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      The long-term effect of tacrolimus on alkali burn-induced corneal neovascularization and inflammation surpasses that of anti-vascular endothelial growth factor

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          To investigate the effect of tacrolimus in alkali burn-induced corneal neovascularization (NV) and inflammation and to compare with anti-vascular endothelial growth factor (anti-VEGF).


          After corneal alkali-burn, 84 Wistar rats were randomly divided into three groups and received either saline solution or 0.05% tacrolimus (0.5 mg/mL) four times daily, or subconjunctival anti-VEGF injection (0.5 mg/0.05 mL). Corneal NV, opacity and epithelial defects, the status of inflammation, and the levels of proinflammatory and angiogenic cytokines were assessed on Days 3, 7, 14 and 28 post-injury.


          Compared with the control, tacrolimus significantly reduced corneal NV on Days 7, 14 and 28 post-injury, and anti-VEGF significantly reduced corneal NV at each assessment. Nevertheless, the tacrolimus group had significantly less corneal NV than the anti-VEGF group on Days 14 and 28. Furthermore, both tacrolimus and anti-VEGF significantly decreased the VEGF-A expression on Days 7 and 14, with no significant difference between the two groups. Moreover, corneal inflammatory response was alleviated, and corneal opacity and epithelial defects were significantly reduced by tacrolimus. Additionally, the expression of IL-1β, IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein-1α and TGF-β were significantly decreased by tacrolimus.


          Our findings suggested that 0.05% tacrolimus suspension eye drops effectively reduced alkali burn-induced corneal NV and inflammation, with a better effect than subconjunctival anti-VEGF injections on Days 14 and 28.

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          Most cited references 35

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          Chemical injuries of the eye: current concepts in pathophysiology and therapy.

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          Chemical injuries of the eye may produce extensive damage to the ocular surface epithelium, cornea, and anterior segment, resulting in permanent unilateral or bilateral visual impairment. Pathophysiological events which may influence the final visual prognosis and which are amenable to therapeutic modulation include 1) ocular surface injury, repair, and differentiation, 2) corneal stromal matrix injury, repair and/or ulceration, and 3) corneal and stromal inflammation. Immediately following chemical injury, it is important to estimate and clinically grade the severity of limbal stem cell injury (by assessing the degree of limbal, conjunctival, and scleral ischemia and necrosis) and intraocular penetration of the noxious agent (by assessing clarity of the corneal stroma and anterior segment abnormalities). Immediate therapy is directed toward prompt irrigation and removal of any remaining reservoir of chemical contact with the eye. Initial medical therapy is directed promoting re-epithelialization and transdifferentiation of the ocular surface, augmenting corneal repair by supporting keratocyte collagen production and minimizing ulceration related to collagenase activity, and controlling inflammation. Early surgical therapy if indicated, is directed toward removal of necrotic corneal epithelium and conjunctiva, prompt re-establishment of an adequate limbal vascularity, and re-establishment of limbal stem cell population early in the clinical course, if sufficient evidence exists of complete limbal stem cell loss. Re-establishment of limbal stem cells by limbal autograft or allograft transplantation, or by transfer in conjunction with large diameter penetrating keratoplasty, may facilitate development of an intact, phenotypically correct corneal epithelium. Limbal stem cell transplantation may prevent the development of fibrovascular pannus or sterile corneal corneal ulceration, simplify visual rehabilitation, and improve the visual prognosis. Advances in ocular surface transplantation techniques which allow late attempts at visual rehabilitation of a scarred and vascularized cornea include limbal stem cell transplantation for incomplete transdifferentiation and persistent corneal epithelial dysfunction, and conjunctival and/or mucosal membrane transplantation for ocular surface mechanical dysfunction. Rehabilitation of the ocular surface may be followed, if necessary, by standard penetrating keratoplasty if all aspects of ocular surface rehabilitation are complete, or by large diameter penetrating keratoplasty if successful limbal stem cell transplantation cannot be achieved but other ocular surface rehabilitation is complete.
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            The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes.

            The intracellular sensor Nod2 is activated in response to bacteria, and the impairment of this response is linked to Crohn's disease. However, the function of Nod2 in host defense remains poorly understood. We found that Nod2-/- mice exhibited impaired intestinal clearance of Citrobacter rodentium, an enteric bacterium that models human infection by pathogenic Escherichia coli. The increased bacterial burden was preceded by reduced CCL2 chemokine production, inflammatory monocyte recruitment, and Th1 cell responses in the intestine. Colonic stromal cells, but not epithelial cells or resident CD11b+ phagocytic cells, produced CCL2 in response to C. rodentium in a Nod2-dependent manner. Unlike resident phagocytic cells, inflammatory monocytes produced IL-12, a cytokine that induces adaptive immunity required for pathogen clearance. Adoptive transfer of Ly6C(hi) monocytes restored the clearance of the pathogen in infected Ccr2-/- mice. Thus, Nod2 mediates CCL2-CCR2-dependent recruitment of inflammatory monocytes, which is important in promoting bacterial eradication in the intestine. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Ocular neovascularization: an epidemiologic review.

               P Lee,  C. C. Wang,  A Adamis (2015)
              Neovascularization occurs in many eye diseases, and its epidemiologic impact is significant. However, data on the prevalence and incidence of ocular neovascularization have never been compiled to demonstrate its pervasiveness. This overview of ocular angiogenesis provides a review of the epidemiologic literature for neovascularization in various parts of the eye, including the cornea, iris, retina, and choroid. Relevant disease states are reviewed, as are their risk factors, so that their pathogenesis can be better understood. Data on the prevalence and incidence of the major diseases involving angiogenesis are synthesized to provide statistical evidence of the span and magnitude of ocular neovascularization. These prevalence and incidence data on ocular neovascularization are extrapolated to USA population data where possible, and "worst-case" estimates are calculated as well. Information was gathered with a search of the MEDLINE database, published monographs and volumes, and consultation with a number of primary authors. This study attempts to unify much of past and present epidemiologic research, and the information is presented in sections divided according to the anatomy of the eye.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                12 September 2018
                : 12
                : 2959-2969
                State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China, yuanjincornea@ 123456126.com
                Author notes
                Correspondence: Jin Yuan, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou 510060, China, Tel/fax +86 20 8733 1550, Email yuanjincornea@ 123456126.com

                These authors contributed equally to this work

                © 2018 Chen et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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