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      Corneal Endothelial Pump Coupling to Lactic Acid Efflux in the Rabbit and Mouse

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          Abstract

          Purpose

          Confirm that the corneal endothelial pump uses a lactate-coupled water efflux mechanism.

          Methods

          Corneal thickness, lactate efflux, and stromal [lactate] were measured in de-epithelialized swollen and nonswollen ex vivo-mounted rabbit corneas perfused with bicarbonate-rich and bicarbonate-free Ringers, ouabain, or acetazolamide to determine if the relationships among these parameters were similar to previous data using intact corneas. The role of barrier function was tested by perfusion with calcium-free EGTA. Predictions of [lactate] in endothelial dystrophy were examined in the Slc4a11 knock out mouse.

          Results

          De-epithelialized corneal swelling, lactate efflux, and stromal [lactate] in response to bicarbonate-free Ringers, ouabain, and acetazolamide perfusion had the same relationship as in intact corneas. The absolute amount of lactate efflux and stromal [lactate] in the de-epithelialized corneas was about half of intact corneas. De-epithelialized, swollen corneas deswelled fully with bicarbonate-rich, partially in the presence of acetazolamide, but continued to swell with bicarbonate-free or ouabain. The relationship among corneal thickness, lactate efflux, and [lactate] was the same as with nonswollen de-epithelialized corneas. In intact corneas swollen by perfusion with calcium-free EGTA, the relationship between swelling and lactate flux was the inverse of control corneas. The relationship between corneal swelling and [lactate] of intact corneas exposed to ouabain, but perfused with 7 mM lactate to simulate aqueous humor, was the same as without lactate. Corneal [lactate] in Slc4a11 knock out was twice that of wild type.

          Conclusions

          The corneal endothelial pump works via a lactate efflux mechanism that requires an intact osmotic barrier.

          Related collections

          Most cited references29

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          The location of the fluid pump in the cornea.

          D Maurice (1972)
          1. Fluid transport across rabbit corneal tissue has been investigated by observing the movement of fluid interfaces under the microscope, or by mounting the tissue between two chambers and observing the displacement of menisci within capillary tubes.2. In both cases, the endothelial layer supported on a thin sheet of connective tissue is capable of pumping fluid in a direction out of the cornea, against a head of pressure. The volume of fluid moved may amount to twelve times the thickness of the endothelial cells in an hour.3. This active fluid movement accounts for the prevention of swelling of the normal corneal stroma. The hypothesis that corneal hydration is regulated by the sodium pump in the epithelial layer is not supported by these experiments.
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            Mice with a targeted disruption of Slc4a11 model the progressive corneal changes of congenital hereditary endothelial dystrophy.

            To establish an animal model of congenital hereditary endothelial dystrophy (CHED) using Slc4a11 knockout (KO) mice and evaluate the abnormalities in the cornea and kidney.
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              Stromal lactate accumulation can account for corneal oedema osmotically following epithelial hypoxia in the rabbit.

              S Klyce (1981)
              1. The mechanism underlying stromal oedema subsequent to epithelial hypoxia was investigated in isolated rabbit corneas. 2. Stromas swelled about 20 micrometer following a 1 hr period of tear side hypoxia in both whole corneal isolates and in preparations in which fluid movement across the endothelium was blocked with silicone oil. In the experiments using whole corneas, stromal thickness was independent of tear side oxygen tension as long as aqueous humour PO2 was greater than 40 mmHg. 3. Neither epithelial thickness nor epithelial electrical resistance, a measure of total ion permeability, was significantly affected by blocking respiration. 4. A 10 degrees C reduction in corneal temperature markedly reduced the rate of hypoxic swelling, suggesting the involvement of a metabolism-dependent hydrating process and implicating the stromal accumulation of a catabolyte. 5. When CN- was used to mimic the hypoxic effect in isolated whole corneas, the passive 36Cl unidirectional flux was unaffected, but lactate production rate and stromal [lactate] more than doubled. 6. These measurements were used with a mathematical model for corneal hydration dynamics to examine the causes of hypoxic oedema. The principal conclusions were: epithelial hypoxia enhances epithelial lactate production and release to the stroma; this process causes an increase in stromal lactate concentration and a decrease in stromal NaCl concentration (primarily through dilution); stromal lactate accumulation exceeds in osmotic load and dilutional effect on [NaCl], producing stromal oedema. Whereas hypoxia produces corneal metabolic acidosis, effects on endothelial permeability of HCO3- transport need not be postulated to explain the stromal oedema that results from hypoxia.
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                Author and article information

                Journal
                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                iovs
                iovs
                IOVS
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                0146-0404
                1552-5783
                07 February 2020
                February 2020
                : 61
                : 2
                : 7
                Affiliations
                [1] Indiana University, School of Optometry , Bloomington, Indiana, United States
                Author notes
                Correspondence: Joseph A. Bonanno, Indiana University, School of Optometry , 800 E. Atwater Avenue, Bloomington, IN 47405, USA; jbonanno@ 123456indiana.edu.
                Article
                IOVS-19-28297
                10.1167/iovs.61.2.7
                7324437
                32031579
                25e7ef6d-1939-4813-bae8-6b781bc83a4c
                Copyright 2020 The Authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 22 November 2019
                : 21 August 2019
                Page count
                Pages: 8
                Categories
                Cornea

                corneal endothelial pump,lactate flux,active transport,slc4a11 mouse

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