglobulin G4-related dacryoadenitis (IgG4-RD) (n = 33), and lymphoma (n = 16). Data on patient demographics, clinical presentation, and CT imaging findings (n = 73) and MRI (n = 43) were collected. The following radiologic features of lacrimal gland enlargement were evaluated: size, unilaterality, wedge sign, angle with the orbital wall, heterogeneity, signal intensity, degree of enhancement, patterns of dynamic contrast-enhanced, and apparent diffusion coefficient value. Radiological features outside the lacrimal glands, such as extra-lacrimal orbital involvement and extra-orbital head and neck involvement, were also evaluated. The clinical and radiological findings were compared among the three diseases.
RESULTS
Compared to the DA and IgG4-RD groups, the lymphoma group was significantly older (mean 59.9 vs. 46.0 and 49.4 years, respectively; = 0.001) and had a higher frequency of unilateral involvement (62.5% vs. 31.0% and 15.2%, respectively; = 0.004). Compared to the IgG4-RD and lymphoma groups, the DA group had significantly smaller lacrimal glands (2.3 vs. 2.8 and 3.3 cm, respectively; < 0.001) and a lower proportion of cases with a wedge sign (54.8% vs. 84.8% and 87.5%, respectively; = 0.005). The IgG4-RD group showed more frequent involvement of the extra-orbital head and neck structures, including the infraorbital nerve (36.4%), paranasal sinus (72.7%), and salivary gland (58.6%) compared to the DA and lymphoma groups (4.8%-28.6%) (all < 0.005).
CONCLUSION
Patient age, unilaterality, lacrimal gland size, wedge sign, and extra-orbital head and neck involvement differed significantly different between lymphoma, DA, and IgG4-RD. Our results will be useful for the differential diagnosis and proper management of chronic lacrimal gland enlargement.
Topics: Biopsy; Dacryocystitis; Humans; Immunoglobulin G; Immunoglobulin G4-Related Disease; Lacrimal Apparatus; Retrospective Studies
PubMed: 36098340
DOI: 10.3348/kjr.2022.0233