Ductal Hyperkeratinization and Acinar Renewal Abnormality: New Concepts on Pathogenesis of Meibomian Gland Dysfunction

Du, Yali; Peng, Xi; Liu, Yang; Wang, Jiasong; Ye, Youfan; Xu, Kang; Qu, Jingyu; Chen, Hua; Xie, Hua-Tao; Zhang, Mingchang

doi:10.3390/cimb45030122

Cited by 5 publications

(3 citation statements)

References 88 publications

(152 reference statements)

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“…Hyperkeratinization 81 of the excretory duct seems to be the initial pathological step in obstructive MGD with PMN infiltration playing a particularly important pathogenic role. 54 , 55 Previous studies reported that the lung overloaded with UPM led to keratinization, and lung protein cysts, as well as promoted neutrophil infiltration by triggering the inflammation response.…”

Section: Discussionmentioning

confidence: 99%

Urban Particulate Matter Triggers Meibomian Gland Dysfunction

Tu,

Liu,

Xue

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose The meibomian gland (MG), as the largest modified sebaceous gland, is potentially damaged by urban particulate matter (UPM) based on epidemiological evidence, but the specific experimental mechanisms remain unknown. This study investigated the effects of UPM on MG dysfunction (MGD) in rodent models. Methods Female C57BL/6J mice received eye drops containing UPM suspension or PBS for 14 days. The proliferative capacity and progenitor of MG were evaluated by immunofluorescence. Cell apoptosis was confirmed by TUNEL assay, along with the analysis of caspase family expression. Lipid accumulation was visualized by Oil Red O staining and LipidTox staining. Ductal hyperkeratinization, neutrophil infiltration, and pyroptosis activation were detected through immunostaining. The relative gene expression and signaling pathway activation were determined by Western blot analysis. Results Administration of UPM caused MGD-like clinical signs, manifested as distinct corneal epithelial erosion, increased MG orifice occlusion, and glandular dropout. UPM exposure significantly induced progenitor loss, cellular apoptosis, and lipogenic disorder in MG, by reducing P63/Lrig1 expression and increasing cleaved caspase-8, -9, and -3 and meibum lipogenic protein (HMGCR/SREBP-1) expression. UPM-treated mice exhibited ductal hyperkeratinization and neutrophil recruitment. Simultaneously, pyroptosis was motivated, as indicated by the heightened expression of NLRP3 and the cleavage of caspase-1 and -4 and gasdermin D, as well as the increase in IL-1β and IL-18 downstream. The underlying pathological mechanisms of UPM involve the phosphorylation of mitogen-activated protein kinase and nuclear factor-κB. Conclusions These results provided direct evidence for the toxicity of UPM in MG. UPM-induced activation of pyroptosis and mitogen-activated protein kinase/nuclear factor-κB signaling pathway might account for the inflammatory MGD.

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Section: Discussionmentioning

confidence: 99%

Urban Particulate Matter Triggers Meibomian Gland Dysfunction

Tu,

Liu,

Xue

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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“…AZR-MD-001 is a topical medication containing selenium sulfide and is believed to be an agent with keratostatic properties that reduce keratin synthesis by slowing keratinocyte proliferation and turnover, preventing hyperkeratinization of the MG ducts, as well as keratolytic properties that promote the effective release of blockages [ 76 ]. As mentioned earlier, MGD has various etiologies, including structural abnormalities of MG secondary to aging that can lead to evaporative DED [ 65 , 77 ]. Concordantly, a negative correlation with age was found in the mean length of the upper ( r = −0.485, p < 0.05) and lower MG ( r = −0.533, p < 0.001), as well as in the percentage area of MG acini of the upper ( r = −0.592, p < 0.05) and lower MG ( r = −0.357, p < 0.05) [ 78 ].…”

Section: Dry Eye Disease Sourcesmentioning

confidence: 99%

Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease

Valdés-Arias,

Locatelli,

Sepulveda-Beltran

et al. 2024

Drugs

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Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual’s well-being. This cumulative impact of DED on an individual’s activities and on society underscores the importance of finding diverse and effective management strategies. Such management strategies necessitate an understanding of the underlying pathophysiological mechanisms that contribute to DED in the individual patient. Presently, the majority of approved therapies for DED address T cell-mediated inflammation, with their tolerability and effectiveness varying across different studies. However, there is an emergence of treatments that target additional aspects of the disease, including novel inflammatory pathways, abnormalities of the eyelid margin, and neuronal function. These developments may allow for a more nuanced and precise management strategy for DED. This review highlights the recent pharmacological advancements in DED therapy in the United States. It discusses the mechanisms of action of these new treatments, presents key findings from clinical trials, discusses their current stage of development, and explores their potential applicability to different sub-types of DED. By providing a comprehensive overview of products in development, this review aims to contribute valuable insights to the ongoing efforts in enhancing the therapeutic options available to individuals suffering from DED.

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“…45 This process has also been termed hyperkeratinization. 46 As a result, recent investigations have demonstrated that the modification of keratin pathways may offer novel mechanistic treatments, spawning the development of keratolytic medications. 47 Selenium sulphide ointment (AZR-MD-001; Azura Ophthalmics Ltd, Tel Aviv, Israel) is the first brand of keratolytic agents for treating lid margin diseases and associated conditions.…”

Section: Selenium Sulphide Ointmentmentioning

confidence: 99%

Peering into the Dry Eye Pipeline for 2023 and Beyond

Mulpuri,

Nijm

2023

touchREVIEWS in Ophthalmology

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The global prevalence of dry eye disease (DED) ranges between approximately 5% and 50% and engenders a substantial socioeconomic burden. In the past decade, an unprecedented collaboration between industry and the vision sciences has spawned numerous potential therapeutic agents for DED. Many of these options possess novel mechanisms of action, potentially allowing clinicians to better tailor their treatment of patients suffering from DED. This review covers several specific pipeline drugs, such as lotilaner, perfluorohexyloctane, and cyclosporine A, along with broader drug classes such as reactive aldehyde species inhibitors, keratolytics, and mitochondrial reactive oxidative species scavengers. This review will summarize the promise and efficacy of upcoming dry eye disease treatments through the lens of data from USA-based phase II and phase III clinical trials.

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Ductal Hyperkeratinization and Acinar Renewal Abnormality: New Concepts on Pathogenesis of Meibomian Gland Dysfunction

Cited by 5 publications

References 88 publications

Urban Particulate Matter Triggers Meibomian Gland Dysfunction

Urban Particulate Matter Triggers Meibomian Gland Dysfunction

Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease

Peering into the Dry Eye Pipeline for 2023 and Beyond

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