scholarly journals Impact of P2X7 Purinoceptors on Goblet Cell Function: Implications for Dry Eye

2021 ◽  
Vol 22 (13) ◽  
pp. 6935
Author(s):  
Donald G. Puro
Keyword(s):  
Dry Eye ◽  
Goblet Cell ◽  
Cell Function ◽  
Tear Film ◽  
Goblet Cells ◽  
High Gain ◽  
High Temporal Resolution ◽  
Triggered Release ◽  
Voltage Gated Calcium Channels ◽  
Conjunctival Goblet Cells

By providing ~70% of the eye’s refractive power, the preocular tear film is essential for optimal vision. However, its integrity is often jeopardized by environmental and pathologic conditions that accelerate evaporation and cause sight-impairing dry eye. A key adaptive response to evaporation-induced tear film hyperosmolarity is the reflex-triggered release of tear-stabilizing mucin from conjunctival goblet cells. Here, we review progress in elucidating the roles of ion channels in mediating this important exocytotic response. Much is now known about the modulatory impact of ATP-sensitive potassium channels, nonspecific cation channels and voltage-gated calcium channels. Recently, we discovered that during unremitting extracellular hyperosmolarity, P2X7 receptor/channels also become activated and markedly impair goblet cell viability. However, our understanding of possible adaptive benefits of this P2X7 activation remains limited. In the present study, we utilized high-temporal resolution membrane capacitance measurements to monitor the exocytotic activity of single goblet cells located in freshly excised rat conjunctiva. We now report that activation of P2X7 purinoceptors boosts neural-evoked exocytosis and accelerates replenishment of mucin-filled granules after exocytotic depletion. Thus, P2X7 activation exerts a yin-yang effect on conjunctival goblet cells: the high-gain benefit of enhancing the supply of tear-stabilizing mucin is implemented at the high-risk of endangering goblet cell survival.

scholarly journals How goblet cells respond to dry eye: adaptive and pathological roles of voltage-gated calcium channels and P2X7 purinoceptors

2020 ◽  
Vol 318 (6) ◽  
pp. C1305-C1315
Author(s):  
Donald G. Puro
Keyword(s):  
Calcium Channels ◽  
Dry Eye ◽  
Goblet Cell ◽  
Adaptive Strategy ◽  
Goblet Cells ◽  
High Gain ◽  
Cell Physiology ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Conjunctival Goblet Cells

Dry eye is a common sight-impairing, painful disorder characterized by disruption of the preocular tear film, whose integrity is required for ~70% of the eye’s refractive power. A universal feature of clinical dry eye is hyperosmolarity of the tears resulting from their accelerated evaporation due to dysfunction of tear- and oil-producing ocular glands. A key adaptive response to dryness/hyperosmolarity is release of tear-stabilizing mucin by conjunctival goblet cells. Yet the mechanisms mediating this response to hyperosmolarity remain poorly understood. In this study of freshly excised rat conjunctiva, perforated-patch recordings revealed that during sustained hyperosmolarity, the development of a nonspecific cation (NSC) conductance depolarizes the goblet cells to a near-optimal voltage for the tonic activation of their voltage-gated calcium channels (VGCCs). In turn, as demonstrated by high-resolution membrane capacitance measurements, VGCC activation boosts the exocytotic response of conjunctival goblet cells to neural input. However, over time, VGCC activation also increases the vulnerability of these cells to the lethality of hyperosmolarity. Viability assays further revealed that hyperosmotic-induced goblet cell death is critically dependent on P2X7 receptor channels. Similar to the yin-yang impact of VGCCs on goblet cell physiology and pathobiology, P2X7 activation not only compromises goblet cell viability but also enhances exocytotic activity. Thus, the NSC/VGCC and P2X7 purinoceptor pathways are components of a previously unappreciated high-gain/high-risk adaptive strategy to combat ocular dryness. These pathways boost release of tear-stabilizing mucin at the risk of jeopardizing the viability of the conjunctival goblet cells, whose loss is a histopathological hallmark of irreversible mucin-deficient dry eye.

scholarly journals Role of ion channels in the functional response of conjunctival goblet cells to dry eye

2018 ◽  
Vol 315 (2) ◽  
pp. C236-C246 ◽  
Author(s):  
Donald G. Puro
Keyword(s):  
Ion Channels ◽  
Dry Eye ◽  
Ocular Surface ◽  
Adaptive Response ◽  
Tear Film ◽  
Goblet Cells ◽  
Cation Conductance ◽  
Conjunctival Goblet Cells

Optimal vision requires an ocular surface with a stable tear film whose many critical tasks include providing >70% of the eye’s refractive power. However, for millions, tear film instability produces uncomfortable sight-impairing dry eye. Despite the multitude of etiologies for dry eye, a universal hallmark is hyperosmolarity of the tear film. Presently, knowledge of how the ocular surface responds to hyperosmolarity remains incomplete with little understood about the role of ion channels. This bioelectric analysis focused on conjunctival goblet cells whose release of tear-stabilizing mucin is a key adaptive response to dry eye. In freshly excised rat conjunctiva, perforated-patch recordings demonstrated that a ≥10% rise in osmolarity triggers goblet cells to rapidly generate a ~15-mV hyperpolarization due to the oxidant-dependent activation of ATP-sensitive K+ (KATP) channels. High-resolution membrane capacitance measurements used to monitor exocytosis revealed that this hyperpolarization results in an approximately fourfold boost in exocytotic activity evoked by cholinergic input, which in vivo occurs via a neural reflex and depends chiefly on calcium influxing down its electro-gradient. We discovered that this adaptive response is transient. During 30–80 min of hyperosmolarity, development of a depolarizing nonspecific cation conductance fully counterbalances the KATP-driven hyperpolarization and thereby eliminates the exocytotic boost. We conclude that hyperosmotic-induced hyperpolarization is a previously unappreciated mechanism by which goblet cells respond to transient ocular dryness. Loss of this voltage increase during long-term dryness/hyperosmolarity may account for the clinical conundrum that goblet cells in chronically dry eyes can remain filled with mucin even though the tear film is hyperosmotic and mucin-deficient.

scholarly journals Stimulation of Basal Secretion in the Treatment of Dry Eye Syndrome

2019 ◽  
Vol 16 (1) ◽  
pp. 70-75
Author(s):  
L. I. Uchakova ◽  
S. V. Balalin ◽  
V. L. Zagrebin
Keyword(s):  
Dry Eye ◽  
Tear Film ◽  
Goblet Cells ◽  
Dry Eye Syndrome ◽  
Ophthalmological Examination ◽  
Basal Secretion ◽  
Tear Production ◽  
Before And After ◽  
The Stability ◽  
Conjunctival Goblet Cells

The aim is to evaluate the effectiveness of Stillavit in the treatment of dry eye syndrome (DES) and its effect on the density of conjunctival goblet cells and the functional parameters of tear production. Methods. There were analyzed treatment results of 18 patients (36 eyes) with DES at the age of 48 to 80 years (average 60.6 ± 1.3 years) including 17 women and 1 male before and after 1 and 3 months after Stillavit prescription. In all patients in addition to a standard ophthalmological examination the results of Schirmer I, Norn, as well as the LIPCOF test were evaluated and the density of conjunctival goblet cells was examined. Results. After 1 and 3 months there was a significant improvement in the results of the Norn test: from 5.17 ± 0.22 seconds to 7.18 ± 0.17 seconds which indicated an increase in the stability of the tear film. After 3 months there was a significant increase in the density of conjunctival goblet cells, improvement in the Schirmer sample: from 9.26 ± 0.89 to 11.7 ± 0.6 mm (t = 2.28, p < 0.05) and LIPCOF test (t = 2.18, p < 0.05) which indicated an increase in tear production and a significant decrease in the inflammatory process and edema of the conjunctiva. Conclusion. Treatment of DES with the use of Stillavit leads after 3 months to a significant increase in the density of conjunctival goblet cells, increases tear production and stability of the tear film.

scholarly journals Distribution and density of conjunctival goblet cells

2002 ◽  
Vol 55 (5-6) ◽  
pp. 195-200 ◽  
Author(s):  
Vesna Vujkovic ◽  
Gostimir Mikac ◽  
Risto Kozomara
Keyword(s):  
Cell Density ◽  
Dry Eye ◽  
Goblet Cell ◽  
Tear Film ◽  
Goblet Cells ◽  
Dry Eye Syndrome ◽  
Bulbar Conjunctiva ◽  
Cell Distribution ◽  
Significant Difference ◽  
Goblet Cell Density

There is a regional variation in conjunctival goblet cell distribution and density per unit of measurement. By secreting mucin goblet cells are involved in formation of tear film. Tear film instability is the basic sign of dry eye syndrome. Although dry eye syndrome can be a side effect of a disease, the most common cause is normal aging. The objective of the research was to determine goblet cell density in bulbar and lower forniceal conjunctiva and possible changes in goblet cell density related to age and sex. The research was conducted on 30 conjunctival samples of patients with no clinical changes of the conjunctiva. Tissue sections were stained with hematoxylin eosin (HE), periodic acid-schiff (PAS), alcian blue (AB)/PAS Giemsa methods. Goblet cell density was 1.24?1.62 in bulbar conjunctiva and 30.21?14.32 in lower forniceal conjunctiva. Goblet cell distribution in the conjunctiva was unequal. A correlation between goblet cell density and age was not determined. Goblet cell density doesn't decrease with aging. No significant difference in goblet cell density between men and women was established.

scholarly journals Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
L. Contreras-Ruiz ◽  
A. Ghosh-Mitra ◽  
M. A. Shatos ◽  
D. A. Dartt ◽  
S. Masli
Keyword(s):  
Sjögren’S Syndrome ◽  
Inflammatory Cytokines ◽  
Goblet Cell ◽  
Ocular Surface ◽  
Cell Function ◽  
Sjögren's Syndrome ◽  
Goblet Cells ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

Ocular surface inflammation associated with Sjögren’s syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren’s syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-αand IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.

scholarly journals Benzalkonium Chloride-Preserved Anti-Glaucomatous Eye Drops and Their Effect on Human Conjunctival Goblet Cells in vitro

2021 ◽  
pp. 69-75
Author(s):  
Anne Hedengran ◽  
Xenia Begun ◽  
Olivia Müllertz ◽  
Zaynab Mouhammad ◽  
Rupali Vohra ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Survival ◽  
Goblet Cell ◽  
Benzalkonium Chloride ◽  
Goblet Cells ◽  
Eye Drops ◽  
Dependent Manner ◽  
The Impact ◽  
Conjunctival Goblet Cells

<b><i>Introduction:</i></b> Most intraocular pressure (IOP)-lowering eye drops are preserved with benzalkonium chloride (BAK). This can increase side effects and decrease adherence. Particularly, damage to the mucin-producing conjunctival goblet cells may be an issue due to instability of the tear film. We aimed to investigate the effect of IOP-lowering eye drops preserved with BAK on cultured human conjunctival goblet cells. <b><i>Methods:</i></b> Eye drops Brimonidine Tartrate Teva (BT) with 0.005% BAK, Dorzolamide Stada (DS) with 0.0075% BAK, Optimol<sup>®</sup> (OP) with 0.01% BAK, and Latanoprost Teva (LT) with 0.02% BAK were included. Human primary cultured goblet cell survival was evaluated using a lactate dehydrogenase assay on human goblet cells after treatment for 30 min and 6 h with the different anti-glaucoma drug formulations. <b><i>Results:</i></b> All eye drops examined, except BT, reduced goblet cell survival. The impact of eye drops on goblet cell viability was correlated with the time of exposure as well as to the concentration of BAK. After 30 min of exposure, cell viability was 93% for BT (0.005% BAK; <i>p</i> = 0.93), 71% for DS (0.0075% BAK; <i>p</i> = 0.067), 70% for OP (0.01% BAK; <i>p</i> = 0.054), and 69% for LT (0.02% BAK; <i>p</i> = 0.022), and exposure for 6 h reduced cell survival to 74% for BT (<i>p</i> = 0.217), 52% for DS (<i>p</i> = 0.011), 34% for OP (<i>p</i> = 0.017), and 31% for LT (<i>p</i> = 0.0007). <b><i>Conclusion:</i></b> LT, OP, and DS reduced human goblet cell survival in a time-dependent manner. BT did not affect goblet cell survival. Cell survival was correlated with the BAK concentration in the eye drops making 0.02% BAK-preserved LT most toxic and 0.005% BAK-preserved BT least toxic. Based on the present study, decreasing BAK in eye drops for chronic use seems important to reduce damage to the goblet cells. However, future studies are needed to further explore this finding.

scholarly journals Bifidobacterium dentiumFortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Melinda A. Engevik ◽  
Berkley Luk ◽  
Alexandra L. Chang-Graham ◽  
Anne Hall ◽  
Beatrice Herrmann ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Signaling Pathways ◽  
Goblet Cell ◽  
Cell Function ◽  
Goblet Cells ◽  
Mucus Layer ◽  
Content Type ◽  
Intestinal Mucus ◽  
Intestinal Mucus Layer

ABSTRACTMuch remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer.Bifidobacteriumspecies colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, selectBifidobacteriumstrains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived speciesBifidobacterium dentiumwould increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans.In silicodata revealed thatB. dentiumlacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating thatB. dentiumcould not use naive mucin glycans as primary carbon sourcesin vitro. To examineB. dentiummucus modulationin vivo, Swiss Webster germfree mice were monoassociated with live or heat-killedB. dentium. LiveB. dentium-monoassociated mice exhibited increased colonic expression of goblet cell markersKrüppel-like factor 4(Klf4),Trefoil factor 3(Tff3),Relm-β,Muc2, and several glycosyltransferases compared to both heat-killedB. dentiumand germfree counterparts. Likewise, liveB. dentium-monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining.In vitro,B. dentium-secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified thatB. dentium-secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates thatB. dentiumis capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production.IMPORTANCEMicrobe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe,Bifidobacterium dentium, which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike otherBifidobacteriumspecies,B. dentiumdoes not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of usingB. dentiumand similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier.

Comparative Study between Dryness Post Phacoemulsification and Post Extra Capsular Cataract Extraction

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Mohammed Elgeshy Alm Eldin ◽  
Saad Mohammed Rashad ◽  
Ayman Mohamed Elsaka ◽  
Samah Mahmoud Fawzy ◽  
Mahmoud Ahmed ElSamkary
Keyword(s):  
Comparative Study ◽  
Cell Count ◽  
Dry Eye ◽  
Goblet Cell ◽  
Tear Film ◽  
Cataract Extraction ◽  
Significant Deterioration ◽  
Meniscus Height ◽  
Significant Difference ◽  
Break Up

Abstract Purpose This study aims to detect and compare the severity and pattern of dry eye occurrence after phacoemulsification and extra capsular cataract extraction surgeries. Methods Twenty eyes of twenty patients in two groups, ten eyes planned for Phacoemulsification(phaco) and ten eyes planned for Extra Capsular Cataract Extraction (ECCE) enrolled in a prospective comparative study. All patients underwent full history taking and full ophthalmological clinical evaluation including (tear film meniscus height, Schirmer 1 test, tear break up time). Evaluations will be done one week before cataract surgery then three and six weeks after the surgery.Also, goblet cell count is measured twice, before and 6 weeks after the operation. Results After both Phaco, andECCE, the changes between means of pre-operative, 3 weeks and 6 weeks visits were significant in tear film meniscus height (p = 0.01) and were insignificant in both Schirmer 1 and tear break up time (p &gt; 0.05). There was a significant deterioration after 3 weeks of surgery in tear film meniscus height followed by significant increase between 3rd and 6th weeks post-operative measurements (p = 0.01). There was a significant difference between the 2 groups in the total change of Schirmer 1 and tear break up time between the6th weeks and the pre-operative measure with more deterioration in group 2. There was no significant difference between the 2 groups in tear film meniscus height 6 weeks post operation.The deterioration in goblet cell count was significantly worse in the ECCE group (mean difference of -22.1±8.5 and was -7.5±5.1 in the phaco group), (p = 0.0005). Conclusions Phacoemulsification surgery may aggravate the signs and symptoms of dry eye and affect dry eye test values in patients in short-term but less than ECCE.

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