Differential Effects of Dexamethasone and Doxycycline on Inflammation and MMP Production in Murine Alkali-Burned Corneas Associated with Dry Eye

Bian, Fang; Pelegrino, Flavia S. A.; Henriksson, Johanna Tukler; Pflugfelder, Stephen C.; Volpe, Eugene A.; Li, Dequan; Paiva, Cintia S. de

doi:10.1016/j.jtos.2015.11.006

Cited by 65 publications

(62 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To test the hypothesis that blocking NLRP3 would improve clinical parameters and reduce inflammation, alkali-burned corneas were treated with either NaB, HBA, or vehicle for 2 or 5 days post-injury. To compare the relative potency of these molecules, a group of alkali-injured corneas treated with dexamethasone (Dex) was also included, as our previous study showed that Dex is very efficacious in preserving corneal clarity and suppressing inflammation in the most severe model of alkali burn and dry eye [20]. …”

Section: Resultsmentioning

confidence: 99%

Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn

Bian

Xiao

Zaheer

et al. 2017

IJMS

Self Cite

View full text Add to dashboard Cite

Epithelial cells are involved in the regulation of innate and adaptive immunity in response to different stresses. The purpose of this study was to investigate if alkali-injured corneal epithelia activate innate immunity through the nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway. A unilateral alkali burn (AB) was created in the central cornea of C57BL/6 mice. Mice received either no topical treatment or topical treatment with sodium butyrate (NaB), β-hydroxybutyric acid (HBA), dexamethasone (Dex), or vehicle (balanced salt solution, BSS) quater in die (QID) for two or five days (d). We evaluated the expression of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as the downstream cytokine interleukin (IL)-1β. We found elevation of NLRP3 and IL-1β messenger RNA (mRNA) transcripts, as well as levels of inflammasome component proteins in the alkali-injured corneas compared to naïve corneas. Treatment with NLRP3 inhibitors using NaB and HBA preserved corneal clarity and decreased NLRP3, caspase-1, and IL-1β mRNA transcripts, as well as NLRP3 protein expression on post-injury compared to BSS-treated corneas. These findings identified a novel innate immune signaling pathway activated by AB. Blocking the NLRP3 pathway in AB mouse model decreases inflammation, resulting in greater corneal clarity. These results provide a mechanistic basis for optimizing therapeutic intervention in alkali injured eyes.

show abstract

Section: Resultsmentioning

confidence: 99%

Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn

Bian

Xiao

Zaheer

et al. 2017

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…108 Application of topical 0.1% dexamethasone four times per day showed a positive effect in the combined model of alkali burn and desiccating stress, by significantly decreasing mRNA and protein levels of MMP-1, -3, -9 and -13, decreasing MMP-9 gelatinolytic activity and NGAL-MMP-9 complex formation, while causing an impressive improvement in corneal opacification and preventing corneal perforation, compared to saline controls. 98 Studies with gene KO and pharmacologic inhibitors showed that part of the beneficial effects from dexamethasone in this model were through an increase in MMP-8. 84 Nonpreserved topical methylprednisolone administered three to four times per day significantly improved signs and symptoms of dry eye in patients with SS.…”

Section: Corticosteroidsmentioning

confidence: 90%

“…96 Doxycycline increased the rate of corneal epithelial wound healing and decreased MMP-13 and -9 mRNA transcripts, MMP-9 activity and immunoreactivity in the combined model of alkali burn and dry eye. 98 This was accompanied by a decrease in production of neutrophil gelatinase-associated lipocalin (NGAL)-MMP-9 formation and lower levels of IL-1β.…”

Section: Doxycycline and Azithromycin Doxycyclinementioning

confidence: 99%

“…[82][83][84][85] This simulated the most severe burn cases, where extensive facial and eyelid thermal injury results in eye exposure and desiccation due to loss of protection from the eyelids and reduced blinking. We found there was an additive pathogenic effect of dry eye to alkali burn, with amplification of MMP-3, -8, -9 and -12, IL-6 and IL-1β mRNA expression and sterile corneal perforation in ~30% of animals subjected to the chemical burn and desiccating conditions.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

Pflugfelder¹,

Bian²,

Paiva³

2017

MNM

View full text Add to dashboard Cite

Dry eye and tear dysfunction are common ocular disorders that cause cornea barrier disruption resulting in a poorly lubricated and irregular cornea epithelium, eye irritation and blurred vision. Increased levels and activities of matrix metalloproteinases (MMPs), particularly MMP-9, have been detected in the tears and ocular surface epithelial and inflammatory cells in dry eye. MMPs have been found to participate in disruption of tight junctions in the apical cornea epithelium leading to their accelerated desquamation and barrier disruption. This review summarizes evidence showing the contribution of MMPs to dry eye pathogenesis and their roles as biomarkers and therapeutic targets. Keywords: matrix metalloproteinase, dry eye, keratitis sicca, cornea, barrier function, Sjögren syndrome Dry eye overviewDry eye and tear dysfunction are common ocular disorders that cause cornea barrier disruption resulting in a poorly lubricated and irregular cornea epithelium, eye irritation and blurred vision. It affects millions of people worldwide and is one of the most frequent conditions for which patients seek eye care.1 Aging and female sex are significant risk factors for dry eye which increases in prevalence around the fifth decade, with further increase every decade thereafter.2-13 Prevalence of dry eye varies from 2% to 50%, depending on the population studied and the diagnostic criteria for dry eye (symptom questionnaire vs. objective signs). [1][2][3]6,7,[9][10][11][14][15][16][17][18][19][20][21][22][23] There is scarce information about the natural history of dry eye, but there is a recognized disconnection between signs and symptoms; patients tend to be more symptomatic at early stages.24,25 Dry eye causes corneal irregularity [26][27][28] and decreases functional vision by altering contrast sensitivity [29][30][31] and, therefore, decreases quality of life with a significant burden on the individual as well as the society. 23,[32][33][34][35] A meta-analysis of 22 published studies showed increased odds ratio for depression and anxiety in patients with ocular Sjögren syndrome (SS). 36 There is increased evidence that dry eye is an inflammatory disease, and this review will focus on matrix metalloproteinases (MMPs) and their role in the pathogenesis of dry eye. Cornea barrier disruption is a feature of dry eyeAs the principal lens of the eye, the cornea has unique features to maintain its transparency and smooth surface that include a lack of blood vessels and a multilayered stratified, non-cornifying epithelium. The differentiated apical epithelial cells produce

show abstract

“…Transcriptome analysis of human corneal epithelial cell line (HCEC) after short-term DEX treatment elucidated significant changes in genes regulating cell movement, cytoskeletal remodeling and permeability [36]. Topical DEX treatment indeed was found to preserve corneal clarity and decrease corneal wound healing in a murine model of alkali burned cornea associated with dry eye [37]. DEX significantly reduced the expression of matrix metalloproteases (MMPs) such as MMP1, 3 and 9 as well as interleukin-6 (IL-6) while it increased the expression levels of MMP8, a collagen cleaving enzyme that plays an important role in inflammation and tissue remodeling [38].…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor signaling in the eye

2018

View full text Add to dashboard Cite

Glucocorticoids (GCs) are essential steroid hormones that regulate numerous metabolic and homeostatic functions in almost all physiological systems. Synthetic glucocorticoids are among the most commonly prescribed drugs for the treatment of various conditions including autoimmune, allergic and inflammatory diseases. Glucocorticoids are mainly used for their potent anti-inflammatory and immunosuppressive activities mediated through signal transduction by their nuclear receptor, the glucocorticoid receptor (GR). Emerging evidence showing that diverse physiological and therapeutic actions of glucocorticoids are tissue-, cell-, and sex-specific, suggests more complex actions of glucocorticoids than previously anticipated. While several synthetic glucocorticoids are widely used in the ophthalmology clinic for the treatment of several ocular diseases, little is yet known about the mechanism of glucocorticoid signaling in different layers of the eye. GR has been shown to be expressed in different cell types of the eye such as cornea, lens, and retina, suggesting an important role of GR signaling in the physiology of these ocular tissues. In this review, we provide an update on the recent findings from in vitro and in vivo studies reported in the last 5 years that aims at understanding the role of GR signaling specifically in the eye. Advances in studying the physiological effects of glucocorticoid in the eye are vital for the elaboration of optimized and targeted GCs therapies with potent anti-inflammatory potential while minimizing adverse effects.

show abstract

Differential Effects of Dexamethasone and Doxycycline on Inflammation and MMP Production in Murine Alkali-Burned Corneas Associated with Dry Eye

Cited by 65 publications

References 55 publications

Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn

Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

Glucocorticoid receptor signaling in the eye

Contact Info

Product

Resources

About