The Controlled-Environment Chamber: A New Mouse Model of Dry Eye

Barabino, Stefano; Shen, Lin Ling; Chen, Lu; Rashid, Saadia; Rolando, Maurizio; Dana, M. Reza

doi:10.1167/iovs.04-1326

Cited by 169 publications

(156 citation statements)

References 22 publications

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“…4,8,9 Desiccating environmental conditions are produced using either an air blower or a controlled-environment chamber (CEC) that allows for the continuous regulation of environmental conditions, such as temperature, humidity, and airflow. 10 Exposing the ocular surface to dry conditions (e.g., low humidity and high airflow) increases tear evaporation and leads to the clinical signs of DED. Aqueous tear deficiency is induced by administering scopolamine (SCP), a tropane alkaloid that antagonizes muscarinic activity.…”

mentioning

confidence: 99%

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Chen

Chauhan

Lee

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED.METHODS. DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b þ and conjunctival CD3 þ T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA.RESULTS. Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3 þ T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. CONCLUSIONS. In vivo inhibition of mAChRs variably affects CD4þ T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms.

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mentioning

confidence: 99%

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Chen

Chauhan

Lee

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Section: Resultsmentioning

confidence: 99%

“…5,6 Although the components of tears have been identified and characterized, 2,5-10 the regulation of tear production is multifaceted involving not only physiology but environmental stimuli. 6 Previous studies in our laboratory have established a relationship between opioidergic systems (i.e., endogenous opioid peptides and opioid receptors) and tear production in diabetic rats.11 A decrease in tear volume in animals with type 1 diabetes (T1D) was reversed within 1 hour of administration following the topical administration of the opioid antagonist naltrexone hydrochloride (NTX); the effect persisted for up to 3 days. During these studies we noted that normal rats occasionally had a marked reduction in Schirmer test scores, suggesting that normal tear production may fluctuate.…”

mentioning

confidence: 99%

Spontaneous Episodic Decreased Tear Secretion in Rats Is Related to Opioidergic Signaling Pathways

Zagon¹,

Campbell²,

Sassani

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To elucidate the factors in tear production, this study examined the role of endogenous opioids and opioid receptors in spontaneous episodic reduced tear volume. METHODS.A model of spontaneous episodic decreases in the quantity of tears was characterized in otherwise normal Sprague-Dawley rats using Schirmer's test. A single eye drop of 10 -5 M naltrexone (NTX), 10 -5 M [Met 5 ]-enkephalin, or sterile vehicle was administered to one eye. Tear secretion, corneal sensitivity, and corneal morphology were examined in both eyes. RESULTS.At any given time period, otherwise normal rats were found to have Schirmer test scores with a bimodal distribution (6.5 mm or less, or 7.0 mm or greater). Decreased tear production was detected in male and female rats aged 4 to 24 weeks at least once per animal. The episodes of reduced tear volume ranged from 1 to 7 days. No changes in corneal sensitivity or corneal morphology were observed in any rat. One drop of NTX given to rats with a decrease in tear volume raised levels of tears to scores of 7.0 mm or greater within 1 hour, and increased tear production persisted for at least 48 hours. NTX had no effect on rats with Schirmer scores of 7.0 mm or higher. Topical application of [Met 5 ]-enkephalin depressed tear secretion from baseline scores of 9.8 6 0.6 mm to as low as 4.5 6 0.7 mm.CONCLUSIONS. Normal rats experience fluctuations in tear production that can be modulated by opioidergic signaling pathways. (Invest Ophthalmol Vis Sci. 2012;53:3234-3240) DOI:10.1167/iovs.11-9051 T ears are important to the health of the cornea, and function in lubrication, nourishment for the cornea, gas exchange, removal of debris from the corneal surface, and prevention of bacterial and viral infections.1 In addition to maintenance of the surface homeostatic environment, the precorneal tear film serves to maintain an optically uniform corneal surface essential for normal vision. The pathophysiology of reduced tear film may involve tear production deficiency that can increase corneal inflammation, impair vision, and even have complications leading to blindness.2-4 Alternatively, changes in environmental factors such as temperature and humidity may lead to transient increases in tear film evaporation. 5,6 Although the components of tears have been identified and characterized, 2,5-10 the regulation of tear production is multifaceted involving not only physiology but environmental stimuli. 6 Previous studies in our laboratory have established a relationship between opioidergic systems (i.e., endogenous opioid peptides and opioid receptors) and tear production in diabetic rats.11 A decrease in tear volume in animals with type 1 diabetes (T1D) was reversed within 1 hour of administration following the topical administration of the opioid antagonist naltrexone hydrochloride (NTX); the effect persisted for up to 3 days. During these studies we noted that normal rats occasionally had a marked reduction in Schirmer test scores, suggesting that normal tear production may fluctuate. The present inv...

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“…43 Therefore, goblet-cell density (adequate numbers of goblet cells) is a critical parameter that reflects the overall health of the ocular surface. [43][44][45][46] CsA emulsion (Restasis), but not artificial tears, increases goblet-cell density in the bulbar conjunctiva in patients with dry eyes. 24,45 To evaluate the effects of sequential treatment with AS and drug formulations on conjunctival goblet-cell density in the rabbit, samples of conjunctiva sacs were stained with H&E solution.…”

Section: Goblet-cell Densitymentioning

confidence: 99%

Cyclosporine A micellar delivery system for dry eyes

Kang¹,

Ho²,

Cho³

et al. 2016

IJN

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Background The objectives of this study were to develop stable cyclosporine A (CsA) ophthalmic micelle solutions for dry-eye syndrome and evaluate their physicochemical properties and therapeutic efficacy. Materials and methods CsA-micelle solutions (MS-CsA) were created by a simple method with Cremophor EL, ethanol, and phosphate buffer. We investigated the particle size, pH, and osmolarity. In addition, long-term physical and chemical stability for MS-CsA was observed. To confirm the therapeutic efficacy, tear production in dry eye-induced rabbits was evaluated using the Schirmer tear test (STT). When compared to a commercial product, Restasis, MS-CsA demonstrated improvement in goblet-cell density and conjunctival epithelial morphology, as demonstrated in histological hematoxylin and eosin staining. Results MS-CsA had a smaller particle size (average diameter 14–18 nm) and a narrow size distribution. Physicochemical parameters, such as particle size, pH, osmolarity, and remaining CsA concentration were all within the expected range of 60 days. STT scores significantly improved in MS-CsA treated groups ( P <0.05) in comparison to those of the Restasis-treated group. The number of goblet cells for rabbit conjunctivas after the administration of MS-CsA was 94.83±8.38, a significantly higher result than the 65.17±11.51 seen with Restasis. The conjunctival epithelial morphology of dry eye-induced rabbits thinned with loss of goblet cells. However, after 5 days of treatment with drug formulations, rabbit conjunctivas recovered epithelia and showed a relative increase in the number of goblet cells. Conclusion The results of this study indicate the potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes.

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The Controlled-Environment Chamber: A New Mouse Model of Dry Eye

Abstract: This study indicates that exposure of normal mice to a low-humidity environment in a CEC can lead to significant alterations in tear secretion, goblet cell density, and acquisition of dry eye-related ocular surface signs.

Cited by 169 publications

References 22 publications

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Spontaneous Episodic Decreased Tear Secretion in Rats Is Related to Opioidergic Signaling Pathways

Cyclosporine A micellar delivery system for dry eyes

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