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Meibomian gland dysfunction (MGD) is a chronic abnormality of the Meibomian glands (MGs) that is recognized as the leading cause of evaporative dry eye worldwide. Despite its prevalence, however, the pathophysiology of MGD remains elusive, and effective disease management continues to be a challenge. In the past 50 years, different models have been developed to illustrate the pathophysiological nature of MGD and the underlying disease mechanisms. An understanding of these models is crucial if researchers are to select an appropriate model to address specific questions related to MGD and to develop new treatments. Here, we summarize the various models of MGD, discuss their applications and limitations, and provide perspectives for future studies in the field., Competing Interests: Declaration of competing interest The authors declare that no competing interests exist., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Patients diagnosed with diabetes are inclined to have abnormalities on stability of tear film and disorder of meibomian gland (MG). This study aims to explore the pathological change of MG induced by diabetes in a rat model., Methods: Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin (STZ) to establish a diabetic animal model. Lipid accumulation in MG was detected by Oil Red O staining and LipidTox staining. Cell proliferation status was determined by Ki67 and P63 immunostaining, whereas cell apoptosis was confirmed by TUNEL assay. Gene expression of inflammatory cytokines and adhesion molecules IL-1α, IL-1β, ELAM1, ICAM1, and VCAM1 were detected by RT-PCR. Activation of ERK, NF-κB, and AMPK signaling pathways was determined by Western Blot analysis. Oxidative stress-related factors NOX4, 4HNE, Nrf2, HO-1, and SOD2 were detected by immunostaining or Western Blot analysis. Tom20 and Tim23 immunostaining and transmission electron microscopy were performed to evaluate the mitochondria functional and structure change., Results: Four months after STZ injection, there was acini dropout in MG of diabetic rats. Evident infiltration of inflammatory cells, increased expression of inflammatory factors, and adhesion molecules, as well as activated ERK and NF-κB signaling pathways were identified. Oxidative stress of MG was evident in 4-month diabetic rats. Phospho-AMPK was downregulated in MG of 2-month diabetic rats and more prominent in 4-month rats. After metformin treatment, phospho-AMPK was upregulated and the morphology of MG was well maintained. Moreover, inflammation and oxidative stress of MG were alleviated after metformin intervention., Conclusions: Long-term diabetes may lead to Meibomian gland dysfunction (MGD). AMPK may be a therapeutic target of MGD induced by diabetes.

Purpose: To determine if a high-fat diet (HFD) induces meibomian gland (MG) inflammation in mice., Methods: Male C57BL/6J mice were fed a standard diet (SD), HFD, or HFD supplemented with the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist rosiglitazone for various durations. Body weight, blood lipid levels, and eyelid changes were monitored at regular intervals. MG sections were subjected to hematoxylin and eosin staining, LipidTox staining, TUNEL assay, and immunostaining. Quantitative RT-PCR and western blot analyses were performed to detect relative gene expression and signaling pathway activation in MGs., Results: MG acinus accumulated more lipids in the mice fed the HFD. Periglandular CD45-positive and F4/80-positive cell infiltration were more evident in the HFD mice, and they were accompanied by upregulation of inflammation-related cytokines. PPAR-γ downregulation accompanied activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways in the HFD mice. There was increased acini cell apoptosis and mitochondria damage in mice fed the HFD. MG inflammation was ameliorated following a shift to the standard diet and rosiglitazone treatment in the mice fed the HFD., Conclusions: HFD-induced declines in PPAR-γ expression and MAPK and NF-κB signaling pathway activation resulted in MG inflammation and dysfunction in mice.

Purpose: To investigate the pathological changes of the meibomian gland (MG) and ocular surface in Apolipoprotein E knockout (ApoE -/- ) mice and to investigate the association of meibomian gland dysfunction (MGD) with hyperlipidemia., Methods: Total plasma cholesterol was measured in different ages of ApoE -/- and wild type (WT) mice, whilst the ocular surfaces were observed by slit-lamp biomicroscopy. MG sections were subjected to H&E staining, Oil Red O staining, TUNEL assay and immunostaining. Quantitate RT-PCR and Western blot analyses were performed to detect the relative gene expression in MGs. The 5-month-old ApoE -/- mice were administered with rosiglitazone or GW9662 + rosiglitazone via oral gavage for 2 months to determine their effect on MG pathological change., Results: We found eyelid abnormality, MG dropout, abnormal MG acinar morphology, dilated MG duct and plugging of the MG orifice in ApoE -/- mice. MG acini in ApoE -/- mice showed exaggerated lipid accumulation. Abnormal keratinization increased in MG duct, accompanied with decreased proliferation and increased apoptosis in ApoE -/- mice. Inflammatory cells infiltrated into the surrounding microenvironment of MG acini, and the NF-κB signaling pathway was activated in MG acinar cells. Oxidative stress was evident in MG acinar cells of ApoE -/- mice. Further investigation showed downregulation of PPAR-γ in MG acinar cells of ApoE -/- mice. PPAR-γ agonist rosiglitazone treatment reduced the morbidity of eyelid, as well as corneal pathological changes and MG inflammation in ApoE -/- mice., Conclusion: MGD and hyperlipidemia are closely associated in ApoE -/- mice, which represent a new model to study the pathophysiology of MGD related to dyslipidemia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The meibomian gland is the major contributor to the tear film lipid layer. It is generally accepted that meibomian gland secretions, i.e, meibum, play a critical role in the homeostasis of the tear film. Lipid components of meibum and their structure, as well as functions were intensively studied. However, the proteins from meibum have not attracted enough attention. This review summarizes current knowledge about protein components of the meibum, particularly their function on tear film and ocular surface, and changes in the proteins during meibomian gland dysfunction (MGD)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The EDA gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of Eda mutant Tabby mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in Tabby mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down-regulated in Tabby mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR, p- EGFR, and p- ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Pterygium is a very common disease in an eye clinic characterized by a benign proliferation of local conjunctiva that often crosses the limber of cornea and extends into corneal surface. Variety of studies has showed that pterygium is able to result in ocular discomfort and the change of ocular surface environment, such as dry eye. However, the link between abnormal tear film function and pterygium is controversial. Meibomian gland dysfunction (MGD) is a common cause of dry eye and ocular discomfort but is often neglected, which may be the missing link between dry eye and pterygium. In this study, our data firstly revealed increased abnormality of meibomian gland structure and function in pterygium patients, representing with increased abnormality of MGD parameters such as meibum expression (P < 0.001) and meibomian gland loss (P < 0.001). Besides, the scores of MGD severity in patients with progressive pterygium were higher than those in patients with resting pterygium. The correlation between MGD parameters and ocular discomfort as well as dry eye indexes is also established. These findings suggest that MGD correlates to the tear film instability and ocular discomfort in patients with pterygium.

Purpose: The aim of this study was to explore the relationship between chronic cigarette smoking and meibomian gland dysfunction (MGD)., Methods: This study enrolled 322 smokers with MGD and 2067 non-smokers with MGD. All enrolled subjects were tested in the following sequence: Ocular Surface Disease Index (OSDI), tear film breakup time (TBUT), corneal fluorescein staining (CFS), Schirmer I test (SIT)and finally slit-lamp microscope examination of lid margin abnormalities, meibomian gland expression as well as meibum., Results: Compared with the MGD patients without smoking, the MGD patients with smoking had significantly increased scores of lid margin abnormality and meibum (P<0.01 for each comparison). No significant difference was noted in OSDI, TBUT, CFS, SIT or the score of Meibomian gland expressibility between the smokers and non-smokers (P>0.05 for each comparison). In the smokers, the smoking index was significantly correlated with the scores of lid margin abnormality (Both sexes, R = 0.19, P<0.01; Male, R = 0.18, P<0.01) and meibum (Both sexes, R = 0.29, P<0.01; Male, R = 0.20, P<0.01), whereas it was not significantly correlated with OSDI, TBUT, CFS, SIT or score of Meibomian gland expressibility (P>0.05 for each comparison)., Conclusion: The findings of this study suggest chronic smoking might be associated with MGD., Competing Interests: The authors have declared that no competing interests exist.

Meibomian gland dysfunction is the most frequent cause of evaporative dry eye, yet its underlying pathophysiology is unknown. To gain insight into this pathophysiology, we characterized the time-dependent tear film and ocular surface changes occurring in X-linked anhidrotic-hypohidrotic ectodermal dysplasia mice (Tabby), which lack the meibomian gland. These mice sequentially developed corneal epithelial defects, central corneal stromal edema, neovascularization, and pannus 8 to 16 weeks after birth. Aqueous tear secretion was normal, whereas tear break-up time and ex vivo tear evaporation times were all shortened. Corneal epithelial microvilli were less numerous, conjunctival goblet cell density was unaffected, and MUC5AC and MUC5B gene expression was increased. Markers of squamous metaplasia (cytokeratin 10 and small proline-rich protein 1B) were noticed in the corneal epithelium of Tabby mice as early as the fourth week. Taken together, the Tabby mouse is a relevant meibomian gland dysfunction-related dry eye model that may lead to a better understanding of how meibomian glands are related to ocular surface health. This model may also help with discovering novel drug options for treating evaporative dry eye., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Transforming growth factor alpha (TGFα) belongs to the epidermal growth factor (EGF) family and is known to play an important role during eyelid morphogenesis. In this study, we showed that ectopic expression of TGFα in the stroma of Kera-rtTA/tet-O-TGFα bitransgenic mice results in precocious eye opening, abnormal morphogenesis of the meibomian gland, tendon and tarsal plate malformation and epithelium hyperplasia. TGFα did not change proliferation and differentiation of meibocytes, but promoted proliferation and inhibited differentiation of the tarsal plate tenocytes. These results suggest that proper formation of the tendon and tarsal plate in the mouse eyelid is required for normal morphogenesis of the meibomian gland., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To evaluate meibomian gland (MG) alterations in patients with primary chronic dacryocystitis (PCD) by in vivo confocal microscopy (IVCM), and to correlate the finding with clinical presentation., Methods: Twenty-eight eyes with the diagnosis of PCD and their contralateral unaffected eyes were studied and compared with 27 normal controls. All subjects completed an Ocular Surface Disease Index questionnaire (OSDI) and underwent slit-lamp biomicroscopy examination, tear break-up time (BUT) measurements, fluorescein staining, Schirmer test I, and an IVCM examination of the MG. IVCM parameters, including the MG acinar unit density (MGAUD), periglandular inflammatory cell density (ICD), MG acinar unit longest diameter (MGALD), and MG acinar unit shortest diameter (MGASD) and their correlation with clinical data were analyzed., Results: The mean MG expressibility scores, BUT values, and staining scores were significantly worse in eyes with PCD compared with the contralateral clinically unaffected eyes and controls (p < 0.05). A significant decrease in MGAUD was observed in PCD eyes compared with the controls and the contralateral clinically unaffected eyes. Conversely, the mean ICD and MGASD values were significantly higher in the PCD eyes. There were no significant differences in mean MGALD value between the PCD eyes and the contralateral clinically unaffected eyes. In addition, there were significant changes in the IVCM parameters in the contralateral unaffected eyes compared with the controls, including MGAUD, ICD, MGALD, and MGASD. All IVCM parameters showed a strong, significant correlation with MG dropout grades, MG expressibility, fluorescein staining scores, and OSDI values (all p < 0.05)., Conclusions: Patients with unilateral PCD demonstrated significant changes in MG as compared with the contralateral clinically unaffected eyes and controls. The MG function should be closely observed in these patients.

This study was done to observe the safety and effect of Xiaoyaosan (XYS) on the stimulated depressive disorder (DD) related dry eye disease (DED) in mice. Normal control (NC) group, Vehicle group, and drug treatment groups, including Sertraline Hydrochloride (SH), XYS low-dose (XYS-LD), medium-dose (XYS-MD), and high-dose (XYS-HD), were established. The drug quality of XYS was assessed by high-performance liquid chromatography (HPLC). XYS toxicity in kidney and liver was assessed with Hematoxylin & Eosin (H&E) staining. Serum enzyme-linked immunosorbent assay (ELISA) and body weights were used to evaluate the depression status of mice. Tear production, corneal sensitivity, Oregon Green Dye (OGD) staining, and corneal confocal microscopy were used to assess ocular surface changes. H&E staining was also used to assess pathological cornea and lacrimal gland changes. HPLC results showed that XYS complied with Chinese drug quality standards. The drug treatment groups observed no drug toxicity reactions in the liver and kidney. SH and XYS groups improved DD-related serological indices as compared with Vehicle. Body weight was enhanced in mice with XYS groups compared to Vehicle and SH. Mice with XYS treatments showed increased tear production and corneal sensitivity, decreased corneal OGD staining scores, improved morphology, and decreased inflammatory cell infiltration in the cornea and lacrimal gland. In conclusion, XYS had no drug toxicity, improved serological indices, and ocular surface pathological changes in DD-related DED mice. XYS is safe and may have a therapeutic effect on DD-related DED. [ABSTRACT FROM AUTHOR]

Cigarette smoke extract (CSE), a complex mixture of compounds, contributes to a range of eye diseases; however, the underlying pathophysiological responses to tobacco smoke remain ambiguous. The purpose of the present study was to evaluate the cigarette smoke-induced phenotypic and transcriptomic changes in the corneal epithelium with a view to elucidating the likely underlying mechanism. Accordingly, for the first time, we characterized the genome-wide effects of CSE on the corneal epithelium. The ocular surface of the mice in the experimental groups was exposed to CSE for 1 h per day for a period of one week, while mice in the control group were exposed to preservative-free artificial tears. Corneal fluorescein staining, in vivo confocal microscopy and scanning electron microscopy were performed to examine the corneal ultrastructure. Transcriptome sequencing and bioinformatics analysis were performed followed by RT-qPCR to validate gene expression changes. The results indicate that CSE exposure disrupted the structural integrity of the superficial epithelium, decreased the density of microvilli, and compromised the corneal epithelial barrier intactness. RNA-seq revealed 667 differentially expressed genes, and functional analysis highlighted the enhancement of several biological processes such as antioxidant activity and the response to oxidative stress. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that glutathione metabolism and drug metabolism cytochrome P450 were the most relevant pathways contributing to the effects of CSE on the corneal epithelium. Protein–protein interaction (PPI) network analysis illustrated that GCLC, NQO1, and HMOX1 were the most relevant nodes. In conclusion, the present study indicates that CSE exposure induces changes in the phenotype and genotype of the corneal epithelium. The antioxidant response element is essential for counteracting the effects of cigarette smoke on this tissue layer. These results shed novel insights into how cigarette smoke damages this ocular surface. [Display omitted] • We established a novel method that could qualitatively and quantitatively characterize alterations in vivo induced by CSE. • CSE destroyed the structure and barrier function of the corneal epithelium in mice in a dose-dependent manner. • CSE activated glutathione metabolism and cytochrome P450-mediated metabolism of xenobiotics in corneal epithelium. • CSE enhanced the antioxidant activity of corneal epithelium by upregulating antioxidant-related genes. Exposure of the corneal epithelium to cigarette smoke altered the phenotypic and genotypic characteristics which compromised its effectiveness at preserving normal vision. [ABSTRACT FROM AUTHOR]

Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: "Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities." The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of Houttuynia eye drops (a Chinese traditional medicine) atomization treatment in meibomian gland dysfunction (MGD)-related dry eye disease (DED) patients. Methods: A total of 240 eligible patients diagnosed with MGD-related DED were assigned either Houttuynia eye drops or placebo for atomization once daily for four weeks in a multi-center, randomized, double-blind, placebo-controlled clinical study. Primary outcome evaluations used included eye symptom score (using the Chinese Dry Eye Questionnaire), meibum quality, and tear break-up time (TBUT), while safety evaluations included adverse events (AEs), visual acuity, and intraocular pressure monitoring. Indicators were measured at baseline as well as one week, two weeks, and four weeks after treatment. Results: Primary outcome measures of the Houttuynia group were improved compared with their placebo counterparts following four-week treatment. Eye symptom scores were significantly reduced relative to the baseline in the Houttuynia group (mean ± standard error of the mean, 9.00 ± 0.61) compared with the placebo group (6.29 ± 0.55; p = 0.0018). Reduction in meibum quality score in the Houttuynia group (0.91 ± 0.10) was also significantly higher compared with the placebo group (0.57 ± 0.10; p = 0.0091), while TBUT in the treatment group (6.30 ± 0.22) was also longer than in the latter (5.60 ± 0.24; p = 0.0192). No medication-related adverse events were observed. Conclusions: Atomization treatment with Houttuynia eye drops is both clinically and statistically effective for the treatment of mild to moderate MGD-related DED patients. This approach is generally safe and was tolerated well by patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pathological changes of meibomian gland (MG) and ocular surface tissues in Apolipoprotein E knockout (ApoE‐/‐) mice and wild type mice fed with high fat diet, and to illustrate the effect of hyperlipidemia on meibomian gland function. Methods: The ocular surface of ApoE‐/‐ male mice and age and sex matched wild type mice fed with standard diet or high fat diet was observed under slit lamp microscope. MG tissue sections underwent H&E staining, Oil Red O staining, TUNEL assay, and immuno‐fluorescence staining for K10, Fabp5, Ki67, K6a, p63, PPAR‐g, NF‐kB p65, p‐NF‐kB p65, caspase 3, caspase 8, and immune‐histochemical staining for CD45. Real‐time RT‐PCR and Western blot was performed to detect above mentioned gene expression in MG tissues. Lipid metabolism related genes expression in MG were also detected by real‐time RT‐PCR. Results: Eyelid thickening, keratinization and corneal neovascularization occurred in ApoE‐/‐ mice at the age of 5 months, and the changes were more obvious at 7 months. H&E staining showed hypertrophy of the meibomian gland acinus, and Oil red O staining showed accumulation of lipid in MG acinus of ApoE‐/‐ mice. Both K10 and Fabp5 expression were increased, while Ki67, K6a, p63 were decreased in ApoE‐/‐ mice compared to the wild type mice. Cytoplasmic and nuclear expression of PPAR‐g was decreased, NF‐kB p65, p‐NF‐kB p65, caspase 3, and caspase 8 expression was higher in the ApoE‐/‐ mice compared to the wild type mice. TUNEL assay showed more positive cells in the meibomian gland acinus of ApoE‐/‐ mice. CD45 positive cell infiltration increased from 5 months to 7 months in ApoE‐/‐ mice. Lipid metabolism related genes such as FFAR1, PAR3, ACSL3, and LIPC were decreased in ApoE‐/‐ mice compared to the wild type mice. Wild type mice fed with high fat diet showed similar pathological changes as ApoE‐/‐ mice. Conclusion: Hyperlipidemia could induce abnormal meibomian gland acinar cell proliferation, differentiation, and lipid metabolism. Hyperlipidemia condition may be an important pathogenesis factor of meibomian gland dysfunction. [ABSTRACT FROM AUTHOR]