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Current Opinion in Ophthalmology Jul 2021Dry eye disease (DED) is a multifactorial disease affecting approximately 5-50% of individuals in various populations. Contributors to DED include, but are not limited... (Review)
Review
PURPOSE OF REVIEW
Dry eye disease (DED) is a multifactorial disease affecting approximately 5-50% of individuals in various populations. Contributors to DED include, but are not limited to, lacrimal gland hypofunction, meibomian gland dysfunction (MGD), ocular surface inflammation, and corneal nerve dysfunction. Current DED treatments target some facets of the disease, such as ocular surface inflammation, but not all individuals experience adequate symptom relief. As such, this review focuses on alternative and adjunct approaches that are being explored to target underlying contributors to DED.
RECENT FINDINGS
Neuromodulation, stem cell treatments, and oral royal jelly have all been studied in individuals with DED and lacrimal gland hypofunction, with promising results. In individuals with MGD, devices that provide eyelid warming or intense pulsed light therapy may reduce DED symptoms and signs, as may topical Manuka honey. For those with ocular surface inflammation, naturally derived anti-inflammatory agents may be helpful, with the compound trehalose being farthest along in the process of investigation. Nerve growth factor, blood-derived products, corneal neurotization, and to a lesser degree, fatty acids have been studied in individuals with DED and neurotrophic keratitis (i.e. corneal nerve hyposensitivity). Various adjuvant therapies have been investigated in individuals with DED with neuropathic pain (i.e. corneal nerve hypersensitivity) including nerve blocks, neurostimulation, botulinum toxin, and acupuncture, although study numbers and design are generally weaker than for the other DED sub-types.
SUMMARY
Several alternatives and adjunct DED therapies are being investigated that target various aspects of disease. For many, more robust studies are required to assess their sustainability and applicability.
Topics: Complementary Therapies; Dry Eye Syndromes; Humans; Lacrimal Apparatus
PubMed: 34010229
DOI: 10.1097/ICU.0000000000000768 -
Cell Stem Cell Jul 2021The lacrimal gland is essential for lubrication and protection of the eye. Disruption of lacrimal fluid production, composition, or release results in dry eye, causing...
The lacrimal gland is essential for lubrication and protection of the eye. Disruption of lacrimal fluid production, composition, or release results in dry eye, causing discomfort and damage to the ocular surface. Here, we describe the establishment of long-term 3D organoid culture conditions for mouse and human lacrimal gland. Organoids can be expanded over multiple months and recapitulate morphological and transcriptional features of lacrimal ducts. CRISPR-Cas9-mediated genome editing reveals the master regulator for eye development Pax6 to be required for differentiation of adult lacrimal gland cells. We address cellular heterogeneity of the lacrimal gland by providing a single-cell atlas of human lacrimal gland tissue and organoids. Finally, human lacrimal gland organoids phenocopy the process of tear secretion in response to neurotransmitters and can engraft and produce mature tear products upon orthotopic transplantation in mouse. Together, this study provides an experimental platform to study the (patho-)physiology of the lacrimal gland.
Topics: Animals; Dry Eye Syndromes; Humans; Lacrimal Apparatus; Mice; Organoids; Stem Cells; Tears
PubMed: 33730555
DOI: 10.1016/j.stem.2021.02.024 -
Arquivos Brasileiros de Oftalmologia 2021The purpose of this article was to report a case of intraconal lacrimal gland tissue and to review the literature on lacrimal gland choristoma. The magnetic resonance... (Review)
Review
The purpose of this article was to report a case of intraconal lacrimal gland tissue and to review the literature on lacrimal gland choristoma. The magnetic resonance imaging findings of a biopsy-proven orbital case are also presented. A PubMed database search was performed using the key terms heterotopic, ectopic, aberrant, choristoma, and lacrimal gland to identify all the previously documented studies on lacrimal gland choristoma, in English, Spanish, and French. We classified the lacrimal gland choristoma cases classified according to the location of the lesions, clinical appearance, management, and outcome. The search targeting the period between 1887 and 2019 returned 79 articles, which were reviewed. We found a total of 113 cases of choristomas with normal lacrimal gland tissue. Only two of them were not associated with the eye or its adnexa while the remaining 111 lesions were found either on the ocular surface (n=46) or in the orbit (n=34). Intraocular choristomas were found in 18 patients, and the rest of the lesions were noted either on the eyelids (n=10) or in the lacrimal drainage system (n=3). Orbital and intraocular choristomas are the most harmful lesions as orbital choristomas are frequently associated with permanent diplopia while intraocular lacrimal gland choristomas have a poor visual prognosis and are a common cause of enucleation of the eye. In one of the reported cases, a corneal lacrimal gland choristoma had been experimentally induced by activating the FGF10 signaling pathway. Lacrimal gland choristomas are not uncommon. This peculiar type of lesion has been experimentally induced and may appear in a variety of locations associated with the globe and its adnexa.
Topics: Choristoma; Cornea; Humans; Lacrimal Apparatus; Orbit
PubMed: 35416898
DOI: 10.5935/0004-2749.20220029 -
Normal and Sjogren's syndrome models of the murine lacrimal gland studied at single-cell resolution.Proceedings of the National Academy of... Oct 2023The lacrimal gland is of central interest in ophthalmology both as the source of the aqueous component of tear fluid and as the site of autoimmune pathology in the...
The lacrimal gland is of central interest in ophthalmology both as the source of the aqueous component of tear fluid and as the site of autoimmune pathology in the context of Sjogren's syndrome (SjS). To provide a foundational description of mouse lacrimal gland cell types and their patterns of gene expression, we have analyzed single-cell transcriptomes from wild-type (Balb/c) mice and from two genetically based SjS models, and (nonobese diabetic), and defined the localization of multiple cell-type-specific protein and mRNA markers. This analysis has uncovered a previously undescribed cell type, Car6+ cells, which are located at the junction of the acini and the connecting ducts. More than a dozen secreted polypeptides that are likely to be components of tear fluid are expressed by acinar cells and show pronounced sex differences in expression. Additional examples of gene expression heterogeneity within a single cell type were identified, including a gradient of Claudin4 along the length of the ductal system and cell-to-cell heterogeneity in transcription factor expression within acinar and myoepithelial cells. The patterns of expression of channels, transporters, and pumps in acinar, Car6+, and ductal cells make strong predictions regarding the mechanisms of water and electrolyte secretion. In and lacrimal glands, distinctive changes in parenchymal gene expression and in immune cell subsets reveal widespread interferon responses, a T cell-dominated infiltrate in the model, and a mixed B cell and T cell infiltrate in the model.
Topics: Female; Mice; Male; Animals; Sjogren's Syndrome; Lacrimal Apparatus; Mice, Inbred MRL lpr; Mice, Inbred NOD; Mice, Inbred BALB C; Disease Models, Animal
PubMed: 37812717
DOI: 10.1073/pnas.2311983120 -
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 -
Indian Journal of Ophthalmology Apr 2023Lacrimal and meibomian glands contribute to the aqueous and lipid components of tear film, respectively. Their evaluation remains central to diagnosing and managing dry... (Review)
Review
Lacrimal and meibomian glands contribute to the aqueous and lipid components of tear film, respectively. Their evaluation remains central to diagnosing and managing dry eye disease (DED). The review discusses the differences and reliability of various diagnostic tests and commercially available devices used for DED diagnosis. Slit-lamp-based techniques are direct palpebral lobe and tear flow assessment, Schirmer test, meibum quality and expressibility, and evaluation of tear meniscus height. Non-invasive tear meniscus height (TMH), tear break-up time (TBUT), lipid layer thickness (LLT), and meibography are machine-based diagnostic tests. The structure-function correlation of the tear-producing glands gives more comprehensive details than either information alone. Many devices are available in the market, which make DED diagnosis an easy feat, but the tests should be interpreted keeping in mind the intra-observer and inter-observer repeatability. Also, the tear film displays a huge variability as per the environmental conditions and impact of blinking. Hence, the examiner should be well versed with the techniques and repeat the test two to three times to obtain an average reading, which is more reliable. The recommended sequence of tests for diagnosing DED is a dry eye questionnaire, TMH, LLT, NIBUT (FBUT if non-invasive test is unavailable but should be performed after osmolarity), tear osmolarity, meibography, and ocular surface staining. Invasive tests such as Schirmer should be performed after the non-invasive tear film diagnostic testing.
Topics: Humans; Meibomian Glands; Reproducibility of Results; Lacrimal Apparatus; Tears; Dry Eye Syndromes; Lipids
PubMed: 37026239
DOI: 10.4103/IJO.IJO_2622_22 -
Asia-Pacific Journal of Ophthalmology... 2017Lacrimal gland tumors are rare and constitute a wide spectrum of different entities ranging from benign epithelial and lymphoid lesions to high-grade carcinomas,... (Review)
Review
Lacrimal gland tumors are rare and constitute a wide spectrum of different entities ranging from benign epithelial and lymphoid lesions to high-grade carcinomas, lymphomas, and sarcomas with large differences in prognosis and clinical management. The symptoms and findings of a lacrimal gland lesion are a growing mass at the site of the lacrimal gland, including displacement of the eyeball, decreased motility, diplopia, and ptosis. Pain is the cardinal symptom of an adenoid cystic carcinoma. Radiological findings characteristically include an oval, well-demarcated mass for benign lesions whereas malignant lesions typically display calcifications, destruction of bone, and invasion of adjacent structures. The diagnosis ultimately relies on histology, as does the choice of treatment and the prognosis. In recent years, the understanding of the biology of numerous types of lacrimal gland neoplasia has improved and the choice of treatment has changed accordingly and holds further promise for future targeted therapies. Treatment of benign epithelial lesions is surgical excision whereas carcinomas often require adjuvant radiotherapy and/or chemotherapy. In contrast, the cornerstone in management of lymphoid lesions is chemotherapy, often including a monoclonal antibody. This article presents an update on the clinical, radiological, histological, and molecular features, along with treatment strategies for tumors of the lacrimal gland.
Topics: Combined Modality Therapy; Eye Neoplasms; Humans; Lacrimal Apparatus; Lacrimal Apparatus Diseases; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Prognosis
PubMed: 28399336
DOI: 10.22608/APO.201707 -
Best Practice & Research. Clinical... Mar 2023This paper addresses how to perform an ultrasound assessment of the salivary and lacrimal glands, how to identify pathological changes, and how to score disease... (Review)
Review
This paper addresses how to perform an ultrasound assessment of the salivary and lacrimal glands, how to identify pathological changes, and how to score disease activity, focusing on the use for primary Sjögren's syndrome (pSS). It addresses the role of salivary gland ultrasound for diagnosing and management of patients with pSS and touches upon the use for differential diagnosis, including how and when to perform ultrasound-guided biopsies and injections.
Topics: Humans; Sjogren's Syndrome; Lacrimal Apparatus; Salivary Glands; Ultrasonography; Diagnosis, Differential
PubMed: 37258318
DOI: 10.1016/j.berh.2023.101837 -
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 -
Investigative Ophthalmology & Visual... Jul 2023Orbital glands and drainage conduits are two distinct entities that constitute the lacrimal apparatus system, the malfunction of which leads to a range of ocular surface...
PURPOSE
Orbital glands and drainage conduits are two distinct entities that constitute the lacrimal apparatus system, the malfunction of which leads to a range of ocular surface disorders. Despite the close functional relationship, how the two parts interact under pathophysiological conditions has not been directly tested. The study aims to investigate the lacrimal gland (LG) structural and functional changes upon the drainage system obstruction, thus, testing their function link.
METHODS
Dacryocystectomy was performed in C57BL/6 mice to create a surgical model for tear duct (TD) obstruction (STDOB). Prickle1 mutant line with congenital nasolacrimal duct dysplasia serves as a genetic model for TD obstruction (GTDOB). Alterations of the LG and the ocular surface in tear duct obstruction mice were examined.
RESULTS
STDOB and GTDOB mice showed similar ocular surface phenotypes, including epiphora, corneal epithelial defects, and conjunctival goblet cell abnormalities. At the molecular and cellular levels, aberrant secretory vesicle fusion of the LG acinar cells was observed with altered expression and localization of Rab3d, Vamp8, and Snap23, which function in membrane fusion. LG secretion was also altered in that lactoferrin, lipocalin2, and lysozyme expression were increased in both LG and tears. Furthermore, STDOB and GTDOB mice exhibited similar LG transcription profiles.
CONCLUSIONS
Physical obstruction of tear drainage in STDOB or GTDOB mice leads to LG dysfunction, suggesting a long-distance interaction between the tear drainage conduits and the LG. We propose that various components of the lacrimal apparatus should be considered an integral unit in diagnosing and treating ocular surface diseases.
Topics: Mice; Animals; Lacrimal Apparatus; Mice, Inbred C57BL; Tears; Lacrimal Apparatus Diseases; Nasolacrimal Duct; Adaptor Proteins, Signal Transducing; LIM Domain Proteins
PubMed: 37440262
DOI: 10.1167/iovs.64.10.13