Browsing by Author "McKay, Tina B."
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Item Arginine Supplementation Promotes Extracellular Matrix and Metabolic Changes in Keratoconus(MDPI, 2021-08-13) McKay, Tina B.; Priyadarsini, Shrestha; Rowsey, Tyler; Karamichos, DimitriosKeratoconus (KC) is a common corneal ectatic disease that affects 1:500-1:2000 people worldwide and is associated with a progressive thinning of the corneal stroma that may lead to severe astigmatism and visual deficits. Riboflavin-mediated collagen crosslinking currently remains the only approved treatment to halt progressive corneal thinning associated with KC by improving the biomechanical properties of the stroma. Treatments designed to increase collagen deposition by resident corneal stromal keratocytes remain elusive. In this study, we evaluated the effects of arginine supplementation on steady-state levels of arginine and arginine-related metabolites (e.g., ornithine, proline, hydroxyproline, spermidine, and putrescine) and collagen protein expression by primary human corneal fibroblasts isolated from KC and non-KC (healthy) corneas and cultured in an established 3D in vitro model. We identified lower cytoplasmic arginine and spermidine levels in KC-derived constructs compared to healthy controls, which corresponded with overall higher gene expression of arginase. Arginine supplementation led to a robust increase in cytoplasmic arginine, ornithine, and spermidine levels in controls only and a significant increase in collagen type I secretion in KC-derived constructs. Further studies evaluating safety and efficacy of arginine supplementation are required to elucidate the potential therapeutic applications of modulating collagen deposition in the context of KC.Item Characterization of Tear Immunoglobulins in a Small-Cohort of Keratoconus Patients(Springer Nature, 2020-06-10) McKay, Tina B.; Serjersen, Henrik; Hjortdal, Jesper; Zieske, James D.; Karamichos, DimitriosKeratoconus (KC) is classically considered a non-inflammatory condition caused by central corneal thinning that leads to astigmatism and reduced visual acuity. Previous studies have identified increased systemic levels of pro-inflammatory factors, including interleukin-6, tumor necrosis factor-alpha, and matrix metalloproteinase-9, suggesting that KC may have an inflammatory component in at least a subset of patients. In this study, we evaluated the levels of different immunoglobulins (light and heavy chains) based on Ig alpha, Ig lambda, Ig kappa, Ig micro, and Ig heavy chain subunits in non-KC tears (n = 7 control individuals) and KC tears (n = 7 KC patients) using tandem-liquid chromatography mass spectrometry. The most abundant Ig heavy chains detected in both control individuals and KC patients were Ig alpha-1 and Ig alpha-2 likely correlating to the higher IgA levels reported in human tears. We identified significant differences in immunoglobulin kappa-chain V-II levels in KC patients compared to control individuals with no significant difference in Ig kappa/Ig lambda ratios or heavy chain levels. Our study supports previous findings suggesting that KC possesses a systemic component that may contribute to the KC pathology. Further studies are required to define causality and establish a role for systemic immune system-dependent factors and pro-inflammatory processes in KC development or progression.Item Prospective Observational Study Evaluating Systemic Hormones and Corneal Crosslinking Effects in Keratoconus(Elsevier B.V., 2023-10-23) Van, Lyly; Bennett, Sashia; Nicholas, Sarah E.; Hjortdal, Jesper; McKay, Tina B.; Karamichos, DimitriosPURPOSE: To evaluate associations between hormone levels and corneal parameters in patients with keratoconus (KC), before and after photooxidative corneal collagen crosslinking (CXL). DESIGN: Prospective, observational cohort study. PARTICIPANTS: Twenty-eight patients with KC who were scheduled for CXL at Aarhus University Hospital in Denmark. METHODS: Androgen (dehydroepiandrosterone sulfate [DHEA-S]) and estrogen (estrone and estriol) plasma levels were measured and clinical assessments were performed before CXL and 2 to 3 months post-CXL, comparing the CXL eye with the control eye from the same participant. MAIN OUTCOME MEASURES: Associations between hormone levels and maximum corneal curvature (K(max)) and minimum central corneal thickness (CCt(min)) before and after CXL. RESULTS: Corneal collagen crosslinking was associated with a 2% reduction in K(max) values in the CXL eye, post-CXL, from baseline (median, 56.8 diopters [D]; 95% confidence interval [CI], 50.4-60.3) to the second visit (55.7 D; 95% CI, 50.4-58.8; P < 0.001). Systemic DHEA-S levels were 5 to 6 orders of magnitude higher than estriol or estrone concentrations in plasma. Importantly, estriol levels, rather than DHEA-S or estrone levels, were more closely correlated with K(max) before CXL (Spearman's r = 0.55, P = 0.01). Post-CXL K(max) and CCt(min) were not associated with DHEA-S, estrone, or estriol plasma levels at the same timepoint. CONCLUSIONS: This study provides supporting evidence based on a KC clinical population that systemic estrogen levels may influence corneal parameters (curvature and thickness) pre-CXL. Further studies evaluating the interplay between the therapeutic benefits of CXL and systemic hormone distributions are needed to determine if perturbation of the local corneal microenvironment influences endocrine function. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.Item Quercetin and Related Analogs as Therapeutics to Promote Tissue Repair(MDPI, 2023-10-28) McKay, Tina B.; Emmitte, Kyle A.; German, Carrie; Karamichos, DimitriosQuercetin is a polyphenol of the flavonoid class of secondary metabolites that is widely distributed in the plant kingdom. Quercetin has been found to exhibit potent bioactivity in the areas of wound healing, neuroprotection, and anti-aging research. Naturally found in highly glycosylated forms, aglycone quercetin has low solubility in aqueous environments, which has heavily limited its clinical applications. To improve the stability and bioavailability of quercetin, efforts have been made to chemically modify quercetin and related flavonoids so as to improve aqueous solubility while retaining bioactivity. In this review, we provide an updated overview of the biological properties of quercetin and proposed mechanisms of actions in the context of wound healing and aging. We also provide a description of recent developments in synthetic approaches to improve the solubility and stability of quercetin and related analogs for therapeutic applications. Further research in these areas is expected to enable translational applications to improve ocular wound healing and tissue repair.Item Quercetin Decreases Corneal Haze In Vivo and Influences Gene Expression of TGF-Beta Mediators In Vitro(MDPI, 2022-07-07) McKay, Tina B.; Kivanany, Pourisika B.; Nicholas, Sarah E.; Nag, Okhil K.; Elliott, Michael H.; Petroll, W. Matthew; Karamichos, DimitriosWe have previously reported the flavonoid, quercetin, as a metabolic regulator and inhibitor of myofibroblast differentiation in vitro. Our current study evaluated the effects of topical application of quercetin on corneal scar development using two different animal models followed by RNA analysis in vitro. Wild-type C57BL/6J mice were anesthetized and the corneal epithelium and stroma were manually debrided, followed by quercetin (0.5, 1, 5, or 50 mM) or vehicle application. Corneal scarring was assessed for 3 weeks by slit lamp imaging and clinically scored. In a separate animal study, six New Zealand White rabbits underwent lamellar keratectomy surgery, followed by treatment with 5 mM quercetin or vehicle twice daily for three days. Stromal backscattering was assessed at week 3 by in vivo confocal microscopy. In mice, a single dose of 5 mM quercetin reduced corneal scar formation. In rabbits, stromal backscattering was substantially lower in two out of three animals in the quercetin-treated group. In vitro studies of human corneal fibroblasts showed that quercetin modulated select factors of the transforming growth factor-beta (TGF-beta) signaling pathway. These results provide evidence that quercetin may inhibit corneal scarring. Further studies in a larger cohort are required to validate the efficacy and safety of quercetin for clinical applications.Item Sex Hormones, Growth Hormone, and the Cornea(MDPI, 2022-01-11) McKay, Tina B.; Priyadarsini, Shrestha; Karamichos, DimitriosThe growth and maintenance of nearly every tissue in the body is influenced by systemic hormones during embryonic development through puberty and into adulthood. Of the ~130 different hormones expressed in the human body, steroid hormones and peptide hormones are highly abundant in circulation and are known to regulate anabolic processes and wound healing in a tissue-dependent manner. Of interest, differential levels of sex hormones have been associated with ocular pathologies, including dry eye disease and keratoconus. In this review, we discuss key studies that have revealed a role for androgens and estrogens in the cornea with focus on ocular surface homeostasis, wound healing, and stromal thickness. We also review studies of human growth hormone and insulin growth factor-1 in influencing ocular growth and epithelial regeneration. While it is unclear if endogenous hormones contribute to differential corneal wound healing in common animal models, the abundance of evidence suggests that systemic hormone levels, as a function of age, should be considered as an experimental variable in studies of corneal health and disease.