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Hydrogen sulfide (H2S) is well known as a highly toxic environmental chemical threat. Prolonged exposure to H2S can lead to the formation of pulmonary edema. However, the mechanisms of how H2S facilitates edema formation are poorly understood. Since edema formation can be enhanced by an impaired clearance of electrolytes and, consequently, fluid across the alveolar epithelium, it was questioned whether H2S may interfere with transepithelial electrolyte absorption. Electrolyte absorption was electrophysiologically measured across native distallung preparations (Xenopus laevis) in Ussing chambers. The exposure of lung epithelia to H2S decreased net transepithelial electrolyte absorption. This was due to an impairment of amiloride-sensitive sodium transport. H2S inhibited the activity of the Na+/K+-ATPase as well as lidocaine-sensitive potassium channels located in the basolateral membrane of the epithelium. Inhibition of these transport molecules diminishes the electrochemical gradient which is necessary for transepithelial sodium absorption. Since sodium absorption osmotically facilitates alveolar fluid clearance, interference of H2S with the epithelial transport machinery provides a mechanism which enhances edema formation in H2S-exposed lungs.
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Figure 2. H2S inhibits amiloride-sensitive Na+ absorption.A) Representative current trace of a control experiment. In order to estimate the amount of Na+ absorption, the ENaC inhibitor amiloride (10 µM) was applied apically. B) Similar experiment showing the effects of amiloride after apical pre-treatment of the lung epithelium with apical NaHS (1 mM). C) Statistical evaluation of experiments as shown in panels A and B. Depicted are amiloride-sensitive (ÎIami) current fractions. NaHS significantly reduced ÎIami from 45.04±5.55 µA/cm2 to 14.84±1.77 µA/cm2 (nâ=â5; Nâ=â3; pâ¤0.001).
Figure 3. Amiloride attenuates the H2S induced current decrease.A) Representative current trace of a control experiment showing the effect of apical treatment with NaHS (1 mM). B) Lungs were treated with 1 µM amiloride apically and NaHS (1 mM) was subsequently applied for the same duration as the parallel conducted control experiment as depicted in panel A. C) Statistical evaluation. Amiloride significantly reduced the NaHS-mediated current decrease (ÎINaHS; nâ=â6, Nâ=â6, pâ¤0.05).
Figure 4. H2S decreases Na+/K+-ATPase currents of Xenopus lung epithelia.A) Representative current trace of a control recording. The apical membrane of the lung epithelium was permeabilized with nystatin (100 µM, apical) in the presence of amiloride (10 µM). This resulted in a current increase. When the current was stable, the Na+/K+-ATPase inhibitor ouabain (1 mM) was applied to the basolateral side. The ouabain-sensitive current fraction (ÎIouab) represents the activity of the Na+/K+-ATPase. B) After permeabilisation with nystatin, NaHS (1 mM) was applied to the apical bath. ISC decreased significantly from 20.83±3.99 µA/cm2 to 16.17±5.23 µA/cm2 (nâ=â6, Nâ=â6, pâ¤0.05). Subsequently, ouabain-sensitive current fractions were determined. C) Statistical evaluation of experiments as shown in panels A and B. NaHS significantly inhibited Na+/K+-ATPase activity (ÎIouab; nâ=â6, Nâ=â6, pâ¤0.05). D) Without permeabilisation with nystatin, ouabain had only a minor effect on transepithelial ion current in the presence of amiloride. Depicted are mean values of non-permeabilized lung epithelia which have been treated with amiloride (10 µM, apical) followed by ouabain (1 mM, basolateral).
Figure 5. H2S inhibits basolateral K+ channels.A) Representative current trace of a control recording. In order to measure basolateral K+ channels, lungs were apically perfused with a high K+ solution. Ouabain (1 mM) was present in the basolateral perfusate in order to exclude a contribution of the Na+/K+-ATPase. Under these conditions, the apical membrane was permeabilized with nystatin (100 µM). This resulted in a current increase which was sensitive to the nonselective K+ channel inhibitor lidocaine (1 mM). B) The application of NaHS (1 mM) after nystatin permeabilisation resulted in a current decrease (from 47.2±5.12 µA/cm2 to 36.4±2.93 µA/cm2; nâ=â5, Nâ=â5, pâ¤0.05). Subsequently applied lidocaine had a smaller effect compared to control recordings as shown in panel A. C) Statistical evaluation of experiments as shown in panels A and B. NaHS significantly reduced lidocaine-sensitive currents (ÎILido) of the basolateral membrane (nâ=â5, Nâ=â5, pâ¤0.01).
Figure 6. Interplay of basolateral K+ channels and the Na+/K+-ATPase.A) Representative current trace of a control recording. The apical membrane of the lung epithelium was permeabilized with nystatin (100 µM, apical) in the presence of amiloride (10 µM). This resulted in a current increase. When the current was stable, the Na+/K+-ATPase inhibitor ouabain (1 mM) was applied to the basolateral side. The ouabain-sensitive current fraction (ÎIouab) represents the activity of the Na+/K+-ATPase. B) After permeabilisation with nystatin, lidocaine (1 mM) was applied to the basolateral bath. This resulted in a decrease of the ISC from 17.20±2.58 µA/cm2 to 12.00±1.67 µA/cm2 (nâ=â5, Nâ=â5, pâ¤0.05). Subsequently, ouabain-sensitive current fractions were determined. C) Statistical evaluation of experiments as shown in panels A and B. Lidocaine (lido.) significantly inhibited Na+/K+-ATPase activity (ÎIouab; nâ=â5, Nâ=â5, pâ¤0.05). D) Without permeabilisation with nystatin, lidocaine had only a minor effect on transepithelial ion current. Depicted are mean values of non-permeabilized lung epithelia which have been treated with amiloride (10 µM, apical) followed by lidocaine (1 mM, basolateral). E) The application of NaHS (1 mM) to nystatin-permeabilized lungs which have been pre-treated with lidocaine (1 mM) additionally decreased ion current. Note that the subsequent application of ouabain was without any further effect. F) NaHS significantly decreased ISC under conditions as shown in panel E (nâ=â6, Nâ=â6, pâ¤0.05).
Figure 1. Exogenous H2S inhibits net ion transport of Xenopus lung epithelia.
A) Representative current trace of an Ussing chamber recording. The application of NaHS (1 mM) to the apical compartment of the chamber led to a strong decrease in transepithelial ion current (ISC). B) Statistical analysis of experiments as shown in panel A. NaHS significantly reduced ISC by approx. 60% (n = 19, N = 13, p≤0.01). C) Following application of NaHS, transepithelial resistance (RT) increased significantly (n = 19, N = 13, p≤0.05). D) The effect of NaHS was partially reversible. Depicted are values of ISC which were normalized to baseline values before application of NaHS. After wash-out of NaHS, there was a significant increase in current (n = 8, N = 5, p≤0.05). E) NaHS dose-dependently decreased ISC (n = 2–3, N = 3). Data were obtained from Ussing chamber recordings in which cumulative doses of NaHS were applied. Total values of ISC were fitted according to the Hill equation. F) Evaporative loss of H2S during experiments. NaHS (1 mM) was applied to NRS and aliquots were taken every 5 min. H2S was indirectly measured by the formation of methylene blue and its absorption at 670 nm (n = 3).
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